1. science
2. medicine
3. surgery
4. transplants

CHAPTER
92
Hematopoietic Cell Transplantation
Jeannine S. McCune, Laura L. Winter, Suzanne D. Day
Overview 92-1
Autologous Hematopoietic Cell Transplantation 92-4
Indications for Autologous HCT 92-4
Harvesting Autologous Bone Marrow 92-4
Mobilization and Collection of Autologous Peripheral
Blood Progenitor Cells 92-5
Myeloablative Preparative Regimens 92-5
Complications of Autologous HCT 92-6
Hematopoietic Growth Factors After Autologous PBPC
Infusion 92-6
Allogeneic Hematopoietic Cell Transplantation 92-7
Indications for Allogeneic Hematopoietic Cell
Transplantation 92-7
Histocompatibility 92-8
Harvesting, Preparing, and Transplanting Allogeneic
Hematopoietic Stem Cells 92-9
Bone Marrow 92-9
Peripheral Blood Progenitor Cells 92-9
Umbilical Cord Blood 92-9
T-Cell Depletion 92-9
Graft-versus-Tumor Effect 92-10
Preparative Regimens for Allogeneic HCT 92-10
Myeloablative Preparative Regimens 92-10
Nonmyeloablative Preparative Regimens 92-11
Post-Transplantation Immunosuppressive
Therapy 92-12
Comparison of Supportive Care Strategies Between
Autologous and Allogeneic Myeloablative HCT 92-12
Comparison of Supportive Care Strategies Between
Allogeneic Myeloablative and Nonmyeloablative
HCT 92-13
Dose Calculations in Obesity 92-13
Complications Associated With HCT 92-13
Busulfan Seizures 92-13
Adaptive Dosing of Busulfan 92-15
Hemorrhagic Cystitis 92-15
Chemotherapy-Induced Gastrointestinal Effects 92-16
Myelosuppression and Growth Factor Use 92-16
Veno-occlusive Disease of the Liver 92-17
Clinical Presentation 92-17
Prevention and Treatment 92-17
Graft Failure 92-18
Graft-versus-Host Disease 92-19
Acute Graft-versus-Host Disease 92-19
Risk Factors 92-19
Clinical Presentation 92-19
Immunosuppressive Prophylaxis 92-20
Adaptive Dosing of Calcineurin Inhibitors 92-21
Overview
Hematopoietic cell transplantation (HCT) is defined broadly
as the infusion of hematopoietic stem cells into a patient to
treat disease and/or restore normal hematopoiesis and lymphopoiesis. Originally, this procedure developed from allogeneic bone marrow transplantation (BMT) as potentially curative therapy for diseases involving the bone marrow or
immune system.1,2 These early allogeneic BMTs involved administration of a myeloablative preparative regimen, which
was followed by true “transplantation” of bone marrow from
one individual to another.1,2 Bone marrow contains pluripotent stem cells and post-thymic lymphocytes, which are responsible, respectively, for long-term hematopoietic reconstitution, immune recovery, and its associated graft-versus-host
disease (GVHD).3 Subsequently, the “dose-intensity” concept
for cancer treatment (see related information in Chapter 88,
Neoplastic Disorders and Their Treatment: General Principles) was expanded to using myeloablative preparative regimens followed by autologous HCT. Autologous HCT, or infusion of a patient’s own hematopoietic stem cells, allows for
the administration of higher doses of chemotherapy, radiation,
or both to treat the malignancy.4 In the setting of autologous
Investigational Therapies for Prophylaxis 92-22
Treatment of Established Acute Graft-versus-Host
Disease 92-22
Chronic Graft-versus-Host Disease 92-23
Clinical Presentation 92-23
Pharmacologic Management 92-24
Adjuvant Therapies 92-24
Infectious Complications 92-25
Prevention and Treatment of Bacterial and Fungal
Infections 92-25
Prevention of Herpes Simplex Virus and Varicella-Zoster
Virus 92-26
Prevention of Cytomegalovirus Disease 92-27
Diagnosis and Treatment of Aspergillus Infection 92-27
Risk Factors 92-27
Treatment 92-28
Antifungals 92-28
Antifungal Toxicities 92-30
Length of Antifungal Therapy and Combination
Antifungal Therapy 92-31
Prevention of Pneumocystis carinii Pneumonia 92-31
Issues of Survivorship After Hematopoietic Cell
Transplantation 92-32
HCT, the hematopoietic stem cells “rescue” the patient from
otherwise dose-limiting hematopoietic toxicity. The recognition of graft-versus-tumor (GVT) effect, which is proposed to
be exerted by cytotoxic T lymphocytes in the donor stem cells
led to investigations with nonmyeloablative transplantations
(NMT), in which less toxic preparative regimens are used
with the hope of expanding the availability of HCT to those
recipients whose medical condition or age prohibits use of
myeloablative regimens.5–7
The combination of chemotherapy and/or radiation administered before infusion of hematopoietic stem cells is referred
to as the preparative or conditioning regimen. In the setting of
an allogeneic HCT, the preparative regimen is designed to
suppress the recipient’s immunity, eradicate residual malignancy, or to create space in the marrow compartment. A myeloablative or nonmyeloablative preparative regimen may be
used with allogeneic HCT; only myeloablative preparative
regimens are used for autologous HCT. The basic schema for
myeloablative preparative regimens with an allogeneic graft is
illustrated in Figure 92-1. Myeloablative preparative regimens
involve administration of near-lethal doses of chemotherapy
and/or radiation, which are generally followed by a 1- to 2-day
92-1
92-2
•
NEOPLASTIC DISORDERS
Chemotherapy
Radiation
5
4
3
2
1
0°
1
2
3
4
5
Days
FIGURE 92-1 Basic schema for myeloablative hematopoietic cell transplant. aDay 0 bone marrow,
peripheral blood progenitor cell, or umbilical cord blood infusion.
rest and then infusion of stem cells.1,2 For most chemotherapy-based regimens, the rest period is necessary to allow for
elimination of toxic metabolites from the chemotherapy that
could damage infused cells. After chemotherapy and radiation, a period of pancytopenia lasts until the infused stem cells
re-establish functional hematopoiesis. This process is called
engraftment and commonly is defined as the point at which a
patient can maintain a sustained absolute neutrophil count
(ANC) of 500 cells/mm3 and a sustained platelet count of
20,000/mm3 lasting 3 consecutive days without transfusions.8 The median time to engraftment is a function of several factors, including the source of stem cells with peripheral
blood progenitor cells (PBPC), which can result in earlier engraftment than bone marrow9–15 (Fig. 92-2). Myeloablative
preparative regimens have significant regimen-related toxicity
and morbidity and thus are usually limited to healthy, younger
(i.e., usually less than 50 years) patients.16 Alternatively, nonmyeloablative transplantations, also referred to as nonablative
stem cell transplantations or “mini-transplants,” are being
performed with the hope of curing more patients with cancer
by increasing the availability of HCT with less regimenrelated toxicity and by using the GVT effect. In the year 2000,
NMT represented approximately 25% of allogeneic HCTs.17
Hematopoietic cell transplantation was previously referred
to as BMT. The term HCT more aptly describes this procedure as, in addition to bone marrow, stem cells may be obtained from the PBPC and umbilical cord blood. For the purpose of an HCT, the key properties of the hematopoietic stem
cells are their ability to engraft, the speed of engraftment, and
the durability of engraftment.3 Transplantation with peripheral blood progenitor cells (PBPCT) has essentially replaced
BMT as autologous rescue after myeloablative preparative
Absolute Neutrophil Count
(106L)
5,000
B
2,500
A
C
40
50
200
10
20
30
60
Days
FIGURE 92-2 Time to engraftment. A, Bone marrow infusion without complications or hematopoietic
growth factors. B, Accelerated engraftment with peripheral blood progenitor cells (PBPCs), and/or combination of autologous bone marrow with hematopoietic growth factors. C, Delayed engraftment caused by
infection, purged bone marrow, and/or inadequate dose of hematopoietic stem cells.
HEMATOPOIETIC CELL TRANSPLANTATION
regimens and is being increasingly used in the allogeneic setting.17 Cord blood stem cell transplantation (CBT), a form of
allogeneic HCT, is currently restricted to select pediatric and
adult recipients because of the limited number of stem cells
obtained from the umbilical cord blood and the necessary cell
dose that is associated with adequate engraftment.18,19
The type of HCT performed depends on a number of factors, including type and status of disease, availability of a
compatible donor, patient age, performance status, and organ
function. Characteristics of autologous and allogeneic transplantation, with either myeloablative or nonmyeloablative
preparative regimens, are compared in Table 92-1. Many diseases have been treated with autologous or allogeneic HCT
and are listed in Table 92-2.17,20–25 Modifications to the basic
schema for HCT are necessary based on the immunologic
source (i.e., allogeneic or autologous) and the anatomic
Table 92-1
•
92-3
source (i.e., bone marrow, PBPC, or umbilical cord blood) of
stem cells infused. The number of autologous transplants exceeds the number of allogeneic transplantations performed
each year. In 2000, approximately 25,000 autologous HCTs
were performed worldwide compared with 15,000 allogeneic
HCTs.17 The number of autologous HCTs performed has decreased because of a dramatic decline in the use of this procedure for breast cancer; this decline is due to the equivocal
benefits of HCT relative to standard-dose chemotherapy in
this patient population.17,22 The number of allogeneic HCTs
has reached a plateau since 1998, most likely because of the
limited availability of suitable donors, the limited success to
date with HLA-disparate donors, and the increasing availability of targeted therapies for diseases that were traditionally
treated with HCT (e.g., imatinib for newly diagnosed chronicphase chronic myelogenous leukemia).17,26
Comparison of Hematopoietic Cell Transplantation
Myeloablative
Nonmyeloablative
Risk
Autologous
Allogeneic
Allogeneic
Relapse after HCT
Rejection
Delayed engraftment
Graft-versus-host disease
Infection
Transplant-related morbidity
Transplant-related mortality
Cost of procedure
–
–
to b
to b
to a
a
b
Risk also varies depending on underlying disease, patient characteristics, and previous medical history.
Risk of infection increases with prolonged immunosuppression and/or chronic graft-versus-host disease.
Table 92-2
Indications for Myeloablative HCT20–25,326
Established Role
Promising/Experimental
Aplastic anemia
Homozygous -thalassemia
Severe combined immunodeficiency disease
Wiskott-Aldrich syndrome
Fanconi`s anemia
Infantile osteopetrosis
AML
ALL
CML
Intermediate and high-grade NHL
Sickle cell anemia
Severe leukocyte adhesion deficiency
X-linked agammaglobulinemia
Common variable immunodeficiency
Intermediate and high-grade NHL
Adults with AML (if lack suitable allogeneic donors)
Relapsed or refractory HD
Testicular cancer
Multiple myeloma
Neuroblastoma
Ovarian cancer
Low-grade lymphomas
Rhabdomyosarcoma
Equivocal
Allogeneic
Nonmalignant
Malignant
Agnogenic myeloid metaplasia
CLL (young patients only)
Multiple myeloma
Myelodysplastic syndrome
Autologous
Malignant
a
Metastatic breast cancer
AML in pediatric patients
Small-cell lung cancer
Timing relative to diagnosis and other therapies may vary.
AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; HCT, hematopoietic cell transplant; HD, Hodgkin’s disease;
NHL, non-Hodgkin’s lymphoma.
92-4
•
NEOPLASTIC DISORDERS
Autologous Hematopoietic Cell Transplantation
The defining characteristic of autologous HCT is that the
donor and the recipient are the same individual. Consequently, pretransplantation and post-transplantation immunosuppression is unnecessary. Autologous hematopoietic cells
must be obtained (i.e., harvested) before the myeloablative
preparative regimen is administered and subsequently stored
for administration after the preparative regimen. Essentially,
these hematopoietic cells are administered as a rescue intervention to re-establish bone marrow function and avoid longlasting, life-threatening marrow aplasia that results from the
myeloablative preparative regimen.27 In addition, autologous
hematopoietic cells obtained during complete remission are
an alternative to allogeneic HCT for the treatment of acute
leukemias in patients who cannot receive an allogeneic HCT
because of their age or limitations in finding a suitable
donor.28
Overall 5-year survival was 53% in the BMT group and 32%
in the conventional chemotherapy patients (P .038). Prospective studies comparing preparative regimens, stem cell mobilization techniques, and stem cell source (i.e., BMT versus
PBPCT) are not available; however, autologous PBPCT has
become the standard of care, most likely owing to the improved outcomes with PBPCT in other disease settings.32 Relative to chemotherapy-sensitive disease, survival is improved
with autologous HCT in a smaller number of patients with
chemotherapy-resistant relapse or patients with refractory disease who do not respond to chemotherapy.32
P.J. has minimal residual disease that has demonstrated
chemotherapy sensitivity (i.e., he had a partial response to
chemotherapy).35 His long-term prognosis will be improved
with autologous PBPCT rather than further conventional
chemotherapy, as described above.35 Thus, autologous PBPCT
is indicated.
Harvesting Autologous Bone Marrow
Indications for Autologous HCT
1. P.J., a 46-year-old man, has diffuse large-cell B-cell nonHodgkin’s lymphoma (NHL) in first relapse after a complete remission of 1 year’s duration. An 80% reduction in measurable
disease is noted after two cycles of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) salvage chemotherapy. P.J.’s
bone marrow biopsy and lumbar puncture are negative for malignant cells. Is a myeloablative preparative regimen with autologous HCT indicated for P.J.? If so, should hematopoietic cells
be obtained from bone marrow or peripheral blood?
Autologous HCT is used to treat a variety of malignancies
(see Table 92-2); NHL and multiple myeloma are the most
common indications for this procedure and represent over
one-third of all autologous HCT.17 Patients with NHL are
more frequently treated with an autologous HCT than with an
allogeneic HCT because autologous HCT has equivalent or
superior survival to allogeneic HCT.29,30 Also, autologous
HCT circumvents the need for histocompatible donors, is associated with lower mortality due to HCT, and is not restricted
by age to patients younger than 50 years.16 In addition, the
usefulness of NMT is currently being evaluated for the treatment of NHL because of the potential advantages of a graftversus-lymphoma effect and of using stem cells unexposed to
prior cytotoxic chemotherapy.5–7
The most appropriate patient population and timing for autologous HCT in the treatment of NHL are being defined. A
significant percentage of patients with aggressive NHL are
cured with conventional chemotherapy alone. Adding autologous HCT to initial combination chemotherapy does not improve outcomes in patients with aggressive NHL.31–33 However, retrospective analyses of some of these trials31,33
suggested that the International Prognostic Index34 may identify a subset of patients who may benefit from the addition of
autologous HCT to initial combination chemotherapy. The
primary eligibility criterion for autologous HCT is relapsed
disease that is chemotherapy sensitive.32,35 Data from several
retrospective and prospective phase II studies support this recommendation; however, only one randomized, controlled trial
has been conducted.35 Autologous BMT, compared with conventional chemotherapy with DHAP, resulted in a 5-year
event-free survival of 46% and 12%, respectively (P .001).
2. What is the best way to harvest and preserve harvested
stem cells?
Autologous hematopoietic stem cells are obtained or harvested from bone marrow or peripheral blood. Because the
harvest occurs before administering the preparative regimen,
autologous hematopoietic cells must be cryopreserved and
stored for future use.36 Dimethylsulfoxide (DMSO) is the
cryopreservative commonly used to protect hematopoietic
cells from damage during freezing and thawing. When infused into the patient, DMSO can be associated with side effects, including nausea and vomiting, arrhythmias, and a temporary unpleasant odor lasting approximately 24 to 36
hours.37 After collection, autologous hematopoietic cells may
be purged using various techniques to minimize tumor contamination or to enrich the hematopoietic cell composition.
“Negative purging” techniques bathe the hematopoietic cells
in either chemotherapy or monoclonal antibodies in an attempt to eradicate remaining tumor cells.38 “Positive selection” techniques involve running the autologous product
through a device (i.e., a column) in an attempt to separate the
earliest hematopoietic progenitor cells from the malignant
cells or committed progenitor cells.39 An example of positive
selection is the use of CD34 antigen in a column as a marker
to select out the earliest hematopoietic progenitor cells.
The technique for harvesting autologous hematopoietic
cells varies based on the anatomic source (i.e., bone marrow
or peripheral blood). Harvesting bone marrow entails a surgical procedure in which marrow is obtained from the iliac
crests. At the time of infusion, the autologous bone marrow is
thawed and then infused into the patient in the same manner
as a blood transfusion. Historically, autologous hematopoietic
cells obtained from the bone marrow were used after myeloablative preparative regimens. Recently, autologous PBPC use
has increased and has essentially replaced bone marrow in
many transplant centers. In 2000, over 95% of autologous
HCTs in adults and 80% in children used PBPC as the source
of hematopoietic cells.17 Peripheral blood was first advocated
as a means of obtaining hematopoietic cells in patients when
bone marrow was difficult to harvest (e.g., patients with bone
marrow involvement of the disease or those treated with
pelvic irradiation).40 Relative to a bone marrow graft, PBPCT
HEMATOPOIETIC CELL TRANSPLANTATION
results in more rapid neutrophil and platelet recovery, fewer
platelet transfusions, fewer days of IV antibiotics, and a
shorter duration of hospitalization.9,10 Thus, the shift to the use
of PBPC over bone marrow for autologous HCT is primarily
because of the more rapid engraftment and decreased health
care resource use. These and other potential advantages or differences between autologous BMT and PBPCT are outlined
in Table 92-3.
Mobilization and Collection of Autologous Peripheral Blood
Progenitor Cells
3. For PBPC mobilization, P.J. received one dose of cyclophosphamide 4,000 mg/m2 IV on day 1, followed by filgrastim
10 g/kg per day SC beginning on day 2 and continuing through
completion of apheresis. Twelve days after receiving cyclophosphamide, P.J.’s WBC count recovered to 3,000/mm3 and apheresis was begun. An adequate number of stem cells are collected after two apheresis sessions are processed and then stored. What
was the rationale for administering filgrastim and cyclophosphamide? What determines the duration of apheresis?
Peripheral blood progenitor cells are obtained by administering a mobilizing agent(s) followed by apheresis; this is an
outpatient procedure similar to dialysis.41 Hematopoietic
growth factors (HGFs) alone or in combination with myelosuppressive chemotherapy are used for mobilization of
PBPC.42 The HGF granulocyte-macrophage colony-stimulating factor (sargramostim, Leukine) and granulocyte colonystimulating factor (filgrastim, Neupogen) are used as mobilizing agents for PBPC collection.43 The most frequently used
filgrastim doses for PBPC mobilization in cancer patients are
in the range of 5 to 16 g/kg per day, administered subcutaneously, with higher doses (>10 g/kg per day) of filgrastim
yielding more PBPC cells.42,43 The highest values of mobilized progenitor cells are observed 5 to 6 days after mobilization with filgrastim alone.42
The combination of chemotherapy with HGF enhances
PBPC mobilization relative to HGF alone.42,44 In addition to
treating the underlying malignancy, this approach lowers the
risk of tumor cell contamination and the number of apheresis
collections required, but there is a greater risk of neutropenia
and thrombocytopenia than the use of HGF alone.42 Examples
of chemotherapy regimens used for PBPC mobilization include: cyclophosphamide 4 g/m2 IV,45 cyclophosphamide 4
g/m2 on day 1 and etoposide 200 mg/m2/day IV days 1 to 3
Table 92-3
b
92-5
(CE), or paclitaxel 200 mg/m2 IV day 1 and cyclophosphamide 3 g/m2 IV day 2.46 When used with chemotherapy,
filgrastim may be superior to sargramostim for PBPC mobilization,44 although confirmatory data are needed. The HGF is
initiated 24-hours after completion of chemotherapy. Apheresis begins when the peripheral white blood cell (WBC) count
begins to recover and the HGF is continued until apheresis is
complete.40,42
Apheresis is continued daily until the target number of
PBPC per kilogram of the recipients’ weight is obtained. For
adult recipients, the number of cells infused that express the
CD34 antigen (i.e., CD34 cells) correlates with time to engraftment.46–49 The CD34 antigen is expressed on 1% to 4% of
human marrow cells. It is expressed on virtually all unipotent
and multipotent colony-forming cells and on precursors of
colony-forming cells but not on mature peripheral blood
cells.50 In adults, the minimal number of CD34 cells needed
for an autologous PBPCT to produce complete (i.e., white
blood cell [WBC], red blood cell [RBC], and platelet) engraftment is not well defined, but it may be in the range of 2
106 CD34 cells/kg of recipient weight.49 A shorter time to
recovery of platelet counts and less supportive care requirements are needed with infusion of 5 106 CD34 cells/kg
of recipient weight; thus, this is the target number of CD34
cells recommended to be obtained with apheresis.46–49 More
intensive prior chemotherapy or radiation therapy is associated with a lower yield of CD34 cells. In addition, lower
yield is associated with administration of stem cell toxic
drugs such as carmustine and melphalan, which should not be
used for mobilizing chemotherapy.42 There is a paucity of information regarding the parameters associated with engraftment in children undergoing an autologous PBPCT.51 After
apheresis, the cells are cryopreserved, stored, thawed, and infused into the patient as described for autologous bone marrow.40
Myeloablative Preparative Regimens
4. What are the goals and characteristics of agents used for
myeloablative preparative regimens in patients like P.J?
The primary goal of the high-dose, myeloablative preparative regimen is to eradicate residual malignancy. Because the
donor and recipient are genetically identical, there is no need
to induce immunosuppression. Consequently, if radiation is
used in conjunction with high-dose chemotherapy and
Comparison of Source of Hematopoietic Cells in Autologous HCT: Bone Marrow versus Peripheral Blood
Duration of neutropenia
Duration of thrombocytopenia
Transfusion support needs
Number of hematopoietic cells collected/infused
Duration of hospitalization
Early complications
Late complicationsa
Tumor contamination of hematopoietic cell productb
Cost of procedure
a
•
Limited comparative date on long-term complications.
Clinical relevance of differences in tumor contamination for certain diseases under evaluation
Bone Marrow
Peripheral Blood
?
?
92-6
•
NEOPLASTIC DISORDERS
hematopoietic cell support, it is because radiation has inherent
activity against the tumor being treated (e.g., lymphoma).
Combination chemotherapy with multiple alkylating agents
comprises the most common high-dose regimens before autologous HCT. Alkylating agents are used because they exhibit a
steep dose-response curve for various malignancies and are
characterized by dose-limiting bone marrow suppression.4 Ideally, if combinations of antineoplastics are used, they should
have nonhematologic toxicities that do not overlap and are not
life-threatening. Examples of common myeloablative regimens used with stem cell support are illustrated in Table 92-4.
care and prevented many patients from being hospitalized.54
In addition, outpatient care during autologous HCT demands
that transplantation centers have appropriate resources, facilities, and staff to provide 24-hour patient care coverage. Patients undergoing outpatient care must meet eligibility criteria, including the availability of caregivers 24 hours a day and
housing within close proximity to the HCT center.
Hematopoietic Growth Factors After Autologous PBPC Infusion
5. What complications must be anticipated as a consequence
of autologous HCT? How can these be minimized? How can
treatment be provided in an outpatient setting?
6. After 10 days of rest, P.J. is admitted for his autologous
BMT. He receives a myeloablative preparative regimen with cyclophosphamide, carmustine, and etoposide (CBV) with an autologous PBPC graft. An order is written to begin filgrastim 5
g/kg/day SQ, beginning on day 0 and continuing until the ANC
has recovered to 500/mm3 for 2 consecutive days. What is the rationale for filgrastim in P.J. following the transplant procedure?
The most common cause of death after autologous HCT is
the primary disease. The more concerning toxicities of the
preparative regimen are infection and organ failure each occurring in less than 5% of the patients.17 Because autologous
HCT is not complicated by profound immunosuppression or
GVHD, supportive care strategies vary from allogeneic HCT
in the early and later recovery periods. Isolation and use of
laminar air flow (LAF) rooms are unnecessary, although many
centers continue to provide care for patients undergoing autologous HCT in HEPA-filtered rooms. The use of autologous
PBPCT is associated with shorter periods of neutropenia and
less need for clinical resources. Thus, some transplant centers
have developed programs that incorporate outpatient care into
the initial recovery; these programs also offer cost savings to
the payer for health services.52,53 Successful outpatient care
during administration of a myeloablative preparative regimen
and the neutropenic period requires careful development and
implementation of the necessary supportive care strategies to
prevent or minimize infection; chemotherapy-induced nausea
and vomiting, pain, and bleeding along with admission criteria for more severe complications. Use of prophylactic oral
antibiotics and once-daily IV antibiotics to prevent or treat
uncomplicated febrile neutropenia have facilitated outpatient
Autologous HCTs, regardless of the stem cell source, are
associated with profound aplasia due to the myeloablative
preparative regimen. Aplasia typically lasts 20 to 30 days after an autologous BMT and 7 to 14 days after an autologous
PBPCT.9 (see Fig. 92-2) During this period of aplasia, patients
are at high risk for complications such as bleeding and infection. Filgrastim and sargramostim exert their effects by stimulating the proliferation of committed progenitor cells and,
once engraftment occurs, hematopoietic recovery may be accelerated.
Several factors need to be considered when discussing the
role of HGF in accelerating engraftment after HCT. First, the
anatomic source of hematopoietic cells predicts the degree of
benefit, with the greatest benefit observed in enhancing neutrophil recovery and decreased associated resources in the setting of autologous BMT. The benefits of the HGF have been
shown in several large multicenter, randomized, double-blind,
placebo-controlled trials.55—57 The majority of the trials suggest HGF administration is associated with a shorter time to
neutrophil engraftment (by 4 to 7 days), less infectious complications, and shorter hospitalization after autologous
BMT.55,56,58 Survival is equivalent in those who received a
HGF or a placebo.55,57
Complications of Autologous HCT
Table 92-4
Representative Myeloablative Preparative Regimens Used in HCT
Type of HCT
Disease State
Regimen
Dose/Schedule
Allogeneic115
Hematologic malignanciesa
CY/TBI
Allogeneic327
Aplastic anemia
CY
Allogeneic
Autologous21,115,116
Acute and chronic leukemias
Bu/CY
Autologous35
Non-Hodgkin’s lymphoma
BEAC (carmustine/etoposide/
cytarabine/cyclophosphamide)
CY 60 mg/kg/day IV on 2 consecutive days before TBI
1,000–1,575 rads fractionated over 1–7 days
CY 60 mg/kg/day IV on 4 consecutive days
(–5, –4, –3, –2)
Bu: adult—1 mg/kg/dose PO Q 6 hr 16 doses
Children 7 yr—37.5 mg/m2 PO Q 6 hr 16 doses
CY 50 mg/kg/day IV QD 4 days after Bu or 60 mg/kg/
day IV QD 2 days after Bu
Carmustine 300 mg/m2/day IV 1, day –6
Etoposide 200 mg/m2/day IV 4, days –5, –4, –3, –2
Cytarabine 200 mg/m2/day IV BID 4,
days –5, –4, –3, –2)
CY 35 mg/kg/day IV 4, days –5, –4, –3, –2
mesna 50 mg/kg/day IV X4, days –5, –4, –3, –2
a
Includes acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s disease.
Ara-C, cytarabine; BCNU, carmustine; Cy, cyclophosphamide; HCT, hematopoietic cell transplantation; TBI, total body irradiation.
HEMATOPOIETIC CELL TRANSPLANTATION
Although some studies in the autologous PBPCT setting
note more rapid neutrophil recovery after HGF use, others report no difference in infection rates and minimal decreases in
associated resource use such as the duration of hospitalization.56,58–60 In addition, sargramostim administration had no
benefit (i.e., neutrophil and platelet engraftment) over placebo
after autologous PBPCT in one trial.61 Concern remains that
platelet engraftment will be delayed by a HGF in patients who
received a PBPCT with a low CD34 count (i.e., 2.5 106/kg).47 Although clinical practice guidelines for HGF support their use after both autologous BMT and PBPCT, pharmacoeconomic analyses are needed to further evaluate the
true benefit of HGFs after autologous PBPCT.
Filgrastim often is used preferentially for this indication in
clinical practice. The reason most commonly cited for using
filgrastim is the desire to avoid febrile reactions associated
with sargramostim, which complicate interpretation of febrile
neutropenia. Although sargramostim or filgrastim theoretically may stimulate proliferation of leukemia myeloblasts, no
evidence to date suggests that the incidence of leukemia relapse is higher in patients who receive these HGFs after autologous or allogeneic HCT.62,63 This may be due to the fact
that patients with leukemia usually are in remission at the
time of HCT. Thus, the population of residual leukemia cells
probably is minimal.
Although both filgrastim and sargramostim successfully
hasten neutrophil recovery, neither agent stimulates platelet
production or augments platelet recovery.55,56 This is an important consideration because thrombocytopenia is often a
cause of prolonged hospitalization in the HCT patient. Successful engraftment of all hematopoietic cell lines likely will
require combinations of growth factors that work in concert to
augment hematopoiesis. However, erythropoietin (Epogen,
Procrit) and interleukin (IL)-11 (Neumega) have only been
used experimentally in the HCT patient. At this time, there is
no established role for either agent in the care of these patients.
In summary, P.J. is undergoing autologous PBPCT for the
treatment of a lymphoid malignancy. Thus, either sargramostim or filgrastim is an acceptable option for accelerating engraftment. Whether the addition of either agent will reduce infection and other clinically relevant outcomes is
debatable.43 A complete blood cell (CBC) count with differential should be obtained daily. Filgrastim should be continued until neutrophil recovery is achieved.
Allogeneic Hematopoietic Cell Transplantation
Allogeneic HCT involves the transplantation of hematopoietic
cells obtained from a donor’s bone marrow, peripheral blood,
or umbilical cord blood to a patient. Unless the donor and the
patient are identical twins (referred to as a syngeneic HCT),
they are dissimilar genetically. Allogeneic transplantation offers the potential for a GVT effect in which immune effector
cells from the donor recognize and eliminate residual tumor in
the recipient.5 GVHD is caused by the activation of donor
lymphocytes leading to immune damage to the skin, gut, and
liver in the recipient. Histocompatibility differences between
the donor and recipient necessitate post-transplantation immunosuppression after allogeneic HCT because considerable
morbidity and mortality are associated with graft rejection and
•
92-7
GVHD. Thus, to understand the application of and complications after allogeneic HCT, a working knowledge of immunology and the major histocompatibility complex (MHC) (referred to as human leukocyte antigen [HLA] in humans) is
necessary; a detailed review of this topic can be found elsewhere.64 (Also see related information in Chapter 35, Solid Organ Transplantation)
Eligibility criteria for allogeneic HCT vary between institutions. Having a matched sibling donor is no longer a requirement for allogeneic HCT as improved immunosuppressive regimens and the National Marrow Donor Program have
allowed an increase in the use of unrelated or related matched
or mismatched HCT.65 Normal renal, hepatic, pulmonary, and
cardiac functions are necessary for eligibility at most centers.
Historically, patients older than 55 were excluded from allogeneic HCT because they were more likely to succumb to
transplantation-related complications.1,2 However, many centers are now considering patients up to 65 years, basing their
selection criteria on physiologic rather than biologic age.
Indications for Allogeneic HCT
7. B.S., a 22-year-old man, has acute myelogenous leukemia
(AML) in first remission after induction chemotherapy with
standard doses of cytarabine and daunorubicin and consolidation with high-dose cytarabine. HLA typing performed on family members has identified a fully HLA-matched sibling donor.
B.S. returns to clinic today for a pretransplantation workup. At
this time, his physical examination is noncontributory, bone
marrow aspirate and biopsy reveal favorable cytogenetics, and a
lumbar puncture is negative for leukemic infiltrates. All laboratory values are within normal limits. A bone marrow biopsy reveals 5% blasts. B.S. has a normal electrocardiogram and normal cardiac wall motion study, renal and hepatic function, and
pulmonary function tests. Is an allogeneic HCT indicated for
B.S.?
B.S. has a diagnosis of AML, which is one of the most
common indications for allogeneic HCT.17 The primary indications for allogeneic HCT include treatment of otherwise fatal diseases of the bone marrow or immune system (see Table
92-2). The optimal role and timing of allogeneic HCT in contrast to other therapies remains controversial,66 especially because treatment options for AML have increased.67 An advantage of allogeneic HCT over chemotherapy is a decreased
incidence of leukemia relapse, since patients in first complete
remission who receive an HLA-matched HSCT from a sibling
have a less than 20% risk of relapse.41,68 The lower risk of relapse is due to the use of the myeloablative preparative regimen and the GVT effect mediated by the donor immune system. The major disadvantage of allogeneic myeloablative
HCT is an increased incidence of early mortality caused by
regimen-related toxicities, GVHD, and infectious complications that result from profound immunosuppression (see
Question 8).41,68 Nonetheless, allogeneic HCT has been advocated for eligible young (under 55-years) patients with AML
in early first remission if there are histocompatible donors.69
This recommendation to perform an allogeneic HCT early
in the course of AML is based on diminishing efficacy of
HCT later in the course of the disease. In adult patients with
AML in first remission, four large studies have evaluated allogeneic HCT in those patients with an HLA-matched sibling
92-8
•
NEOPLASTIC DISORDERS
donor and randomized the remaining patients to autologous
HCT or chemotherapy.70–73 Disease-free survival after autologous HCT was superior70,73 or equivalent71,72 to chemotherapy
in two trials; however, up to 45% of those randomized to autologous HCT did not receive a transplant. Similarly, allogeneic HCT had similar71,72 or improved disease-free survival
when compared with chemotherapy.70 Higher early mortality
in the HCT arms (particularly those undergoing an allogeneic
HCT) and a higher incidence of relapse in chemotherapytreated patients equalized overall survival between transplant
arms. The association of cytogenetics with response to the
three different treatment arms has been evaluated; however,
conflicting results have been obtained perhaps due to the
small numbers of patients within each category.73,74 For older
patients or patients who do not have an appropriate allogeneic
donor, the decision to proceed with conventional chemotherapy in first remission appears clear. The key issue for young
patients with an available HLA-matched sibling donor, such
as B.S. has, is whether to undergo an allogeneic HCT at the
time of first remission or first relapse.28 Unfortunately, no trials have addressed this question. Data from the International
Bone Marrow Transplant Registry (IBMTR) indicated that
60% of patients with AML in first remission who received a
matched sibling allogeneic HCT have a 3-year probability of
survival; survival decreases to 44% in those in second or subsequent remission.17 The 3-year probability of survival for recipients of unrelated HCT in first or second remission are
40% and 37%, respectively.17 Current research efforts focus
on retrospective analysis of completed trials to identify subsets of patients (e.g., those with unfavorable cytogenetics)
who may respond favorably to allogeneic HCT transplantation
and the use of novel preparative regimens in hopes of improving the outcome of allogeneic HCT.74,75
B.S. is eligible for allogeneic HCT by virtue of his diagnosis and the availability of a histocompatible donor. In addition, he meets age and organ-function eligibility requirements
and is in complete remission with minimal residual disease.
The decision regarding timing of allogeneic HCT compared
with other therapies must be made weighing the aforementioned risks and benefits. B.S. can either undergo allogeneic
HCT now or receive consolidation chemotherapy and delay
HCT until early in his first relapse.
Histocompatibility
8. How does histocompatibility influence the risks for graft
rejection and graft-versus-host reactions in patients like B.S.
who undergo an allogeneic HCT?
The tissue transplanted in allogeneic HCT is immunologically active, and thus there is potential for bidirectional graft
rejection.1,2,76 In the first scenario, cytotoxic T cells and natural killer (NK) cells belonging to the host (recipient) or recognize MHC antigens of the graft (donor hematopoietic cells)
and elicit a rejection response. In the second scenario, immunologically active cells in the graft recognize host MHC
antigens and elicit an immune response. The former is referred to as host-versus-graft disease and the latter as graftversus-host disease (GVHD). Host-versus-graft effects are
more common in solid organ transplantation. When hostversus-graft effects occur in allogeneic HCT, they are referred
to as graft failure, which results in ineffective hematopoiesis
(i.e., adequate ANC and/or platelet counts were not obtained).
Therefore, an essential first step for patients eligible for HCT
is finding an HLA-compatible graft with an acceptable risk of
rejection and GVHD.
Rejection is least likely to occur with a syngeneic donor,
meaning that the recipient and host are identical (monozygotic) twins. Identical twins occur spontaneously in nature in
approximately 1 in 100 births; thus, it is unlikely that a patient
would have a syngeneic donor. In those patients without a
syngeneic donor, initial HLA typing is conducted on family
members because the likelihood of complete histocompatibility between unrelated individuals is remote. Siblings are the
most likely individuals to be histocompatible within a family.
However, because each offspring inherits only one parental
haplotype, the chance for complete histocompatibility occurring in an individual with only one sibling is 25%.1,2 Approximately 40% of patients with more than one sibling have an
HLA-identical match.1,2
Determination of histocompatibility between potential
donors and the patient is completed before allogeneic HCT.64
Initially, HLA typing performed using blood samples and
compatibility for class I MHC antigens (HLA-A, HLA-B, and
HLA-C), is determined through serologic and DNA-based
testing methods.77 In vitro reactivity between donor and recipient can also be assessed in mixed-lymphocyte culture, a
test used to measure compatibility of the MHC class II antigens (HLA-DR, HLA-DP, HLA-DQ).77 Currently, most clinical and research laboratories are also performing molecular
DNA typing using polymerase-chain reaction methodology to
determine the HLA allele sequence.77 A donor–recipient pair
with different HLA antigens (i.e., “antigen mismatched”) always have different alleles, whereas pairs with the same allele
always have the same antigen and are termed “matched.”
However, some pairs have the same HLA antigen but have
different alleles and are thus “allele mismatched.”78
Lack of an HLA-matched sibling donor can be a barrier to
allogeneic HCT. The use of alternative sources of allogeneic
hematopoietic cells, such as related donors mismatched at one
or more HLA-loci, or phenotypically (i.e., serologically)
matched unrelated donors has been evaluated.65 Establishment of the National Marrow Donor Program has helped increase the pool of potential donors for allogeneic HCT.65
Through this program, an HLA-matched unrelated volunteer
donor might be identified. Recipients of an unrelated graft are
more likely to experience graft failure and acute GVHD relative to recipients of a matched-sibling donor.79 Thus, work is
ongoing to identify factors that predict graft failure or GVHD
to improve the availability and safety of unrelated donor
transplants.80 (See Graft Failure section below.)
The preparative regimen or GVHD prophylaxis may be altered based on the mismatch between the donor and recipient.
The risk of graft failure decreases with better matches, such
that those with a class I (i.e., HLA-A, B, or C) antigen mismatch have the highest risk of rejection compared with those
with just one class I allele mismatch who have a minimal risk.
Graft failure does not appear to associated with mismatch at a
single class II antigen or allele.78 GVHD, both acute and
chronic, and survival have also been associated with disparity
for class I and II antigens and alleles.81,82
HEMATOPOIETIC CELL TRANSPLANTATION
Harvesting, Preparing, and Transplanting Allogeneic Hematopoietic
Stem Cells
9. What methods can be used to harvest stem cells from
B.S.’s histocompatible sibling and prepare them for transplant?
Are there any advantages to the use of bone marrow, peripheral
blood, or umbilical cord blood as a source for stem cells?
BONE MARROW
The technique of obtaining allogeneic hematopoietic stem
cells varies according to the anatomic site (i.e., bone marrow,
peripheral blood, or umbilical cord blood) from which the
cells are being harvested. Allogeneic bone marrow is obtained
from the donor under spinal or general anesthesia in the operating room under sterile conditions on day 0 of BMT.1,2 Multiple aspirations of marrow are obtained from the anterior and
posterior iliac crests until a volume with a sufficient number
of hematopoietic cells is collected (e.g., 600 to 1,200 mL of
bone marrow). The bone marrow then is processed to remove
fat or marrow emboli and is usually immediately infused intravenously into the patient like a blood transfusion. The marrow may need additional processing if the donor and recipient
are ABO incompatible, which occurs in up to 30% of HCTs.
RBCs may need to be removed before infusion into the recipient to prevent immune-mediated hemolytic anemia and
thrombotic microangiopathic syndromes.83
PERIPHERAL BLOOD PROGENITOR CELLS
When obtaining allogeneic hematopoietic cells from peripheral blood, the compatible donor first undergoes mobilization
therapy with a HGF to increase the number of hematopoietic
cells circulating in the peripheral blood.84 The most commonly
used regimen to mobilize allogeneic (healthy) donors is a 4- to
5-day course of filgrastim, 10 to 16 g/kg per day, administered
subcutaneously, followed by leukapheresis on the fourth or fifth
day when peripheral blood levels of CD34 cells peak.85 An adequate number of hematopoietic cells is usually obtained with
one to two apheresis collections, with the optimal number of
CD34 collected being 5 to 8 106 cells/kg of recipient body
weight.86,87 Higher cell doses have been associated with not
only more rapid engraftment, but also fewer fungal infections
and improved overall survival.88 Hematopoietic cells obtained
from the peripheral blood are processed like bone marrow–
derived stem cells and may be infused immediately into the recipient or frozen for future use. Allogeneic donation of PBPC
has a similar level of physical discomfort to bone marrow donation; however, PBPC donation leads to quicker recovery.87
The donor may experience musculoskeletal pain, headache,
mild increases in hepatic enzyme or lactate dehydrogenase levels due to filgrastim administration and hypocalcemia due to
citrate accumulation, which decreases ionized calcium concentrations during apheresis.84,89
The use of allogeneic PBPC is increasing; in the year 2000,
40% of allogeneic HCTs performed worldwide used PBPC as
the sources of hematopoietic cells rather than bone marrow.17
In HLA-matched sibling donors, retrospective comparison
suggested that PBPC infusions were associated with quicker
engraftment15,90 with similar costs to BMT.91 Transplantation
with PBPC in HLA-matched sibling donors results in quicker
neutrophil and platelet engraftment, with equivalent or higher
•
92-9
rates of acute and chronic GVHD with PBPCT relative to
BMT in several randomized clinical trials.11–14 Similar trends
have been found with unrelated donors.92,93 Allogeneic PBPC
grafts contain approximately 10 times more T and B cells than
bone marrow grafts. Because these cells survive long-term,
lymphocytes subsets are higher and the rate of severe infections after engraftment is lower in PBPCT.94 However, there
has also been significant concern that the greater T- and B-cell
content of PBPCT could increase the risk of acute and/or
chronic GVHD. The relative risk of acute and chronic GVHD
after PBPCT were 1.16 and 1.53, respectively, compared with
BMT (P .006 for both), with a 66% higher risk of clinically
extensive chronic GVHD with PBPCT.95
UMBILICAL CORD BLOOD
The use of allogeneic hematopoietic cells from umbilical
cord blood (UCB) is increasing in recipient’s age 20 years.17
Transplantation with UCB offers an alternative stem cell
source to those patients who do not have an acceptable
matched related or unrelated donor. When allogeneic
hematopoietic cells are obtained from UCB, the cord blood is
obtained from a consenting donor in the delivery room after
birth and delivery of the placenta.96 The cord blood is then
processed as described earlier, a sample is sent for HLA typing, and the cord blood is frozen and stored for future use.
Numerous UCB registries exist with the goal of providing alternative sources of allogeneic stem cells.97 Functional
hematopoietic progenitor and stem cells can be found in UCB
cryopreserved for up to 15-years; however, their ability to successfully engraft in a patient is unknown.98 Case series have
shown that UCB transplantation, from a related or unrelated
donor, is effective in children with cancer and non-malignant
conditions.99,100 Retrospective comparisons of BMT to UCB
transplant have been conducted in recipients of grafts from unrelated101,102 and related103 donors. Engraftment is slower in
UCB transplants, with a lower risk of GVHD and similar survival rates relative to a BMT.101–103 In children, engraftment is
related to the dose of nucleated cells with an optimal dose of
approximately 2 107 nucleated cells per kilogram of recipient body weight.19 This raises the question as to whether a
UCB transplant can provide enough nucleated cells to adequately engraft within an adult. In adults who do not have a related or unrelated donor for bone marrow or PBPC donation, a
UCB transplant is feasible when at least 1 107 nucleated
cells per kilogram of recipient body weight are administered.18
In summary, it is most reasonable to harvest PBPC from
B.S.’s sibling to use for B.S. myeloablative transplant.
T-CELL DEPLETION
10. What are the risks and benefits of removing T cells from
the donor bone marrow before its infusion into the recipient? If
bone marrow is harvested from B.S.’s sibling, should T cells be
removed?
Immunocompetent T lymphocytes may be depleted from
the donor bone marrow ex vivo before infusion (referred to as
T-cell–depleted hematopoietic cells) into the recipient as a
means of preventing GVHD.36 Depletion of T lymphocytes in
donor hematopoietic cells is completed ex vivo using physical
(e.g., density gradient fractionation) and/or immunologic
92-10
•
NEOPLASTIC DISORDERS
(e.g., CAMPATH-1 antibodies) methods.104 Functional recovery of T cells in the recipient is delayed, and the risk of
Epstein-Barr virus–associated lymphoproliferative disorders
is higher with the use of T-cell–depleted bone marrow.104
T-cell–depleted grafts reduce the incidence of GVHD,104 but
graft failure is more common. Before T-cell depletion, graft
failure rates with a myeloablative BMT ranged from 1% to
5% but were as high as 50% to 80% with the use of T-cell–
depleted bone marrow.105,106 The higher relapse rates with
T-cell–depleted BMT is discussed in the section, Graftversus-Tumor Effect. Data are evolving regarding the use of
selective T-cell depletion in hopes of reducing GVHD while
maintaining the GVT effect.107 Donor lymphocyte infusion in
patients who suffer relapse after receiving a T-cell–depleted
BMT also is under study.108
Presently, it is not clear which patients should receive a
T-cell–depleted bone marrow or PBPC. Thus, B.S. should not
receive a T-cell–depleted preparation of his donor PBPC, unless he is participating in a clinical trial evaluating the risks
and benefits of T-cell depletion.
Graft-versus-Tumor Effect
11. What is the graft-versus-tumor effect? Which tumors are
most responsive to this effect?
Initial clinical evidence of a graft-versus-tumor (GVT) effect came from the observation that patients with GVHD had
lower relapse rates compared with those who did not.109,110
This suggests a GVT effect due to the donor lymphocytes.
Further support for a GVT effect is the higher rate of
leukemia relapse after T-cell–depleted BMT, in part due to
the reduction in GVHD and concomitant loss of GVT effect.104,111 The effectiveness of donor lymphocyte infusions in
patients who experienced relapse after allogeneic HCT also
suggest a GVT effect. Lymphocytes are collected from the peripheral blood of the donor and administered to the recipient.
Eradication of the recurrent malignancy is due to either specific targeting of the tumor antigens or to GVHD, which may
affect cancer cells preferentially. Different illnesses vary in
their responsiveness to donor lymphocyte infusions, with
CML and acute leukemias being the most and least responsive, respectively.112 Patients with certain solid tumors (e.g.,
renal cell carcinoma) also appear to benefit from a GVT effect.113 These data gave rise to the use of nonmyeloablative
preparative regimens, which are discussed later in this
chapter.
Preparative Regimens for Allogeneic HCT
MYELOABLATIVE PREPARATIVE REGIMENS
12. What is the rationale for using myeloablative preparative
regimens for patients like B.S. who are to receive an allogeneic
HCT? What types of regimens are used and what is recommended for B.S.?
The combination of chemotherapy and/or radiation used in
allogeneic HCT is referred to as the preparative or conditioning regimen. The initial rationale for high-dose myeloablative
preparative regimens was similar to that discussed under Autologous HCT in this chapter. Specifically, infusion of stem
cells circumvents dose-limiting myelosuppression, maximizing the potential value of the steep dose-response curve to
alkylating agents and radiation,4 suppressing the host immune
system, and creating space in the marrow compartment to facilitate engraftment.1,2 The preparative regimen is designed to
eradicate immunologically active host tissues (lymphoid tissue and macrophages) and to prevent or minimize the development of host-versus-graft reactions. In contrast, a myeloablative preparative regimen may not be necessary if a
histocompatible allogeneic HCT is performed on a patient
with a poorly functioning immune system (e.g., severe combined immunodeficiency disease [SCID]).114 In the absence of
a functioning immune system, the likelihood of a host-versusgraft reaction to histocompatible donor hematopoietic cells is
small. Similarly, patients undergoing syngeneic transplantation do not require immunosuppressive preparative regimens
before HCT because the donor and the patient are genetically
identical.1,2 Thus, the preparative regimen is tailored to
the primary disease and to HLA compatibility between the
recipient–donor pair.
Examples of common preparative regimens for allogeneic
HCT are shown in Table 92-4.21,35,115,116 Most allogeneic
preparative regimens for the treatment of hematologic malignancies contain either cyclophosphamide or radiation, or
both. The combination of cyclophosphamide and total body
irradiation (TBI) was one of the first preparative regimens
used and is still used widely today.1,2 This regimen is immunosuppressive and has inherent activity against hematologic malignancies (e.g., leukemias, lymphomas). TBI has the
added advantage of being devoid of active metabolites that
might interfere with the activity of donor hematopoietic cells.
In addition, TBI eradicates residual malignant cells at sanctuary sites such as the central nervous system. Modifications of
the cyclophosphamide–TBI preparative regimen include replacing TBI with other agents (e.g., busulfan) and adding
other chemotherapeutic or monoclonal agents to the existing
regimen. These measures are designed to minimize the longterm toxicities associated with TBI (e.g., growth retardation in
children, cataracts) or to provide additional antitumor activity,
respectively. In the case of a mismatched allogeneic HCT with
a substantially increased chance of graft rejection, antithymocyte globulin (ATG) may also be added to the preparative regimen to further immunosuppress the recipient.
The optimal myeloablative preparative regimen for allogeneic HCT is challenging to study because several indications for HCT (e.g., SCID, thalassemia) are rare enough that
it is not feasible or is cost-prohibitive to conduct clinical trials that are adequately powered to detect clinically relevant
differences. However, the long-term outcomes of busulfan/cyclophosphamide (BU/CY) and cyclophosphamide/total body
irradiation (CY/TBI) in patients with AML and CML—the
more common indications for allogeneic HCT—have been
compared in a meta-analysis of four clinical trials.117 Equivalent rates of long-term complications were present between
the two preparative regimens, except for a greater risk of
cataracts with CY/TBI and alopecia with BU/CY. Overall and
disease-free survival rates were similar in patients with CML,
whereas there was a trend for improved disease-free survival
with CY/TBI in AML patients. Thus, the preparative regimen
can be tailored to the primary disease and to the HLA compatibility.
Based on these data, the CY/TBI preparative regimen is
preferred for B.S.
HEMATOPOIETIC CELL TRANSPLANTATION
NONMYELOABLATIVE PREPARATIVE REGIMENS
13. Describe the rationale for nonmyeloablative preparative
regimens. Is B.S. a candidate for such a regimen?
The regimen-related toxicity of a myeloablative preparative regimen (Table 92-5) limits the use of HCT to younger
patients who have minimal comorbidities. Most patients diagnosed with cancer are elderly, and thus myeloablative HCT
cannot be offered to a substantial portion of these patients.118
The concept of donor immune response having a GVT effect
gave rise to the theory that a strongly immunosuppressive but
not myeloablative preparative regimen (i.e., a nonmyeloablative transplantation or NMT) may result in a state of chimerism in which the recipient and donor are co-existing.119
The toxicity and efficacy of NMT are also being evaluated in
patients with nonmalignant conditions, such as congenital immunodeficiency, who are not eligible for a myeloablative
HCT.120
A nonmyeloablative preparative regimen allows for development of mixed chimerism (defined as 5% to 95% peripheral
donor T cells) between the host and recipient to allow for a
GVT effect as the primary form of therapy (Fig. 92-3). Chimerism is evaluated to monitor disease response and engraftment at varying time points after NMT. Chimerism is assessed within peripheral blood T cells and granulocytes and
Table 92-5 Common Toxicities Associated With
Myeloablative Allogeneic HCT
Early
Late
Nausea, vomiting, diarrhea
Mucositis
Increased susceptibility to infections
Endocrine disorders (hypothyroidism,
infertility, growth retardation)
Secondary malignant neoplasms
Chronic GVHD
Cataracts
Hemorrhagic cystitis
Veno-occlusive disease
Renal dysfunction
Cardiotoxicity
Pneumonitis
Graft rejection
Acute GVHD
Recipient
Donor
GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation.
Mixed
donor-host
chimerism
HSCT
No GVHD
All-donor
chimerism
Donor
lymphocyte infusion
MMF/CSP
GVHD
200 cGy TBI
Microsatellite
markers
Malignant disease,
genetic disorder,
autoimmune disease
92-11
bone marrow using conventional (e.g., using sex chromosomes for opposite sex donors) and molecular (e.g., variable
number of tandem repeats) for same sex donors. The methods
used to characterize chimerism after HCT are reviewed elsewhere.121
The nonmyeloablative regimen does not completely eliminate host normal and malignant cells. The donor cells eradicate residual host hematopoiesis, and the GVT effects generally occur after the development of full donor T-cell
chimerism.122 After engraftment, mixed chimerism should be
present as evidenced by the ability to detect both donor- and
recipient-derived cells. Thus, if the graft is rejected, autologous recovery should promptly occur. The intensity of immunosuppression required for engraftment depends on the
immunocompetence of the recipient histocompatibility, and
the composition of the HCT.123 More intensive regimens that
are required for engraftment in the setting of unrelated-donor
or HLA-mismatched related HCT have recently been termed
“reduced-intensity” myeloablative transplants.123 After chimerism develops, donor–lymphocyte infusion can be safely
administered in patients without GVHD to eradicate malignant cells.
Nonmyeloablative preparative regimens typically consist
of a purine analog (e.g., fludarabine) in combination with an
alkylating agent or low-dose TBI.120,124,125 Adverse effects are
decreased because of the lower-intensity preparative regimen.
Thus, patients who were not healthy or young enough to receive a myeloablative preparative regimen could undergo a
nonmyeloablative preparative regimen. However, the risk of
GVHD remains with NMT. Therefore, GVHD prophylaxis,
though different from that used with myeloablative regimens,
is still necessary, as is follow-up for infectious complications.126,127
Presently, NMT is not indicated as first-line therapy for any
malignant or nonmalignant conditions and therefore is not an
option for B.S. Clinical research over the past 6-years has focused on developing preparative regimens with acceptable
toxicity that are capable of achieving mixed chimerism.128
Currently, NMT should only be conducted in the setting of a
clinical trial. NMT is being evaluated for cancers sensitive to
a GVT effect (e.g., CML, AML), in older patients or for those
with comorbidities who would not be able to tolerate a myeloablative HCT.7,123,129,130
T-cell deficiency
disease
No pregrafting
conditioning
•
Correction of
genetic disease
Cure of
malignant or
autoimmune
disease
FIGURE 92-3 Nonmyeloablative allogeneic hematopoietic cell transplantation. (CSP,; GVHD, graftversus-host disease; HSCT,; MMF, mycophenolate mofetil; TBI, total body irradiation.)
92-12
•
NEOPLASTIC DISORDERS
There is a paucity of data regarding the optimal source of
hematopoietic stem cells after NMT. Most case series have
combined data from peripheral blood progenitor and marrow
grafts (Table 92-6). Some data suggests that, compared with
bone marrow grafts, PBPC is associated with more favorable
outcomes, such as quicker engraftment, earlier T-cell chimerism, longer progression-free survival, and lower risk of
graft rejection.131,132
Post-Transplantation Immunosuppressive Therapy
14. What is the rationale for immunosuppressive therapy after an allogeneic HCT? What is recommended for B.S.?
After infusion of hematopoietic cells, immunosuppressive
therapy is administered to prevent or minimize GVHD. Patients receiving syngeneic transplants or a T-cell–depleted histocompatible allogeneic transplant generally do not receive
post-transplantation immunosuppressive therapy. In the former, the donor and the patient are genetically identical and
GVHD should not be elicited. In the latter, the volume of
donor T cells infused into the patient usually is insufficient to
elicit a significant graft-versus-host reaction.104,133 Numerous
immunosuppressive agents given alone or in combination
have been evaluated for the prevention of GVHD. Commonly
used regimens after myeloablative HCT include cyclosporine
or tacrolimus administered with a short course of low-dose
methotrexate.134 Corticosteroids may also be used to prevent
GVHD but are more commonly used to treat GVHD. In allogeneic HCT recipients without GVHD, immunosuppressive
therapy is slowly tapered and discontinued over 6 months to 1
year because of immunologic tolerance.1,2 GVHD prophylaxis
Table 92-6
varies between a myeloablative and nonmyeloablative HCT.
Over time, the immunologically active tissue between host
and recipient become tolerant of one another and cease recognizing the other as foreign. In contrast, solid organ transplant recipients usually must continue immunosuppressive
therapy for the duration of the recipient’s life.
Thus, B.S. should receive cyclosporine or tacrolimus
administered with a short course methotrexate for posttransplantation immunotherapy. This combination regimen
will lower the risk of GVHD after his allogeneic HCT with a
myeloablative preparative regimen.
Comparison of Supportive Care Strategies Between
Autologous and Allogeneic Myeloablative HCT
15. How do supportive care strategies used for myeloablative
preparative regimens with an autologous graft differ from those
described for an allogeneic graft?
Supportive care strategies common to patients receiving a
myeloablative preparative regimen, regardless if an autologous or allogeneic HCT, include use of indwelling central venous catheters; blood product support; and pharmacologic
management of chemotherapy-induced nausea and vomiting
(CINV), mucositis, and pain. These similarities are a function
of the adverse drug reactions (ADRs) that occur as a result of
administering high-dose, myeloablative chemotherapy.
The supportive care diverges because of the different needs
for immunosuppression with an autologous and allogeneic
HCT. Allogeneic HCT patients experience an initial period of
pancytopenia followed by a more prolonged period of im-
Representative Nonmyeloablative Preparative Regimens Used in Allogeneic HCT
Disease State
Donor
Preparative Regimen
Post-Transplantation Immunosuppression
Hematologic
malignanacies128
HLA-matched or mismatched
unrelated
PBPC or marrow
Fludarabine 30 mg/m2/day IV on 3 consecutive days (–4, –3, –2), TBI 2 Gy as single
fraction on day 0
Metastatic
renal cell124
0–1 HLA mismatched sibling
PBPC
Lymphoid
malignancies7
HLA-identical
PBPC or marrow
Various328
HLA-matched or mismatched
sibling or HLA-matched
unrelated
PBPC or marrow
HLA-matched sibling or unrelated
PBPC or marrow
CY 60 mg/kg/day IV on 2 consecutive days
(–7, –6), fludarabine 25 mg/m2/day IV on
5 consecutive days (–5, –4, –3, –2, –1) ATG if HLA mismatch
One of three different regimens with:
CY, followed by fludarabine daily for 3 days
or
CY for 2 days and fludarabine for 5 days or
Cisplatin for 4 days, fludarabine for 3 days,
and cytarabine for 2 days
Various regimens, with final one being:
Fludarabine 25 mg/m2/day IV for 5-days and
melphalan 90 mg/m2/day IV for 2 days
Cyclosporine 6.25 mg/kg PO BID, days –3 to
day 100 with taper from day 100 to
180
Mycophenolate mofetil 15 mg/kg PO BID, day
0 to 40 with taper from day 40 to 90
Cyclosporine 3 mg/kg/day IV (6 mg/kg/day
PO BID if tolerated), started day –4 and tapered based on the speed and degree of
donor cell engraftment
Tacrolimus 0.03 mg/kg/day IV, started day –2,
beginning taper day 90 if no GVHD present;
used alone or in combination with
methotrexate 5 mg/m2/day day 1, 3, 6
Various131
Various regimens, with the most common
one being:
Fludarabine 25–30 mg/m2/day IV for 5–6
days, busulfan 2 or 4 mg/kg/day for 2
days, ATG 2.5 mg/kg/day for 5 days
Tacrolimus to maintain blood concentration of
5–10 ng/mL with methotrexate 5 mg/m2/day
IV days 1, 3, 6, 11
Various regimens, cyclosporine, cyclosporine
in combination with methotrexate or cyclosporine in combination with corticosteroids
ATG, antithymocyte globulin; CY, cyclophosphamide; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; PBPC, peripheral blood progenitor cells; TBI,
total body irradiation.
HEMATOPOIETIC CELL TRANSPLANTATION
munosuppression, which substantially increases the risk of
bacterial infections, but, more important, fungal, viral, and
other opportunistic infections.135 The risk of infection increases as additional immunosuppressive therapy is incorporated to prevent or treat GVHD. Supportive strategies designed to minimize infection during immunosuppression are
essential after allogeneic HCT (see Infectious Complications
section in text that follows).
Comparison of Supportive Care Strategies Between
Allogeneic Myeloablative and Nonmyeloablative HCT
16. How do supportive care strategies used for myeloablative
and nonmyeloablative preparative regimens with an allogeneic
graft differ?
A direct comparison of the toxicities with a myeloablative
and nonmyeloablative preparative regimen is difficult because
NMT is offered only to patients who are not candidates for
myeloablative allogeneic HCT. These preparative regimens
differ substantially in terms of the chemotherapy agents used
(see Tables 92-4 and 92-6) and the degree of myelosuppression. NMT may have a different time pattern of infectious
complications and has a similar incidence and severity of
acute GVHD; however, comparisons between the preparative
regimens is challenging because of the differences in the preHCT health of the recipients.123 Clinical research within NMT
is focusing on designing optimal preparative regimens with
acceptable efficacy and toxicity (i.e., mixed chimerism, disease response). Thus, more variability is seen for immunosuppression after a NMT than for that following a myeloablative HCT (see Table 92-6).
Dose Calculations in Obesity
17. K.M. is a 36-year-old woman with CML in chronic phase.
After her initial diagnosis, a successful search for an unrelated
6/6 HLA–matched allogeneic donor was conducted. K.M. is being
admitted for myeloablative allogeneic BMT. Orders for K.M.’s
preparative regimen are written as follows: height, 162 centimeters; actual body weight (ABW), 80 kg; ideal body weight (IBW
54 kg; body surface area (BSA), 1.85 m2; body mass index (BMI),
30.5 kg/m2; busulfan, 16 mg/kg total dose to be administered over
4 days (1 mg/kg per dose PO Q 6 hr for 16 doses, days –9, –8, –7,
and –6). Cyclophosphamide 50 mg/kg IV to be administered on
days –5, –4, –3, and –2. Day –1 is a “rest” day, followed by infusion of bone marrow on day 0. Which weight should be used to
calculate doses of K.M.’s preparative regimen?
K.M.’s ABW is 48% over her ideal body weight. She is
considered obese since her ABW is 30% greater than her ideal
body weight and her BMI is between 27 to 35 kg/m2. Obesity
has numerous effects on the pharmacokinetic disposition of
medications; unfortunately, there is a paucity of data regarding the effects of obesity on the clinical outcomes of anticancer agents. The risk associated with inaccurate dosing of
the preparative regimen for a myeloablative HCT leaves a particularly challenging situation since using a weight that is too
high can cause lethal toxicity and one that is too low could result in inadequate marrow ablation or disease eradication.
Few studies have evaluated the association of body weight
and outcome to preparative regimens for myeloablative
•
92-13
HCT.136–138 Differing conclusions regarding optimal dose adjustment of oral busulfan were made from two small case series, with 16 and 20 patients, respectively.136,137 Busulfan’s apparent oral clearance (CL/F) expressed in relation to adjusted
ideal body weight (AIBW) or body surface area (BSA) was
similar in normal (BMI of 18 to 27 kg/m2) and obese patients
in a case series of 279 adolescent and adults undergoing
HCT.138 Thus, routine dosing of oral busulfan based on AIBW
or BSA does not require a specific accommodation for obesity.
K.M.’s busulfan dose should not be based on her ABW because it does not accurately correct for her obesity and may
predispose her to hepatic veno-occlusive disease (VOD). Her
initial busulfan doses should be based on AIBW or BSA.
Complications Associated With HCT
18. What is the nature of the toxicities associated with myeloablative preparative regimen that must be anticipated in K.M.?
Are they similar to those anticipated after standard-dose
chemotherapy?
Myelosuppression is a frequent dose-limiting toxicity for
antineoplastics when administered in conventional doses used
to treat cancer. However, because myelosuppression is circumvented with hematopoietic rescue in the case of patients
receiving HCT, the dose-limiting toxicities of these myeloablative preparative regimens are nonhematologic (i.e., extramedullary) in nature. The toxicities vary with the preparative regimen used.
Most patients undergoing HCT experience toxicities commonly associated with chemotherapy (e.g., alopecia, mucositis, nausea and vomiting, infertility). (Also see related information in Chapter 89, Adverse Effects of Chemotherapy.)
However, these toxicities are magnified in the HCT population. For example, mucositis often is severe enough to warrant
airway protection, preclude oral intake, and require IV opioids for pain control. Table 92-5 depicts a range of toxicities
that can occur after myeloablative preparative regimen for
HCT, and Figure 92-4 depicts the time course for complications after HCT. Specific toxicities are discussed in detail in
the following sections.
Busulfan Seizures
19. In addition to her preparative regimen, the following supportive care agents and monitoring parameters are prescribed
for K.M: on the day of admission (day –10), administer a phenytoin loading dose (10 to 15 mg/kg) orally in divided doses (300,
300, and 400 mg Q 3 hr). Continue 300 mg PO daily from days
–9 to –6. Busulfan pharmacokinetic blood sampling is to occur
after dose 1 to a target busulfan concentration at steady state
(Css) greater than 900 ng/mL. Begin normal saline hydration
3,000 mL/m2/day 4 hours before cyclophosphamide and continue
for 24 hours after the last cyclophosphamide dose. Mesna to be
given concurrently with cyclophosphamide as 10% of the cyclophosphamide dose administered intravenously (IV) 30 minutes before starting cyclophosphamide dose, then as 100% of cyclophosphamide dose administered as a continuous IV infusion
over 24 hours after each dose of cyclophosphamide. Beginning
on day –5, weigh patient twice daily, check fluid input and urinary output every 4 hours, and monitor urine for RBCs daily until 24 hours after the last cyclophosphamide dose. If urine output
Nausea
and
vomiting
Hemorrhagic
cystitis
Busulfaninduced
seizures
0
VOD
Days
Neutropenia
30
Time After Transplant
Hypertension°
Cardiotoxicity
Acute GVHD
Thrombocytopenia
Graft failure/graft rejection
Idiopathic interstital pneumonitis
CMV/adenovirus
HSV
Anemia
Aspergillosis
Candida
Bacterial infections
30
100
100
Months
Chronic GVHD
VZV
Encapsulated organisms
FIGURE 92-4 Complications after hematopoietic cell transplantation by time. aPatients undergoing allogeneic HCT only. CMV, cytomegalovirus;
GVHD, graft-versus-host disease; HSV, herpes simplex virus; VOD, veno-occlusive disease; VZV, varicella-zoster virus.
10
Noninfectious
Infectious
0
Cataracts
12
12
•
10
92-14
NEOPLASTIC DISORDERS
HEMATOPOIETIC CELL TRANSPLANTATION
drops below 300 mL over 2 hours, administer an IV bolus of 250
mL normal saline and give furosemide 10 mg/m2, not to exceed
20 mg IV. What is the rationale for these supportive care therapies and monitoring parameters prescribed for K.M. as they relate to busulfan therapy?
•
92-15
Seizures have been reported in both adult and pediatric patients receiving high-dose busulfan for HCT preparative regimens.139,140 Busulfan is highly lipophilic and crosses the
blood–brain barrier with an average CSF:plasma ratio of 0.95
after administration of high doses.141 Neurotoxicity appears to
be dose related, and the incidence of seizures is significantly
higher in children with an elevated CSF:plasma ratio.141 Although the exact incidence of busulfan-induced neurotoxicity
is unknown, 7.5% of 96 children experienced seizures during
or within 24-hours of completing busulfan.139
Anticonvulsants are used to minimize the risk of seizures.
Anticonvulsants are begun shortly before busulfan, with the
loading dose completed at least 6 hours before the first busulfan dose. Most centers monitor phenytoin concentrations after 2 days of dosing, particularly when using an oral regimen.
Oral loading and maintenance regimens are generally sufficient because target concentrations of 10 to 20 g/mL can be
achieved by the peak time of seizure risk. If patients are experiencing significant vomiting or are having difficulty maintaining therapeutic phenytoin concentrations, IV phenytoin
should be substituted for oral doses. Benzodiazepines such as
lorazepam or clonazepam have also been used for seizure prophylaxis during high-dose busulfan therapy before HCT.142
Antiseizure medications are usually discontinued 24 to 48
hours after administration of the last dose of busulfan.
Seizures can still occur despite the use of prophylactic anticonvulsants and usually do not result in permanent neurologic
deficits.
tween busulfan CSS and outcome with each patient population
and with each preparative regimen. Most studies have shown
a pharmacodynamic relationship in patients receiving the
BU/CY preparative regimens. Data are also represented as
area under the plasma concentration time curve (AUC) or CSS;
data are easily converted to CSS (CSS AUC divided by the
dosing interval). One must also pay close attention to the units
used in these studies. Results are expressed as M-min or
ng/mL; an AUC of 1,500 ng/mL is roughly equivalent to a CSS
of 1,025 ng/mL based on busulfan’s molecular weight of 246.
Hepatic VOD was observed more frequently in patients receiving BU/CY with a busulfan CSS 925 to 1,025 ng/mL. In
BU/CY regimens, busulfan CSS 600 ng/mL favor engraftment, although contradictory data exist. Higher busulfan concentrations (Css 900 ng/mL) were associated with lower relapse rates in adult CML patients receiving BU/CY before
HLA-matched grafts, without unacceptable rates of VOD.
Thus, a busulfan Css 900 ng/mL is targeted for K.M. because she has CML.
An intravenous busulfan product, Busulfex, was FDA approved in February 1999 in combination with cyclophosphamide as a preparative regimen before allogeneic HCT for
CML. The FDA-approved dose is 0.8 mg/kg IV every 6 hours
for 16 doses, which is similar to the oral busulfan dose of 1
mg/kg with a mean fraction absorbed (F) of 90%.148 Recent
data with Busulfex in combination with either cyclophosphamide or fludarabine suggest that therapeutic drug monitoring may be needed.150 In addition, the product labeling
states “high busulfan area under the plasma concentration
versus time curve (AUC) values (>1,500 M-min) may be associated with an increased risk of developing hepatic VOD)”
which also has caused many HCT centers to institute therapeutic drug monitoring after Busulfex is administered.
Adaptive Dosing of Busulfan
Hemorrhagic Cystitis
20. What dosing strategies can be used to minimize busulfan
toxicities?
21. What is the rationale for these supportive care therapies
and monitoring parameters prescribed for K.M. as they relate to
cyclophosphamide therapy?
The considerable interpatient variability in the clearance of
both oral and IV busulfan, along with the identified concentration–effect relationships, has led to the adaptive dosing of
busulfan. The clearance of Busulfex (IV busulfan) exhibited
interpatient variability adjusted for weight with a coefficient
of variation (CV, standard deviation/mean) of 25% in 59 patients.143 There is similar variability with oral busulfan, with
a CV of CL/F adjusted for actual body weight (mL/min per
kilogram) of 21% in 279 adult patients, the largest patient
population analyzed for busulfan pharmacokinetics.138
Weight, disease, and age are factors that may influence the
clearance of oral busulfan.138 Busulfan CL/F is enhanced in
young children (4 years old) compared with adults and
older children (>10 years old).144
Adjusting the busulfan dose to achieve a target concentration appears to minimize the toxicities of the BU/CY regimen,
particularly VOD while improving engraftment and relapse
rates.145–147 The pharmacodynamic relationships are briefly reviewed; more complete reviews of these relationships after
oral busulfan administration are available elsewhere.148,149
When reviewing pharmacodynamic data with busulfan, close
attention should be taken in their interpretation because of the
potential changes in the concentration–effect relationships be-
In HCT patients receiving cyclophosphamide, moderate to
severe hemorrhagic cystitis occurs in 4% to 20% receiving
hydration alone.151 The putative bladder toxin is acrolein, a
metabolite of cyclophosphamide.152 Consequently, a variety
of preventive measures are taken to lower the risk of hemorrhagic cystitis in HCT patients receiving cyclophosphamide.
The methods used include forced hydration with normal
saline or D5 normal saline 3,000 mL/m2 per day, continuous
bladder irrigation with normal saline 200 to 1,000 mL/hour
via a three-way Foley catheter, and/or concomitant use of the
uroprotectant, mesna. ASCO Guidelines for the Use of
Chemotherapy and Radiotherapy Protectants recommends the
use of mesna plus saline diuresis or forced saline diuresis to
lower the incidence of urothelial toxicity with high-dose cyclophosphamide in the setting of HCT.153
In three randomized controlled clinical trials, the efficacy
of mesna has been compared with forced hydration with or
without the addition of continuous bladder irrigation for prevention of cyclophosphamide-induced hemorrhagic cystitis in
HCT patients.151,154,155 Although the interpretation of their results is complicated by varying definitions of hematuria, all
three studies report similar or lower rates of hematuria (of any
92-16
•
NEOPLASTIC DISORDERS
grade or severity) in mesna-treated patients.151,154,155 However,
this difference was statistically significant in only two of these
studies.154,155 It is important to note that hematuria or hemorrhagic cystitis can occur despite the use of any of these methods.151,154,155 Thus, the decision to use one method over another
will depend on the relative merits of the various methods,
whether the patient will be receiving cyclophosphamide as an
inpatient or outpatient, and the preference of the HCT center
personnel.
Disadvantages of Foley catheter irrigation include intensive nursing time, patient dissatisfaction, and a higher incidence of microbiologically detected urinary tract infections.155 Furthermore, Foley trauma itself can cause mild
hematuria, which can confuse the diagnosis of cyclophosphamide-induced hemorrhagic cystitis.155 Concern that was
initially posed regarding delayed engraftment in mesnatreated patients154 has not been borne out in subsequent randomized trials.151,155 Also, a cost analysis comparing Foley
bladder irrigation with mesna demonstrated very little difference between the two methods when total costs, including
urine cultures and laboratory tests were compared.155
The optimal mesna dose with high-dose cyclophosphamide in preparation for myeloablative HCT is unknown. A
variety of different regimens have been used, including intermittent bolus dosing (mesna dose 20% to 40% of cyclophosphamide dose, administered for three or four doses) or continuous infusion regimens (mesna 80% to 160% of
cyclophosphamide dose).151,154,155 To date, there have been no
randomized, comparative trials evaluating the most effective
dose or method of administration. Mesna should be continued
for 24 to 48 hours after the last cyclophosphamide dose, such
that mesna is present within the bladder to donate free thiol
groups at the same time as the urotoxic metabolite acrolein.
After IV administration of mesna, most of it (i.e., 60% to
100%) is excreted within the urine over 4 hours.156 Cyclophosphamide has an average half-life of 7 hours after administration of 60 mg/kg,157 and acrolein may be present
within the urine for 24 to 48 hours after cyclophosphamide
administration.158
Thus, K.M. is receiving hydration with normal saline and
mesna, administered as a continuous infusion, to minimize
her risk of hemorrhagic cystitis due to cyclophosphamide.
K.M. should also be monitored for any RBC present in the
urine along with her urinary output to allow for rapid intervention if hemorrhagic cystitis occurs.
Chemotherapy-Induced Gastrointestinal Effects
22. What other end-organ toxicities must be watched for?
Should any medications be ordered for K.M. to prevent and
treat the gastrointestinal effects associated with myeloablative
therapy?
Preparative regimens for myeloablative HCT result in
other end-organ toxicities such as renal failure159 and idiopathic pneumonia syndrome.160 In addition, recipients of myeloablative preparative regimens are at risk for severe gastrointestinal toxicity, specifically chemotherapy-induced
nausea and vomiting (CINV) and mucositis. In this population, CINV can be due to administration of highly emetogenic
chemotherapy over several days, the administration of total
body irradiation, and also poor control of CINV prior to con-
sideration for HCT. Thus, patients such as K.M. who are undergoing a myeloablative HCT should be treated with a serotonin antagonist plus a corticosteroid.161 Higher doses of serotonin antagonists may be necessary in the patient
population161,162 ; however, few randomized trials have been
conducted in this area and most of the information comes
from case series.162 Recent data suggest that ondansetron may
increase cyclophosphamide clearance in breast cancer patients undergoing a myeloablative HCT163,164; however, further
work is needed to identify the clinical implications of this
finding because, to date, cyclophosphamide concentrations
have not been consistently associated with clinical outcomes
in patients undergoing a myeloablative HCT.165,166 In patients
who do not have thrombocytopenia, electropuncture may also
be beneficial when used in conjunction with antiemetics.167 In
addition, severe mucositis may require parenteral opioid analgesics for pain relief168 and total parenteral nutrition to prevent the development of nutritional deficits (see Chapter 9,
Pain, and Chapter 37, Adult Parenteral Nutrition).
Myelosuppression and Growth Factor Use
23. An order is written to begin filgrastim on day 0 and to continue administration until the ANC has recovered to 500/mm3 for
2 consecutive days. Is this therapy appropriate for K.M.?
Primary administration of the HGFs filgrastim and sargramostim accelerate neutrophil recovery and lower costs after allogeneic HCT with a bone marrow or umbilical cord
graft.169,170 Fear of exacerbating GVHD by stimulating macrophage production (hence, tumor necrosis factor [TNF], a
cytokine implicated in the pathogenesis of GVHD) initially
limited the use of sargramostim. Enhanced GVHD has been
reported with sargramostim after allogeneic BMT in a small
number of patients.171 In contrast, other trials have failed to
substantiate this concern.62,63 In a phase III trial, patients receiving sargramostim after allogeneic HCT experienced more
rapid neutrophil recovery, less severe mucositis, and fewer
days in the hospital compared with patients receiving
placebo.169 No difference in the incidence of GVHD, relapse,
or survival was observed among groups. Filgrastim also has
been evaluated in the allogeneic setting and has hastened neutrophil recovery without increasing the incidence of
GVHD.172
The use of HGFs after infusion of allogeneic PBPC is controversial. Administration of HGFs may not provide further
acceleration of hematopoietic recovery after PBPC infusion
because large numbers of progenitor cells can be obtained and
the number of progenitor cells correlate with hematopoietic
recovery in the this setting. However, hematopoietic recovery
may be hindered by proliferation of stem and progenitor cells
by HGFs being concomitantly administered with methotrexate, which is used after myeloablative allogeneic HCTs for
GVHD prophylaxis.27 There is concern that HGFs will increase the risk of GVHD as filgrastim administration after
PBPC is associated with abnormal antigen-presenting cell
function and T-cell reactivity.173–175 Nevertheless, preliminary
data indicate that filgrastim accelerates neutrophil recovery
compared with placebo in patients receiving PBPCT with no
differences in the incidence of acute GVHD, although the trials were not powered to address this specific issue.176,177 The
ASCO Guidelines do not specifically recommend filgrastim
HEMATOPOIETIC CELL TRANSPLANTATION
in regard to allogeneic PBPC, but states that HGF “are recommended to help mobilize PBPC and after PBPC infusion”
without consideration for the donor type.43 K.M. is receiving
a bone marrow graft, and thus can receive filgrastim starting
on day 0.
Veno-Occlusive Disease of the Liver
24. K.M.’s pretransplantation admission laboratory values
are within normal limits. Her weight on admission is 80 kg. During the first 5 days after marrow infusion, K.M.’s weight begins
to increase by approximately 0.5 kg/day, her inputs exceeding
her outputs by about 500 to 1,000 mL/day, and she is mildly
febrile with an axillary temperature of 38°C. Blood and urine
cultures are all negative. On day 6 her weight is 85 kg. Laboratory values drawn on day 7 are significant for a total bilirubin of 1.5 mg/dL, an aspartate aminotransferase (AST) of 40 U/L
(normal, 0 to 45), and an alkaline phosphatase of 120 U/L (normal, 30 to 120). By day 10, K.M. is complaining of midepigastric and right upper quadrant pain and a liver that is tender to
palpation. Over the next few days, K.M. begins to look icteric.
Her liver function tests continue to rise slowly, until day 18
when they reach the following peak values: total bilirubin 5.0
mg/dL (normal, 0.1 to 1), AST 150 U/L, and alkaline phosphatase 180 U/L. On day 18, K.M.’s weight is 90 kg. “Rule out
VOD of the liver” is listed on her problem list in the medical
record. What is VOD?
[SI units: total bilirubin, 25.65 and 85.5 mol/L, respectively; AST, 0.67 and
2.5 kat/L, respectively; alkaline phosphatase, 2.0 and 3.0 kat/L, respectively]
Hepatic VOD (veno-occlusive disease) is a life-threatening
complication that may occur secondary to preparative regimens or radiation used in myeloablative HCT with an autologous or allogeneic HCT or in nonmyeloablative HCT.128,178,179
Considerable variability exists in the incidence of VOD, with
larger case series suggesting the incidence ranges from 5.3%
to 54%.179,180 Although the pathogenesis is not understood
completely, several mechanisms have been proposed. The key
event appears to be endothelial damage caused by the preparative regimen. Since recent studies have shown that the primary site of the toxic injury is the sinusoidal endothelial cells,
the term “sinusoidal obstruction syndrome (SOS)” has been
proposed to use in place of “VOD.”181 The endothelial damage
initiates the coagulation cascade, induces thrombosis of the
hepatic venules, and eventually leads to fibrous obliteration of
the affected venules.180 The cardinal histologic features are
marked sinusoidal fibrosis, necrosis of pericentral hepatocytes, and narrowing and eventual fibrosis of central veins.181
In patients with VOD, early microscopic changes include
subendothelial swelling leading to several physiologic
changes, including narrowing of hepatic venules and necrosis
of centrizonal hepatocytes.180
CLINICAL PRESENTATION
25. What signs and symptoms in K.M. are consistent with a
diagnosis of VOD?
The signs and symptoms associated with VOD are hyperbilirubinemia (2 mg/dL), weight gain (>5% above baseline), hepatomegaly, azotemia, elevated alkaline phosphatase,
ascites, elevated AST, and encephalopathy.182 Insidious weight
•
92-17
gain exceeding 5% of baseline usually is the first manifestation of impending VOD, occurring in over 90% of patients
within 3 to 6 days after marrow infusion.179 Weight gain is
caused by sodium and water retention, as evidenced by decreased renal sodium excretion. This usually is distinguished
from cyclophosphamide-induced syndrome of inappropriate
secretion of antidiuretic hormone by the time course relative
to administration of the preparative regimen. Hyperbilirubinemia, which also occurs in virtually all patients, follows
the onset of weight gain and usually appears within 10 days
after hematopoietic cell infusion. In over half of the patients,
the peak bilirubin concentration is 6 mg/dL. Other liver
function test abnormalities usually occur after hyperbilirubinemia and include elevations in AST and alkaline phosphatase. Ascites, right upper quadrant pain, and encephalopathy lag behind changes in liver function tests and develop
within 10 to 15 days after infusion of hematopoietic cells.179
A clinical diagnosis of VOD is made when two of the following features occur within the first 20 days of HCT: (1) hyperbilirubinemia (total serum bilirubin 2 mg/dL), (2) hepatomegaly or right upper quadrant pain, and (3) sudden
weight gain.179 To make a clinical diagnosis of VOD, the features listed previously must occur without other causes of
post-transplantation liver failure, including GVHD, viral hepatitis, fungal abscesses, and drug reactions. A clinical diagnosis can be confirmed histologically via liver biopsy.
In summary, the signs and symptoms consistent with VOD
in K.M. include insidious weight gain, hyperbilirubinemia,
and right upper quadrant pain. The onset and timing of these
signs and symptoms are consistent with VOD and occurred
without other causes of hepatic toxicity.
PREVENTION AND TREATMENT
26. What is the likelihood that K.M. will recover from her
VOD? How should she be treated?
The overall mortality for patients who develop VOD is approximately 50% and is correlated with the onset and severity
of disease.179,182 For example, patients with early weight gain,
severely elevated bilirubin and/or AST, and encephalopathy
are more likely to die of VOD when compared with patients
with mild elevations of liver function tests and no encephalopathy.182 Mortality for patients with severe VOD exceeds 90% and usually is accompanied by multiorgan system
failure.179
Several case series have focused on identifying risk factors
and algorithms predicting VOD risk in hopes of preventing
this condition or its progression through early treatment.183
Although various risk factors have been identified, their association is variable and conflicting reports of their association
can be found. Risk factors identified before administration of
the preparative regimen include a mismatched or unrelated
graft, cyclophosphamide administration, increased transaminases before HCT, and a history of hepatitis.180 The administration of intravenous immunoglobulin (IVIG) does not appear to be associated with VOD after BMT.184 Interpatient
variability in the metabolism and clearance of the chemotherapy used within the preparative regimen may also be associated with a poor outcome, although the relationships vary
within the various preparative regimens.148,185 The association
of VOD with busulfan concentrations is discussed in Adaptive
92-18
•
NEOPLASTIC DISORDERS
Dosing of Busulfan in this chapter. Preliminary data suggest
that IV busulfan may be associated with a lower risk of VOD,
although more data are needed.186 More recently, VOD risk
has been associated with elevated concentrations of a metabolite of cyclophosphamide, carboxyethylphosphoramide mustard (CEPM), in patients receiving the CY/TBI preparative
regimen.166 Elevations in plasminogen activator inhibitor-1
antigen has been associated with the occurrence and severity
of VOD and may also be used as a diagnostic marker for
VOD.187
In addition, pharmacologic methods to prevent VOD have
been evaluated. Although initial data were positive, VOD is
not prevented by pentoxifylline, which is thought to inhibit
production of TNF- from monocyte-macrophages.188,189
Prostaglandin E1 (PGE1) appeared promising initially but further data demonstrated considerable toxicity.190 Results of
clinical trials evaluating low-dose unfractionated heparin or
low-molecular-weight heparin as VOD prophylaxis have not
been consistent. The efficacy of ursodiol combined with unfractionated heparin is equivalent to heparin alone; thus, the
use of this combination is not recommended as prophylaxis
for VOD.191,192 Single-agent ursodiol (600 mg/day PO) has
been associated with a lower incidence of VOD,193,194 or with
a lower frequency of total serum bilirubin 3 mg/dL.195 Ursodiol, which is a bile acid, has also been associated with a decreased incidence of severe acute GVHD and a greater 1-year
survival relative to placebo.195 However, more evidence is
needed because this finding has not been consistent.194 Based
on these data, the use of single-agent ursodiol, at a dose of
600 mg PO daily, is recommended for VOD prophylaxis.
The mainstay of treatment for established VOD is supportive care aimed at sodium restriction, increasing intravascular
volume, decreasing extracellular fluid accumulation, and minimizing factors that contribute to or exacerbate hepatotoxicity
and encephalopathy. Thus, volume expanders such as albumin
and colloids may be used to maintain intravascular volume;
spironolactone may be used to minimize extravascular fluid
accumulation; and protein restriction and lactulose may be
used if encephalopathy develops. Unfortunately, improved
outcomes with these measures have not been confirmed. In
addition, avoidance of central nervous system–active drugs, if
possible, helps provide an accurate assessment and interpretation of the patient’s mental status.
Because mortality after development of severe VOD exceeds 90%179 and available treatment options are limited, investigational alternatives are being sought. Although positive
data emerged from a pilot study, recombinant human tissue
plasminogen activator (rh-TPA) with heparin has not proved
beneficial for the treatment of established severe VOD.196 Defibrotide, an investigational new drug, has shown promising
results in the treatment of VOD.197–199 Defibrotide, a ribonucleotide, has antithrombotic, anti-ischemic, and thrombolytic
activity without producing significant systemic anticoagulation. In a compassionate-use trial of 88 patients with severe
VOD and associated organ dysfunction, 36% of patients had
complete resolution of VOD and 35% survived past day 100
after HCT.199 Numerous predictors of survival were observed.
Younger patients and those who received an autologous graft
were more likely to have better outcomes, whereas those who
received a busulfan-based preparative regimen had worse outcomes. A decrease in plasminogen activator inhibitor-1 con-
centrations and serum creatinine during defibrotide treatment
predicted better survival as well. A prospective phase II study
of defibrotide (25 versus 40 mg/kg/day) is ongoing.
Since K.M. does not meet the criteria for severe VOD, she
should be managed conservatively with fluid restriction and
spironolactone. Her signs and symptoms should resolve over
the next 2 weeks. Because she has mild VOD, she has a 50%
chance of recovering completely without sequelae.
Graft Failure
28. E.R. is a 65-year-old woman diagnosed with AML in first
remission. After her initial diagnosis, a successful search for an
unrelated completely HLA matched unrelated donor was conducted. E.R. will receive a nonmyeloablative allogeneic HCT using PBPC. E.R.’s preparative regimen orders are written as follows: fludarabine 30 mg/m2 per day on days –4, –3 and –2 and 2
Gy total body irradiation on the day of PBPC infusion with postgrafting cyclosporine and mycophenolate mofetil.
It now is day 40, and E.R.’s CBC reveals the following:
WBC count, 0.1 cells/mm3 (normal, 3,200 to 9,800); no granulocytes or monocytes detected on differential; platelets
18,000/mm3 (normal, 130,000 to 400,000), and Hct, 22% (normal, 33% to 43%). A bone marrow biopsy reveals a hypocellular
bone marrow with no evidence of leukemic infiltrates. What is
E.R. experiencing and how should she be treated?
Engraftment usually is evident within the first 30 days in
patients undergoing a NMT with this preparative regimen;
however, rejection can occur after initial engraftment.6 Because E.R. has no evidence of engraftment by day 40, she
most likely is experiencing primary graft failure.
Graft rejection is defined as the lack of functional
hematopoiesis after HCT1,2 and is classified as primary graft
failure (failure to engraft) or graft failure. With a myeloablative preparative regimen, primary graft failure is more likely
to occur after autologous HCT. In these patients, the likelihood of graft failure is increased with intense prior
chemotherapy, residual malignancy in grafts from patients
with leukemias or lymphomas, or use of ex vivo purging
methods. In myeloablative allogeneic HCT, graft rejection is
less common because the donor PBPC or marrow is unmanipulated and free from the toxic effects of prior chemotherapy.1,2 However, a delicate balance between host and donor effector cells is necessary, and residual host-versus-graft effects
may lead to graft rejection. The incidence of graft rejection is
higher in patients with aplastic anemia and in patients undergoing HCT with histoincompatible marrow or T cell–depleted
marrow.1,2 Graft rejection is uncommon in leukemia patients
receiving myeloablative preparative regimen with a histocompatible allogeneic donor.
Therapeutic options for the treatment of graft rejection or
graft failure are limited. A second HCT is the most definitive
therapy, although the toxicities are formidable.200 Graft rejection is best managed with immunosuppressants such as antithymocyte globulin. Primary graft failure occasionally can
be treated successfully using hematopoietic growth factors,
although patients who received purged autografts are less
likely to respond.201,202
E.R. has primary graft failure. Although she has no evidence of residual leukemia, she has a history of extensive
prior chemotherapy and has received an allogeneic NMT. The
HEMATOPOIETIC CELL TRANSPLANTATION
role of a second NMT is not well studied, and E.R. is not a
candidate for a myeloablative preparative regimen followed
by an allogeneic graft. Thus, a trial of filgrastim 5 g/kg per
day is an option. E.R.’s hematopoietic function should be
monitored with daily CBCs and a bone marrow biopsy every
2 weeks. Two to three weeks of therapy often is necessary before engraftment is noted.
Graft-versus-Host Disease
GVHD is divided into two forms (i.e., acute or chronic) based
on clinical manifestations and an arbitrarily designated time
relative to day 0 of HCT. GVHD can occur after allogeneic
HCT regardless of the preparative regimen used. The vast majority of the data regarding the prevention and treatment of
GVHD have been obtained after myeloablative preparative
regimens. Therefore, this section refers only to trials conducted in recipients of a myeloablative allogeneic HCT.
Acute GVHD is a clinical syndrome affecting primarily the
skin, liver, and gastrointestinal (GI) tract and usually occurs in
the first 100 days after allogeneic HCT. In contrast, chronic
GVHD can affect almost any organ system, closely resembles
several autoimmune diseases, and usually occurs after day 100.
Immune-mediated destruction of tissues, a hallmark of
GVHD, disrupts the integrity of protective mucosal barriers
and thus provides an environment that favors the establishment of opportunistic infections. The combination of GVHD
and infectious complications are leading causes of mortality
for allogeneic HCT patients.
Acute Graft-versus-Host Disease
RISK FACTORS
29. M.P., a 22-year-old, 70-kg man, undergoes a one-antigen
mismatched allogeneic HCT from his sister for the diagnosis of
CML in chronic phase. After a preparative regimen of cyclophosphamide and TBI, the following immunosuppressive regimen is ordered: Cyclosporine 1.5 mg/kg IV Q 12 hr from days
–1 until tolerating oral medications, then switch to cyclosporine
(Neoral) 4 mg/kg PO Q 12 hr until day 50. Methotrexate 15
mg/m2 IV on day 1, then 10 mg/m2 day 3, 6, and 11. What
factors are associated with an increased risk of acute GVHD?
The single most important factor associated with the development of GVHD is the degree of histocompatibility between donor and recipient. Clinically relevant grade II–IV
acute GVHD occurs in 20% to 50% of HLA-matched sibling
grafts and 50% to 80% of HLA-mismatched sibling or HLAidentical unrelated donors.203 The pathophysiology for acute
GVHD in the setting of well-matched grafts is unclear.204 In
addition, the onset of acute GVHD is earlier and severity is
increased in mismatched grafts relative to matched grafts and
also in matched unrelated donors relative to matched sibling
donors.79,205 Other factors that consistently increase the risk of
developing acute GVHD include increasing recipient or
donor age (older than 20 years), female donor to a male recipient, and previous recipient infections with herpesvirus.79,203 T-cell depletion and receipt of an umbilical cord
blood graft lower the risk of acute GVHD.101–104,133
M.P. is receiving allogeneic bone marrow from a female
sibling donor that is mismatched at one HLA antigen. These
two factors increase his risk of developing acute GVHD.
•
92-19
CLINICAL PRESENTATION
30. On day 14, the time at which engraftment occurred,
M.P. is noted to have a diffuse macular papular rash on his arms,
hands, and front trunk. He does not have diarrhea, and his liver
function tests are within normal limits. At the onset of his rash,
M.P.’s empiric antibiotics are changed from cefepime to
imipenem. Despite the change in antibiotics, M.P.’s rash persists.
How is M.P.’s presentation consistent with acute GVHD?
The primary targets of immune-mediated destruction of host
tissue by donor lymphocytes in acute GVHD are the skin, liver,
and GI tract.203 Acute GVHD of the skin usually manifests as a
diffuse maculopapular rash that starts on the palms of the hands
or soles of the feet or behind the ears. In more severe cases, skin
GVHD can progress to a generalized total body erythroderma,
bullous formation, and skin desquamation.1,2 In patients with
acute GVHD of the GI tract, persistent nausea and anorexia may
be early signs.206 Watery or bloody diarrhea also occurs, which
can result in electrolyte abnormalities, dehydration, or ileus in
severe cases can occur. Clinical manifestations of liver GVHD
include, primarily, elevated bilirubin but may also include increased alkaline phosphatase and hepatic transaminases, which
can progress to fulminant hepatic failure. Acute GVHD usually
is not evident until the time of engraftment, when donor lymphoid elements begin to proliferate. The skin usually is the first
organ to be involved. The onset of liver or GI GVHD usually
lags behind the onset of skin GVHD by approximately 1 week
and infrequently occurs without skin GVHD.1,2
Acute GVHD must be distinguished accurately from other
causes of skin, liver, or GI toxicity in the HCT patient. For example, a maculopapular rash, which may occur as a manifestation of an allergic reaction to antibiotics, usually begins on
the trunk or upper extremities and rarely presents on the
palms of the hands or soles of the feet. Diarrhea can be caused
by chemotherapy, radiation, infection, or antibiotic therapy.
However, diarrhea caused by the preparative regimen is rarely
bloody and usually resolves within 3 to 7 days after discontinuation of drugs and radiation. Diarrhea caused by infectious agents such as Clostridium difficile or CMV should be
distinguished from GVHD. Liver GVHD must be distinguished primarily from VOD and, to a lesser extent, hepatitis
induced by drugs, blood products, or parenteral nutrition. Although liver function test abnormalities between these syndromes are similar, liver GVHD rarely is associated with insidious weight gain or right upper quadrant pain. A tissue
biopsy of the affected organ in conjunction with clinical evidence is the only way to definitively diagnose acute GVHD.
Acute GVHD is associated with characteristic histologic
changes to affected organs.1,2 A staging system based on clinical criteria is used to grade acute GVHD. The severity of organ involvement is determined first (Table 92-7), and then an
overall grade is established based on number and extent of involved organs (Table 92-8).1,2
M.P. developed a rash at the time of engraftment that could
have been consistent with either an antibiotic-induced rash or
acute GVHD. Although it was appropriate to change antibiotics, the fact that M.P.’s rash did not improve is suggestive of
acute GVHD. M.P.’s rash is present on 36% of his body, but
because there are no signs of GI or liver involvement at this
time, M.P. is likely to have grade I GVHD (see Tables 92-7
and 92-8).
92-20
•
NEOPLASTIC DISORDERS
Table 92-7
Proposed Clinical Staging of Graft-versus-Host Disease According to Organ System
Stage
Skin
Liver
Intestinal Tract
Maculopapular rash
25% of body surface
Maculopapular rash
25–50% body surface
Generalized erythroderma
Generalized erythroderma with
bullous formation and desquamation
Bilirubin 2–3 mg/dL
>500 mL/day diarrhea
Bilirubin 3.1–6 mg/dL
>1,000 mL/day diarrhea
Bilirubin 6.1–15 mg/dL
Bilirubin 15 mg/dL
>1,500 mL/day diarrhea
>2,000 mL/day diarrhea or severe abdominal pain with
or without ileus
Reprinted with permission from Thomas ED et al. Bone-marrow transplantation. N Engl J Med 1975;292:895. Copyright © 2003 Massachusetts Medical Society. All rights reserved.
Table 92-8 Overall Clinical Grading of Severity
of Graft-versus-Host Disease
Grade
Degree of Organ Involvement
I
to skin rash; no gut involvement; no liver involvement;
no decrease in clinical performance
to skin rash; gut involvement or liver involvement (or both); mild decrease in clinical performance
to skin rash; to gut involvement or to liver involvement (or both); marked decrease in
clinical performance
Similar to grade III with to organ involvement
and extreme decrease in performance status
II
III
IV
Reprinted with permission from Thomas ED et al. Bone-marrow transplantation. N
Engl J Med 1975;292:895. Copyright 2003 Massachusetts Medical Society. All
rights reserved.
IMMUNOSUPPRESSIVE PROPHYLAXIS
31. Why did M.P. receive prophylactic immunosuppressive
therapy with cyclosporine and methotrexate?
GVHD is a leading cause of morbidity and mortality after
allogeneic HCT. Thus, efforts have focused on identifying
prophylactic measures for GVHD, with two approaches having been taken. The first and most common method is to administer post-transplantation immunosuppressive therapy that
successfully minimizes GVHD risk but is also associated with
toxicity. The second approach involves T-cell–depletion,
which was more fully discussed in the T-Cell Depletion section above.
Initially, acute GVHD was prevented with single-drug
therapy using antithymocyte globulin (ATG), cyclophosphamide, methotrexate, or cyclosporine.207–209 ATG binds nonspecifically to mononuclear cells and depletes hematopoietic
progenitor cells in addition to lymphocytes; consequently,
ATG is rarely used for fear of a high incidence of graft failure.207 In most patient populations, randomized comparative
trials have documented the superiority of combination immunosuppressive therapy for cyclophosphamide, methotrexate, or cyclosporine.210,211 However, in patients with acute
leukemia who are at high risk of relapse, combination immunosuppression was associated with an early decrease in
mortality from acute GVHD but an increase in late mortality
due to an increased incidence of leukemic relapse.211 This is
most likely due to the GVT effect mediated in conjunction
with acute GVHD, since an inverse relationship between
Table 92-9
Drug
Regimens of Prophylaxis of Acute GVHD
Dosing Examples
Single Agent
Methotrexate1,2
ATG207
Cyclosporine208
15 mg/m2 IV, day 1
10 mg/m2 IV, days 3, 6, 11
15 mg/kg every other day for 6 doses
1.5 mg/kg IV or 6.25 mg/kg (Sandimmune) PO Q
12 hr, days –1 to 50, then taper 5% per week and
discontinue by day 180
Combination Therapy
Cyclosporine/
short-term
methotrexate209
Tacrolimus/
short-term
methotrexate134
Cyclosporine/
methotrexate/
prednisone215
Same doses as listed for single agents
Tacrolimus 0.03 mg/kg/day continuous IV infusion
or 0.12 mg/kg/day PO BID
Methotrexate as above
Cyclosporine 5 mg/kg/day IV continuous infusion,
day –2 to 3, then 3–3.75 mg/kg IV until day
35; then 10 mg/kg/day (Sandimmune) PO,
dose adjusted to cyclosporine concentrations (via
RIA) of 200–600 ng/mL. Taper by 20% Q 2 wk;
then discontinue by day 180
Methotrexate 15 mg/m2 IV day 1, 10 mg/m2 IV
day 3, 6
Methylprednisolone 0.5 mg/kg/day IV, day 7 until day 14, then 1 mg/kg/day IV until day 28,
then prednisone 0.8 mg/kg/day PO until day
42, then taper slowly and discontinue by day
180
ATG, antithymocyte globulin; GVHD, graft-versus-host disease.
acute GVHD and leukemic relapse has been observed.5 Patients with acute leukemias at high risk for relapse may receive single-agent prophylaxis for acute GVHD because the
development of some acute GVHD may facilitate a GVT effect.
A variety of two- and three-drug combination immunosuppressive regimens have been used for prophylaxis against
GVHD (Table 92-9). Methotrexate, cyclosporine or
tacrolimus, and corticosteroids are the agents most commonly
incorporated into combination immunosuppressive regimens.
Although the most widely published regimen is short-course
methotrexate plus cyclosporine (Seattle regimen),209 there is
no national consensus with regard to the most effective regi-
HEMATOPOIETIC CELL TRANSPLANTATION
men. Methotrexate is administered up to day 11, although
the incidence of acute GVHD is reduced when the duration of
therapy is increased (59% compared with 25% incidence with
methotrexate administered to day 102).212 The combination
of tacrolimus and short-course methotrexate has been compared with cyclosporine plus short-course methotrexate in
patients undergoing allogeneic HCT using HLA-matched
siblings213,214 and unrelated donors.134 Recipients of matchedsibling grafts treated with tacrolimus had a lower incidence of
grade II to IV acute GVHD but a similar incidence of chronic
GVHD.213 Overall survival was lower in the tacrolimus group
as a result of more toxic deaths in patients with advancedstage disease; however, a higher number of advanced stage
disease patients in the tacrolimus/methotrexate group make
the results of this trial somewhat difficult to determine.213
Subsequently, the IBMTR conducted a matched control
study that suggested that the survival difference between the
two arms was in fact due to the imbalance in the underlying
risk factors.214 In patients receiving HLA-matched or slightly
mismatched unrelated grafts, those given tacrolimus had a
lower incidence of grade II to IV acute GVHD, a similar incidence of chronic GVHD and similar disease-free and overall
survival rates.134 Patients with advanced hematologic malignancies were excluded from this study. Both regimens are currently used in allogeneic HCT after myeloablative preparative
regimens. Several studies have compared triple-drug with
two-drug immunosuppression. The incidence of acute GVHD
has been similar or lower with triple-drug regimens, but infectious complications are higher and overall survival is similar to two-drug regimens.215,216 Three-drug immunosuppression regimens are still being evaluated and are used mainly in
mismatched or unrelated allogeneic HCT, where the risk of
acute GVHD is increased.
M.P. received acute GVHD prophylaxis with a two-drug
regimen of short-course methotrexate and cyclosporine. This
regimen is effective for the prophylaxis of acute GVHD in
CML patients undergoing allogeneic HCT.217
32. What principles are used in dosing medications used for
acute GVHD prophylaxis?
Although the various combination immunosuppressive regimens vary slightly by drug, dose, and combination, several
guidelines are consistent throughout all the regimens. First, cytotoxic agents used in combination for prophylaxis of acute
GVHD (e.g., methotrexate, cyclophosphamide) are withheld
or given in reduced doses if mucositis or myelosuppression is
severe.209,215 Methotrexate for GVHD prophylaxis can delay
engraftment, increase the incidence and severity of mucositis
and cause liver function test elevations. The methotrexate dose
is reduced in the setting of renal or liver impairment.204
The calcineurin inhibitors (i.e., cyclosporine, tacrolimus)
should be initiated before or immediately after donor cell infusion (day –1 or 0) when used for GVHD prophylaxis. This
schedule is recommended because of the known mechanism
of action of cyclosporine (see Chapter 35, Solid Organ Transplantation), which entails blocking the proliferation of cytotoxic T cells by inhibiting production of helper T-cell–derived
IL-2. Administering cyclosporine before the donor cell infusion allows inhibition of IL-2 secretion to occur before a rejection response has been initiated.
•
92-21
Cyclosporine usually is administered intravenously until
the GI toxicity from a myeloablative preparative regimen has
resolved (e.g., for 7 to 21 days).209 This is because GI effects
of the preparative regimen (e.g., CINV, diarrhea) and GVHD
affect the oral absorption of microemulsion cyclosporine and
may result in inconsistent blood concentrations.218 Most centers have switched the standard oral formulation of cyclosporine to the new microemulsion formulation, Neoral, or
to other new generic microemulsion formulations that have
improved bioavailability. When the old formulation is used
(i.e., Sandimmune) a ratio of 1:4, IV to oral, is commonly
used when converting IV therapy to oral. With the Neoral
formulation, a ratio of 1:2 or 1:3 is used. The most common
ratio used when converting tacrolimus from IV to oral is 1:4.
Different conversion ratios for IV to oral regimens may be
used when patients are receiving concomitant medications
that affect cytochrome P450 3A or P-glycoprotein, which are
involved in the metabolism and transport of the calcineurin
inhibitors (e.g., itraconazole). Thus, careful monitoring for
drug interactions with the calcineurin inhibitors is warranted.219
The dose of cyclosporine or tacrolimus is adjusted based
on serum drug levels and the serum creatinine (SrCr) concentration. Doses usually are reduced by 50% if the SrCr concentration doubles above baseline and are withheld for SrCr
concentrations 2 mg/ dL.209,217 Although the calcineurin inhibitors do not contribute to myelosuppression, common adverse effects to these agents include neurotoxicity, hypertension, and/or nephrotoxicity (which may lead to an impaired
clearance of methotrexate).
When corticosteroids are added to combination immunosuppressive regimens, they usually are withheld until engraftment is expected (7 to 14 days after marrow infusion). Administering corticosteroids earlier in the post-transplantation
period (e.g., day 0) paradoxically increases the incidence of
GVHD when used in combination with methotrexate and cyclosporine.220 Corticosteroids are associated with several adverse effects, including infectious complications, hyperglycemia and an increased incidence of hypertension when
used in combination with a calcineurin inhibitor.
Tapering schedules for cyclosporine or tacrolimus and corticosteroids vary widely between institutions. The general
goal is to keep calcineurin inhibitor doses stable to day 50,
and then slowly taper with the intent of discontinuing all immunosuppressive agents by 6 months after HCT. By this time,
immunologic tolerance has developed, and patients no longer
require immunosuppressive therapy.
ADAPTIVE DOSING OF CALCINEURIN INHIBITORS
32. On day 18, a cyclosporine level is drawn right before the
morning dose and is reported to be 150 ng/mL (by radioimmunoassay [RIA]). Why are cyclosporine levels being obtained
for M.P.?
The role of pharmacokinetic monitoring of cyclosporine in
HCT patients is not well defined. An association between cyclosporine concentrations and acute GVHD was not found in
early studies, however, other studies have suggested that cyclosporine trough concentrations less than 200 ng/mL are associated with an increased risk of acute GVHD.221,222 Pharmacokinetic monitoring may play a more important role in
92-22
•
NEOPLASTIC DISORDERS
minimizing the risk of cyclosporine-induced nephrotoxicity.
Cyclosporine trough concentrations 400 ng/mL (via RIA
and high-pressure liquid chromatography assay) are associated with a higher incidence of nephrotoxicity in some series.223 However, it is important to note that cyclosporineinduced nephrotoxicity can occur despite low or normal concentrations of cyclosporine and may be a consequence of
other drug- or disease-related factors known to influence the
development of nephrotoxicity (e.g., genetic risk factors, concurrent use of other nephrotoxic agents, sepsis).
Thus, it is reasonable to adjust doses to maintain cyclosporine trough concentrations between 200 to 400 ng/mL
in patients undergoing allogeneic HCT with a myeloablative
preparative regimen. Recommendations for dose adjustments
should be based on cyclosporine concentrations and SrCr
concentration. Dosage adjustments should be made for SrCr,
regardless of cyclosporine concentration, as recommended
previously. No standard dosage adjustment schedule exists,
but most centers adopt their own standardized approach. M.P.
has a normal SrCr, and his cyclosporine level is 200 ng/mL.
Therefore, his cyclosporine dosage should be increased.
Pharmacokinetic monitoring of tacrolimus is more defined
in terms of target concentrations. In general, desired trough
concentrations are in the range of 5 to 15 ng/mL. Tacrolimus
concentrations 20 ng/mL have been associated with increased risk of toxicity, primarily nephrotoxicity.224,225 Adjustments in tacrolimus dosing for increased SrCr should be made
in a manner similar to that described for cyclosporine.
INVESTIGATIONAL THERAPIES FOR PROPHYLAXIS
33. What other therapies have been proposed for the prophylaxis of acute GVHD?
The role of intravenous immunoglobulin (IVIG) in the prevention of GVHD is controversial. Two large studies noted a
relationship between administration of immunoglobulins and
a decreased prevalence of acute GVHD, with the most benefit
observed in patients younger than 20 years of age.226,227 Administration of immunoglobulin throughout the first year after
allogeneic HCT has not reduced post-transplantation complications or chronic GVHD and may actually impair humoral
immunity.228 Given the multitude of other factors that influence the development of acute GVHD, it is unlikely that minimal differences between products would result in major differences in the incidence of acute GVHD. Although patients
with acute GVHD have been shown to have increased levels
of circulating TNF-, two clinical trials evaluating pentoxifylline as a means of decreasing circulating TNF- levels and
thereby preventing GVHD have not shown beneficial effects.188,229 Investigational agents being considered for prophylaxis of acute GVHD include high-affinity IL-2 receptor
antibodies (i.e., daclizumab, basiliximab), mycophenolate
mofetil (MMF), sirolimus, CTLA4Ig and monoclonal antibodies against CD40 ligand, and GLAT.204,230,231 The role of
these agents is yet to be defined.
TREATMENT OF ESTABLISHED ACUTE GRAFT-VERSUS-HOST DISEASE
34. On day 19, the suspicion of acute skin GVHD is confirmed by biopsy. On the same day, M.P. experiences 1,000 mL
of diarrhea over the next 24 hours and is noted to have a biliru-
bin of 2.8 mg/dL. He is started on methylprednisolone 35 mg IV
Q 6 hr. What is the rationale for methylprednisolone therapy in
M.P.?
The most effective way to treat GVHD is to prevent its development. Once GVHD has presented, only 40% of patients
respond to corticosteroids, which are the first-line therapy for
treatment of established disease.232 In addition, patients with
mild to moderate (grades I to III) acute GVHD who respond
to initial therapy have a significantly better survival advantage
when compared with patients with severe acute GVHD disease that does not respond to initial therapy. Patients who do
not respond to therapy or have ongoing severe GVHD usually
die from a combination of GVHD and infectious complications.233
When treating acute GVHD, corticosteroids are generally
tapered based on response. The rate at which tapering occurs
depends on the patient. Patients who develop acute GVHD or
who experience flares of existing GVHD during a tapering
trial will have to have their dosages increased or tapered more
slowly as tolerated.
Because M.P. has objective evidence of established acute
GVHD, he was given systemic corticosteroids at the first sign
of progressive disease. This was appropriate because singleagent corticosteroids are considered are the therapy of choice
for established acute GVHD.232 Corticosteroids indirectly halt
the progression of immune-mediated destruction of host tissues by blocking macrophage-derived IL-1 secretion. IL-1 is
a primary stimulus for helper T-cell–induced secretion of IL2, which in turn is responsible for stimulating proliferation of
cytotoxic T lymphocytes (see Chapter 35). The recommended
dosage of methylprednisolone for the treatment of established
acute GVHD is 2 mg/kg per day, given intravenously or orally
in four divided doses for a minimum of 14 days, followed by
a tapering schedule that is determined by response.233 The
dosage of methylprednisolone in M.P. (35 mg intravenously
every 6 hours) is approximately 2 mg/kg/day and thus is consistent with these recommendations. Comparative trials suggest no advantage to higher dosage of corticosteroids (i.e., 10
mg/kg per day) compared with 2 mg/kg per day as initial
treatment of acute GVHD.234 Nonetheless, high-dose pulse
therapy with IV methylprednisolone 20 to 60 mg/kg per day
or 500 mg/m2 every 6 hours followed by a rapid taper has
been advocated.235
Other therapies that have been used to treat established
acute GVHD include ATG 15 to 30 mg/kg per day intravenously daily or every other day for 3 to 10 doses,233 cyclosporine 3 mg/kg per day intravenously or 12.5 mg/kg per
day orally (Sandimmune),233 and murine monoclonal antibody
(OKT3) 5 mg/day intravenously for 14 days.236 Single-agent
therapy and combination therapy also have been used, although a high incidence of death resulting from infection is
seen when more than two agents are used, most likely because
of enhanced immunosuppression.235 Cyclosporine is used to
treat established GVHD only in patients who did not receive
cyclosporine as part of their prophylactic regimen. In addition, cyclosporine levels do not correlate with response in the
setting of acute GVHD.235 If a patient fails to respond to one
drug, switching to another agent for rescue therapy occasionally is successful. However, response rates to salvage therapy
for acute GVHD are low.237
HEMATOPOIETIC CELL TRANSPLANTATION
New agents directed against blocking the accelerated cytokine cascade are under investigation for the treatment of established acute GVHD. These include anti–IL-2 receptor
monoclonal antibody, monoclonal anti–TNF- antibody, and
soluble TNF receptor and humanized anti–CD3 monoclonal
antibody.238–240 The most effective dose, timing, or combination of these new therapies still is unknown.
M.P. should be evaluated for response to methylprednisolone after 4 to 7 days. If his acute GVHD has improved or
stabilized, he should be continued on therapy at this dose for
a total of 14 days. If M.P. responds to therapy, his steroid dose
should be tapered slowly over a minimum of 1 month, and he
should be monitored for any evidence of recurrent GVHD. If
GVHD flares during his steroid taper (as evidenced by worsening skin reactions, increased bilirubin, or increased diarrhea volume), the dose should be increased again until his disease is stable, with the subsequent taper initiated at a slower
rate. If M.P. fails to respond to first-line therapy with methylprednisolone, he should receive salvage therapy with ATG,
OKT3, or an investigational drug on protocol. Extracorporeal
photochemotherapy with ultraviolet A radiation and a photosensitizing agent (e.g., psoralen) have shown benefit in treating cutaneous GVHD.241
Chronic Graft-versus-Host Disease
CLINICAL PRESENTATION
35. M.P. was successfully treated for his acute GVHD, is no
longer taking corticosteroids, and currently is tapering his cyclosporine. On day 200, M.P. comes to clinic for follow-up
after a 2-week vacation in Florida. On examination, M.P. is
found to have a mild skin rash on his arms and legs, hyperpigmentation of the tissue surrounding the eyes, and white plaquelike lesions in his mouth. He also is complaining of dry eyes. Laboratory tests reveal an increased alkaline phosphatase and total
bilirubin concentration. What is the most likely cause of M.P.’s
findings?
Chronic GVHD is the most common late complication of
allogeneic HCT, which occurs in 30% to 70% of long-term
survivors of myeloablative allogeneic HCT.242,243 In addition,
chronic GVHD is the major cause of nonrelapse mortality and
morbidity.76,244,245 Chronic GVHD occurs in approximately
45% of patients undergoing allogeneic HCT and is unrelated
to the regimen used for prophylaxis of acute GVHD.207–210,215
•
92-23
In recipients of HLA-identical grafts, an increased incidence
of chronic GVHD is associated with grades II to IV acute
GVHD, female donor to a male recipient, increasing donor or
recipient age, transfusion of donor buffy coat and the use of
PBPC (see previous section on Peripheral Blood Progenitor
Cells for discussion of allogeneic PBPC and GVHD risk). Recipients of a graft from an unrelated donor have a higher incidence of chronic GVHD.242,244 The most important risk factors
for developing extensive chronic GVHD are a prior diagnosis
of acute GVHD and the use of corticosteroids at day 100.246
The time course for the onset of chronic GVHD follows
three typical patterns: progressive, quiescent, or de novo.247,248
Progressive chronic GVHD evolves directly from acute
GVHD, with no resolution of acute disease in between. This
form of chronic GVHD carries the worst prognosis.249 Quiescent chronic GVHD appears slowly after a period of complete
resolution of acute GVHD, and de novo late-onset chronic
GVHD occurs spontaneously with no history of acute GVHD.
Chronic GVHD tends to occur during or shortly after tapering
of the 6-month duration cyclosporine used for preventing
acute GVHD.250 Therefore, the efficacy of extending the duration of cyclosporine from 6 months to 24 months has been
studied in patients who experienced acute GVHD or had
chronic GVHD of the skin at day 80, when the cyclosporine
taper usually is ongoing.251 Unfortunately, there were no significant differences in the rate of developing chronic GVHD,
transplant-related mortality, or overall survival.251
The clinical course of chronic GVHD is multifaceted, involving almost any organ in the body. Because of its diffuse
nature, chronic GVHD is not graded by organ system and instead is described as limited or extensive, based on the extent
of involvement. Limited chronic GVHD is characterized by
localized skin or liver involvement. Extensive chronic GVHD
is characterized by extensive skin or hepatic involvement, mucosal changes, and/or involvement of any other organ system.
Signs and symptoms of chronic GVHD in various organ systems are listed in Table 92-10.
The signs and symptoms of chronic GVHD in M.P. include
a rash in sun-exposed areas of the skin, hyperpigmentation of
tissues surrounding his eyes, white plaquelike lesions in the
mouth, dry mucous membranes, and increased alkaline phosphatase and total bilirubin levels. These symptoms appeared
after a period of complete resolution of acute GVHD. Thus,
M.P. has limited-involvement, quiescent chronic GVHD.
Table 92-10
Signs and Symptoms of Chronic GVHD329
Affected Organ
Clinical Manifestations
Skin
Rash, hypopigmentation or hyperpigmentation, erythema, alopecia, sclerosis, or scleroderma with joint contractures if severe, lichen
planus lesions
↓ tear formation, dry eyes, burning, photophobia
↓ saliva production, dry mouth leading to cracking or fissure formation, change in taste sensation, diarrhea and abdominal pain, fat
malabsorption, chronic malnutrition, web formation
Increased LFTs, histologic changes consistent with combined hepatocellular injury and cholestasis
Nonproductive cough, wheezing, bronchospasm, diffuse interstitial pneumonitis, restrictive or obstructive abnormalities on PFTs
Eosinophilia, thrombocytopenia, antibody formation and subclass distribution
Myalgias, arthralgias, clinical picture resembling systemic lupus erythematosus or rheumatoid arthritis
Circulating autoantibodies (antinuclear antibody, rheumatoid factor, positive direct Coombs’ test)
Eyes
GI Tract
Liver
Lings
Bone Marrow
Musculoskeletal
Miscellaneous
GI, gastrointestinal; GVHD, graft-versus-host disease; LFTs, liver function tests; PFTs, pulmonary function tests.
92-24
•
NEOPLASTIC DISORDERS
PHARMACOLOGIC MANAGEMENT
36. M.P. is started on prednisone 1 mg/kg PO QD for the treatment of his chronic GVHD. His cyclosporine taper is stopped,
and the dosage is raised to therapeutic concentrations. Is this
therapy rational? What other agents are available to treat
chronic GVHD?
There is no specific prophylactic therapy for chronic
GVHD.244 The mainstay of therapy for chronic GVHD is
long-term immunosuppressive therapy. Although oral prednisone, azathioprine, procarbazine, and cyclophosphamide all
have been used, prednisone, azathioprine, and cyclosporine
have emerged as the most commonly used agents with the
best efficacy and toxicity profiles. M.P. was started on singleagent prednisone for chronic GVHD. This is a reasonable decision because single-agent immunosuppressive therapy is the
treatment of choice for standard-risk (i.e., limited involvement quiescent or de novo chronic GVHD) patients. The use
of combination immunosuppressive therapy in this setting
with prednisone and azathioprine resulted in a higher incidence of nonrelapse mortality and lower survival than with
prednisone alone.252 However, if M.P. fails to respond to prednisone alone or if he had presented initially with progressive
or extensive chronic GVHD, combination therapy with prednisone and cyclosporine would be a reasonable alternative.248
For high-risk patients, specifically those with thrombocytopenia associated with chronic GVHD, the combination of cyclosporine and prednisone has resulted in higher survival and
lower nonrelapse mortality when compared with prednisone
or cyclosporine alone.
When used alone or in combination, the dosage of prednisone for the treatment of chronic GVHD is 1 mg/kg per day,
administered orally in divided doses for 30 days. After 30
days, the dosage is converted slowly to alternate-day therapy
by increasing the “on-day” and decreasing the “off-day” dose
until a total of 2 mg/kg per day on alternate days is administered.248,252 Once the alternate-day conversion has occurred,
the patient is tapered slowly to the final dosage of 1 mg/kg
every other day. Alternate-day therapy is preferred to minimize adrenocortical suppression.248,252 The dosage of azathioprine to treat chronic GVHD, alone or in combination, is 1.5
mg/kg per day.
Other therapies may be required for patients considered to
be at high risk for developing chronic GVHD (defined as patients with GVHD that progresses from acute GVHD or the
presence of thrombocytopenia). Cyclosporine in combination
with prednisone in an alternating sequence has a similar incidence of transplant-related mortality and overall survival
compared with prednisone alone.253 However, the two-drug
combination has a lower disease-free survival with a slight reduction in avascular necrosis (13% for two-drug combination
versus 22% for prednisone alone, P .04).253 The dosage of cyclosporine (Sandimmune) is 6 mg/kg orally every 12 hours
every other day, alternating with prednisone 1 mg/kg orally
every other day.253 When using the microemulsion formulations of cyclosporine (Neoral), lower doses may be used because of improved bioavailability.
Thalidomide, a sedative hypnotic with immunosuppressive
properties, can be used as salvage therapy for chronic GVHD,
although data supporting its clinical benefit are equivacol.254
In addition, the adverse effects of thalidomide complicate
therapy (e.g., neurotoxicity, neutropenia, constipation).255,256
Because of its adverse effects, escalation to the desired dose
of 800 mg/day could not be achieved in most patients receiving thalidomide with cyclosporine and prednisone.256 No clinical benefit, even if full doses of thalidomide could be attained, was apparent with the addition of thalidomide to a
variety of immunosuppressants (i.e., cyclosporine and prednisone, corticosteroids, or calcineurin inhibitors).255,256
Once immunosuppressive therapy is initiated, 1 to 2
months may pass before an improvement in clinical symptoms is noted; therapy usually is continued for 9 to 12 months.
If after this time there has been resolution of signs and symptoms of chronic GVHD, immunosuppressive therapy can be
tapered slowly. If a flare-up of chronic GVHD occurs during
the tapering schedule or after therapy is discontinued, immunosuppressive therapy is restarted. Other potential approaches for patients who are refractory to initial therapy include etanercept, infliximab, mycophenolate mofetil and
tacrolimus, tacrolimus alone, extracorporeal photochemotherapy, acitretin, clofazimine, or hydroxychloroquine.244,257
When immunosuppressive therapy is administered for long
periods, the patient must be monitored closely for chronic toxicity. Blood counts should be monitored routinely in patients
on azathioprine because hematologic toxicity resulting in infection and bleeding may occur. Cushingoid effects, aseptic
necrosis of the joints, and diabetes can develop with long-term
corticosteroid use. Other severe complications include a high
incidence of infection with encapsulated organisms and atypical pathogens such as P. carinii pneumonia, CMV, and herpes
zoster. Cyclosporine therapy is associated with nephrotoxicity,
neurotoxicity, and hypertension, although these effects are
minimized with an alternate-day schedule.
ADJUVANT THERAPIES
37. Suggest some adjuvant therapies that should be instituted
in a patient like M.P. with chronic GVHD.
Patients being treated for chronic GVHD should receive
trimethoprim-sulfamethoxazole for prophylaxis of P. carinii
and also encapsulated organisms, such as Streptococcus
pneumoniae and Haemophilus influenzae. Ensuring optimal
prophylactic antibiotics in chronic GVHD patients is critical
since infection is primarily the cause of death during treatment.257 In addition, the use of artificial tears and saliva may
improve lubrication and decrease the occurrence of cracking
and fissures in mucous membranes. If nutritional intake is
poor, consultation with a clinical nutritionist and use of oral
nutritional supplementation may be advisable. Also, patients
should be instructed to apply sunscreens to exposed areas
whenever prolonged sun exposure is anticipated. Liver function abnormalities have been improved by up to 30% with the
use of ursodiol as bile acid displacement therapy.193–195 Calcium supplements, estrogen replacement, or other antiosteoporosis agents should be considered in women or other patients at risk for fracture or bone loss while receiving
prolonged regimens with immunosuppressant therapy.258 Last,
patient education regarding the delay in improvement of
symptoms, anticipated duration of therapy, and importance of
compliance with oral immunosuppressive therapy is essential.
HEMATOPOIETIC CELL TRANSPLANTATION
Infectious Complications
Opportunistic infections are a major source of morbidity and
mortality after myeloablative and nonmyeloablative HCT.
Three major periods of infectious risks have been described
(see Fig. 92-4). During the early period pre-engraftment, particularly for patients undergoing myeloablative HCT, the primary pathogens are aerobic bacteria and herpes simplex virus
(HSV). Chemotherapy-induced mucosal damage serves as a
portal of entry for many organisms into the bloodstream such
as Streptococcus viridans and aerobic Gram-negative bacteria. Staphylococcus is also a predominant organism because
all patients undergoing HCT have indwelling IV central
catheters. HSV rarely occurs now with the routine use of antiviral prophylaxis. Systemic and oral candidiasis may occur
during this period. Respiratory viruses such as respiratory
syncytial virus, influenza, adenovirus, and parainfluenza are
being increasingly recognized as pathogens causing pneumonia, particularly during community outbreaks of infection
with these organisms.259 To reduce potential exposure of HCT
recipients to such respiratory viruses, visitors and staff members with respiratory signs and symptoms of a viral illness
may not be allowed direct contact with patients.
A potential advantage of NMT (nonmyeloablative transplantation) is the relative nontoxicity associated with the
preparative regimen compared with myeloablative HCT. Frequently, NMT regimens do not result in true neutropenia,6 and
the incidence of mucositis during the early period is reduced
compared with myeloablative HCT.127 In a matched controlled
study designed to assess the incidence of bacterial and fungal
infections after NMT compared with myeloablative HCT,
investigators noted a significantly reduced incidence of
bacteremia (9% versus 27%) during the first 30 days posttransplantation in the NMT group.127 Moreover, episodes of
infection attributable to mucositis in the first 30 days were
significantly fewer (2% versus 14%) in the NMT group.
The second or middle period of infectious risk occurs after
engraftment to post-transplantation day 100. Although bacterial infections may still occur, pathogens such as CMV, adenovirus, and Aspergillus are common during this period. Interstitial pneumonitis is a common manifestation of infection
and can be caused by several infectious agents, including
CMV, adenovirus, Aspergillus and P. carinii. Immune suppression resulting from acute GVHD and corticosteroids may
contribute to the risk of such infections during this period.
Therefore, patients undergoing NMT who experience GVHD
and are treated with corticosteroids can be expected to have a
similar risk for infection as those undergoing myeloablative
HCT during this time period.127 Invasive fungal infections
over the first year after HCT occur at a similar rate in patients
with NMT when compared with historical controls receiving
a myeloablative preparative regimen.126
During the late period (after day 100), the predominant
organisms are the encapsulated bacteria (e.g., S. pneumoniae,
H. influenzae, Neisseria meningitidis), fungi, and varicellazoster virus (VZV). The encapsulated organisms commonly
cause sinopulmonary infections. The risk of infection during
this late period is increased in patients with chronic GVHD as
a result of prolonged immunosuppression.
Because of the morbidity associated with these opportunistic infections in HCT recipients, optimal pharmacother-
•
92-25
apy for preventing and treating infections in this patient population is critical. In 2000, the Centers for Disease Control
and Prevention (CDC) published guidelines for preventing
these infections among HCT recipients.8 These guidelines
were constructed from available data by an expert panel from
the CDC, the Infectious Disease Society of America, and the
American Society for Blood and Marrow Transplantation.
The guidelines provide a comprehensive review of the data regarding prevention of opportunistic infections in HCT recipients. The review below incorporates information from the
CDC guidelines and also provides an update on the pharmacotherapy of opportunistic infections for all types of HCT
(i.e., myeloablative autologous, myeloablative allogeneic and
nonmyeloablative allogeneic HCT recipients).
Prevention and Treatment of Bacterial and Fungal Infections
38. S.D. is a 26 year-old woman with Ph acute lymphocytic
leukemia (ALL) in her first complete remission who is admitted
for allogeneic myeloablative HCT. The following orders are written: Admit to a room with a positive-pressure high-efficiency
particulate air (HEPA) filter. Flush double-lumen Hickman
catheter per protocol. Immunosuppressed patient diet as tolerated. Begin fluconazole 400 mg PO Q 24 hr, acyclovir 800 mg PO
Q 12 hr on admission. Begin ceftazidime 2 g IV Q 8 hr with first
fever when ANC 500/mm3. Transfuse 2 units of packed RBCs
for hematocrit 25% and 1 unit of single-donor platelets when
20,000/mm3. What is the rationale for these supportive measures?
As a result of disease-related immunosuppression, intensive preparative regimens, and/or post-transplantation immunosuppressive therapy, patients undergoing allogeneic
HCT require careful vigilance for regimen-related toxicities
and intensive supportive care directed toward maintaining an
adequate CBC, preventing or treating infection, and providing
adequate nutrition.
Placement of a semipermanent double-lumen or triplelumen central venous catheter (e.g., Hickman, Groshong,
Broviac, Neostar) is mandatory in all patients. The need for
prolonged administration of chemotherapy, blood products,
antibiotics, parenteral nutrition, and adjunctive medications
such as immunoglobulin therapies preclude the use of peripheral access sites that require frequent rotation. In addition, the
use of central venous catheters allows delivery of maximum
concentrations of all medications into an area of high blood
flow, a measure that can reduce administration time and minimize daily fluid infusion.
After administration of the preparative regimen and preceding successful engraftment, allogeneic myeloablative HCT
patients undergo a period of pancytopenia that can last from 2
to 6 weeks. During this time, patients may require multiple
transfusions with RBCs and platelets. Packed RBCs and
platelets usually are given for a hematocrit 25% and
platelets 10,000 or 20,000/mm3, respectively.1,2 Transfusions with multiple blood products put patients at risk for
blood product–derived infection (e.g., CMV, hepatitis). In addition, sensitization to foreign leukocyte HLA antigens (i.e.,
alloimmunization) can cause immune-mediated thrombocytopenia. Thus, blood product support in the myeloablative allogeneic HCT patient must incorporate strategies that reduce
92-26
•
NEOPLASTIC DISORDERS
the risk of viral infection and alloimmunization. Methods
used include minimizing the number of pretransplant infusions, use of single-donor rather than pooled-donor blood
products, irradiating blood products, or filtering blood products with leukocyte-reduction filters.
Given the reduced intensity of the preparative regimen,
NMT patients may or may not experience neutropenia and
generally have reduced requirements for blood products. In
fact, many centers perform NMT in the outpatient setting and
admit patients to the hospital only if they have complications
requiring more intensive management.
Several measures are recommended to minimize the risk of
infection in autologous and allogeneic myeloablative HCT patients. Private reverse isolation rooms equipped with positivepressure HEPA filters and adherence to strict handwashing
techniques reduce the incidence of bacterial and fungal infections.8 To reduce exposure to exogenous sources of bacteria in
immunosuppressed patients, low-microbial diets are instituted
on hospital admission, and visitors are not allowed to bring
plants or flowers into the patient’s room. In addition, patients
are encouraged to maintain good oral hygiene because the
mouth can be a focus of bacterial and fungal infections. The
mouth should be kept clean by using frequent (four to six
times daily) mouth rinses with sterile water, normal saline, or
sodium bicarbonate.8 Brushing or flossing teeth is avoided
during periods of thrombocytopenia and neutropenia. Other
measures designed to reduce the risk of infection include aggressive use of antibacterial, antifungal, and antiviral therapy—both prophylactically and for treatment of documented
infection.
Antibiotics with a broad Gram-negative spectrum may be
instituted prophylactically once the patient becomes neutropenic, or empirically after the patient is neutropenic and
experiences a first fever. S.D. will be receiving ceftazidime
empirically when she becomes neutropenic and has her first
fever. Alternatively, some HCT centers prescribe a prophylactic fluoroquinolone (e.g., ciprofloxacin) on admission for
HCT and then switch to a broad-spectrum IV antibiotic such
as ceftazidime when the patient is neutropenic and experiences a first fever. Fluoroquinolones significantly reduce the
incidence of Gram-negative bacteremia, however, they do not
make an impact on the number of days with fever or on mortality in these patients.8 Concerns regarding quinolone use in
the prophylactic setting during HCT include the emergence of
resistant organisms and an increased risk of streptococcal infection.8,260 The incidence of streptococcal infection due primarily to S. viridans is increasing during HCT, and prompt,
aggressive treatment of these infections is warranted because
of their morbidity (e.g., streptococcal shock syndrome).8,261
Prophylactic antibiotics (e.g., penicillin, vancomycin) have
been studied; however, because of their lack of efficacy in preventing streptococcal infections and concern over antibioticresistant bacteria, their use is not recommended.8 The antibacterial prophylactic regimens vary substantially among
HCT centers. At a minimum, broad-spectrum IV antibiotics
should be initiated or added at the time of the first neutropenic
fever under the treatment guidelines endorsed by the Infectious Disease Society of America practice guidelines for management of fever of unknown origin in the neutropenic
host.8,262 (Also see Chapter 68, Prevention and Treatment of
Infections in Neutropenic Cancer Patients.)
Finally, S.D. is to be given fluconazole 400 mg/day because
prophylactic use of this agent until day 75 after transplantation has been shown to decrease the incidence of systemic
fungal infection and death caused by fungal infection compared with placebo in patients undergoing BMT.263,264 Of note,
use of prophylactic fluconazole by most HCT centers has led
to increasing reports of breakthrough infections with resistant
fungi.265,266 In the setting of a persistent fever during neutropenia after HCT despite use of broad-spectrum antibiotics,
amphotericin B is substituted for fluconazole to maximize antifungal coverage. (See Chapter 70, Opportunistic Infections
in HIV-Infected Patients, for a complete discussion of the use
of antimicrobials and antifungal therapy in the immunocompromised host.)
Another azole antifungal agent, itraconazole, has better in
vitro activity against fungi that are resistant to fluconazole
(e.g., Aspergillus and some Candida species). A randomized
clinical trial demonstrated that itraconazole (200 mg IV Q 24
hr or oral solution 200 mg BID) was more effective than fluconazole (400 mg/day) for long-term prophylaxis of invasive
fungal infections after allogeneic HCT; itraconazole was associated with more frequent gastrointestinal side effects (e.g.,
nausea, vomiting).267 Patient education should be provided regarding the importance of compliance with the unpleasant
tasting itraconazole solution and the necessity of maintaining
plasma concentrations 500 ng/mL for effective prophylaxis.266
Prevention of Herpes Simplex Virus and Varicella-Zoster Virus
39. On routine screening before transplantation, S.D. is found
to be HSV and VZV seropositive. How will this affect her management?
Before engraftment, patients who are HSV antibody
seropositive before HCT are at high risk for reactivation of
their HSV infection (e.g., 43% to 70% of HSV-seropositive
patients undergoing myeloablative allogeneic HCT experience reactivation).268,269 Acyclovir is highly effective in preventing HSV reactivation, and thus prophylactic acyclovir is
commonly used in HSV-seropositive patients who are undergoing an allogeneic or autologous HCT.8 Dosing regimens for
prophylactic acyclovir vary widely; acyclovir is given at 250
mg/m2 IV Q 12 hr, whereas oral doses of acyclovir range between 600 and 1,600 mg/day with 200 mg PO TID being a
commonly used dose.8 The recommended duration of acyclovir prophylaxis is also controversial, but most centers continue therapy until between day 30 and day 180 after
transplantation. Valacyclovir, a prodrug of acyclovir with improved bioavailability, may allow for adequate serum concentrations to prevent HSV in patients with mucositis or gastrointestinal GVHD.270 Typically, valacyclovir is administered
as 500 mg PO Q 12 hr in the prophylactic setting.271,272 In addition, VZV-seropositive patients are at risk for developing
herpes zoster, particularly in the late period (3 to 6 months)
after HCT.270 Prophylactic acyclovir also reduces the risk of
VZV reactivation.273 The appropriate duration of VZV prophylaxis is controversial8; some centers continue therapy
through the period of greatest risk for reactivation (6 months
to 1-year post-transplantation) in all patients, and others reserve treatment for those who are more severely immunosuppressed.
HEMATOPOIETIC CELL TRANSPLANTATION
In contrast, patients who are HSV or VZV seronegative
rarely develop primary HSV or VZV infection; therefore, prophylactic acyclovir is not warranted. If HSV does occur, lesions usually appear on the oral mucosa, nasolabial mucous
membranes, or genital mucocutaneous area and can be managed with treatment doses of acyclovir.
Because S.D. is HSV and VZV seropositive, she is at risk
for reactivating these infections and will be given prophylactic acyclovir.
Prevention of Cytomegalovirus Disease
40. S.D. is also CMV seropositive. What is the significance of
this finding and what measures can be taken to prevent reactivation of CMV?
CMV infection is common after allogeneic HCT, and the
associated morbidity and mortality are high. Allogeneic HCT
patients are at greater risk for CMV disease than autologous
HCT recipients primarily because autologous HCT patients
more efficiently reconstitute their immune system after transplantation. However, autologous HCT recipients who are
CMV seropositive before HCT are at risk for CMV infection,
and prophylaxis should be considered in selected patients.8,274
Two CMV syndromes may occur. CMV infection is usually
asymptomatic and occurs when replication of CMV is noted
primarily in body fluid such as the blood (viremia), bronchoalveolar fluid, or urine (viruria). CMV disease is symptomatic and occurs when CMV invades an organ or tissue. The
most common types of CMV disease after allogeneic HCT
are pneumonia and gastritis. A CMV infection substantially
increases the risk for developing invasive CMV disease.
Strategies to prevent CMV infection have resulted in dramatic
reductions in the incidence of CMV infection and disease.
Primary CMV can be prevented in the CMV-seronegative
recipient by avoiding exposure to the virus. This can be accomplished by transplanting PBPC or bone marrow from
CMV-seronegative donors and infusing CMV-negative blood
products. However, HCT from a CMV-seronegative donor
into a CMV-seronegative recipient and exclusive use of blood
products from CMV-seronegative donors are not always possible. Therefore, other strategies, such as the use of filtered
blood products (leukopoor), prophylactic antiviral therapy,
IVIG, or a combination of these, may be used.
Antiviral drugs are the mainstay of preventing secondary
CMV or its reactivation in the seropositive recipient. Prophylactic IVIG has had mixed results and is not recommended for
preventing CMV among HCT recipients.8,228,275 Use of ganciclovir to prevent CMV is the standard of care after allogeneic
HCT, with two primary methods of choosing when prophylaxis is initiated—universal prophylaxis or pre-emptive prophylaxis. With universal prophylaxis, ganciclovir administration begins at the time of engraftment and continues until
approximately day 100 in allogeneic recipients who are
CMV seropositive or in a seronegative recipient receiving a
CMV-positive graft. This strategy significantly decreases the
incidence of CMV infection and disease compared with
placebo, although mortality is not decreased.276 Prophylactic
ganciclovir therapy is associated with neutropenia in 30% of
patients, which contributes to an increased risk of invasive
bacterial and fungal infections.276,277 Neutropenia associated
with ganciclovir therapy may lead to interruptions in antiviral
•
92-27
therapy or necessitate administration of filgrastim daily or several times per week to maintain adequate neutrophil counts.
Pre-emptive therapy, also called risk-adjusted therapy, has
evolved as the most commonly used strategy for preventing
CMV disease after allogeneic HCT.270,278 The ability to detect
early reactivation of CMV using shell vial cultures, assays of
blood for CMV antigens (such as pp65) or viral nucleic acids
using polymerase chain reaction (PCR) allow for rapid and selective initiation of ganciclovir therapy in patients at highest
risk for developing CMV disease.279–281 In a randomized trial,
antigenemia-based pre-emptive therapy has similar efficacy in
preventing CMV disease as universal ganciclovir prophylaxis,277,282 and pre-emptive therapy has also been associated
with a significant reduction in CMV mortality.283–285 Pre-emptive strategies typically use an induction course of ganciclovir
5 mg/kg IV Q 12 hr for 7 to 14 days followed by a maintenance
course of 5 mg/kg IV daily until 2 or 3 weeks after the last positive antigenemia result or until day 100 after HCT.8 The
ability to selectively administer ganciclovir based on detection
of CMV reactivation ensures that only patients at highest risk
for developing CMV disease are exposed to the potential toxicity of ganciclovir and thus reduces overall cost.270
Foscarnet may be given as an alternate to ganciclovir to prevent CMV disease, although its use is complicated by nephrotoxicity and electrolyte wasting.285,286 Oral valacyclovir at a dose
of 2 g QID has shown efficacy equal to that of IV ganciclovir in
the prevention of CMV in CMV-seropositive allogeneic HCT
recipients.287 Autologous HCT recipients who are CMV
seropositive pre-HCT should receive antiviral treatment preemptively as outlined above.8,274 Similarly, data regarding the
risk of CMV infection and disease in patients undergoing NMT
are emerging. Since host T cells may persist in the peripheral
blood for up to 6 months after NMT, it has been postulated that
their presence may provide protection against early CMV disease. A matched controlled study comparing the incidence and
outcome of CMV infection between myeloablative and nonmyeloablative HCT demonstrated that although the time of
CMV antigenemia onset was similar between the groups, fewer
patients post-NMT developed CMV disease in the early period.288 It is interesting that the overall 1-year incidence of CMV
disease was similar between groups, indicating that patients undergoing NMT have an increased risk for developing late CMV
disease (>100 days after transplantation) compared with their
myeloablative counterparts.288 For this reason, it is recommended that NMT patients should receive pre-emptive antiviral
therapy and should be monitored for development of CMV antigenemia for 1 year after transplantatopm.288,289
S.D.’s absolute neutrophil count recovers to 1,000 cells/
L
on day 20, and on day 32 her weekly surveillance blood
sample is positive for CMV by PCR. Pre-emptive ganciclovir
therapy is initiated at 5 mg/kg IV every 12 hours. After 3 weeks
of therapy, S.D.’s surveillance samples are negative and ganciclovir is discontinued. Weekly surveillance sampling continues
until day 100. If surveillance samples again become positive
for CMV by PCR, ganciclovir therapy should be re-instituted.
Diagnosis and Treatment of Aspergillus Infection
RISK FACTORS
41. A.W., a 60-kg, 165-cm, 15-year-old boy, is day 79 after a
matched, unrelated nonmyeloablative PBPC transplantation for
92-28
•
NEOPLASTIC DISORDERS
acute lymphocytic leukemia (ALL) in his third complete remission. He presents to the clinic for evaluation of a temperature of
102.3°F and a 3-day history of a nonproductive cough. Significant medical history includes skin and gut GVHD (which is stable on his current regimen of cyclosporine, mycophenolate
mofetil, and prednisone) and congestive heart failure thought to
be secondary to anthracycline exposure. A.W. has chronic lowgrade nausea and magnesium wasting necessitating daily IV hydration with magnesium supplementation. Relevant laboratory
values are as follows: Na, 138 mEq/L (normal, 135 to 147); K, 4.2
mEq/L (normal, 3.5 to 5.0); Cl, 100 mEq/L (normal, 95 to 105);
CO2, 23 mEq/L (normal, 22 to 28); blood urea nitrogen (BUN),
18 mg/dL (normal, 8 to 18); SrCr, 0.8 mg/dL (normal, 0.6 to 1.2);
total bilirubin, 0.6 mg/dL (normal, 0.1 to 1); Mg, 1.5 mg/dL (normal, 1.6 to 2.4); WBC count, 3,500/mm3 (normal, 3,200 to 9,800);
platelets, 78,000/mm3 (normal, 130,000 to 400,000); ANC, 1810
cells/L (normal, 1,700); and Hgb, 10.8 g/dL (normal, 12 to 15).
He was CMV and HSV seropositive before HCT. Oral medications include cyclosporine 275 mg Q 12 hr; mycophenolate
mofetil 900 mg Q 12 hr; prednisone 60 mg Q AM and 12.5 mg Q
PM (tapering); co-trimoxazole 160 mg/800 mg BID on Monday
and Tuesday; fluconazole 400 mg daily; valacyclovir 500 mg
BID; digoxin 0.125 mg Q 12 hr; enalapril 10 mg Q 12 hr and a
One a Day Plus vitamin daily.
On physical examination, A.W. is a chronically ill-appearing
child with moon facies, dry skin with thickened areas, a pleural
friction rub and thinning hair. Blood cultures, a urinalysis, and
a chest x-ray are obtained. Chest x-ray revealed several small
cavitary lesions worrisome for fungal disease. A.W. is admitted
for further workup and management of presumed Aspergillus
infection. What risk factors does A.W. have for developing infection with aspergillus?
[SI units: Na, 138 mmol/L; K, 4.2 mmol/L; Cl, 100 mmol/L; CO2, 23
mmol/L; BUN, 6.34 mmol/L; SrCr, 61 mol/L; total bilirubin, 10.26
mol/L; Mg, 0.61 mmol/L; WBC count, 3, 500 106 cells/L; platelets,
78 109 cells/L; ANC, 1,810 106 cells/L; Hgb, 108 g/L]
An increasing cause of morbidity and death after allogeneic and autologous HCT are invasive mold infections (e.g.,
Aspergillus species, Fusarium species, Zygomycetes, and
Scedosporium species).265 This trend is largely because (1)
bacterial and viral infections are more effectively prevented
(as described above) and (2) fluconazole prophylaxis reduced
the incidence of candidemia and candida-related mortality.263–265,290,291 Infections with the Aspergillus species are the
most common mold infections.265 The incidence of invasive
aspergillosis (IA) has risen over the past decade. The annual
incidence of IA was 10.5% among allogeneic and 5.3%
among autologous HCT recipients in the 1998.265
Several risk factors for developing invasive fungal disease
have been identified.290,291 Given that neutrophils are critical
for host defense against fungal infections, prolonged neutropenia is considered the single most important predictor of
development of invasive fungal infections at all time points
after HCT.266,290
GVHD, both acute and chronic, and treatment with corticosteroids are also important risk factors for developing invasive fungal infection, particularly late-onset (i.e., day 40 to
100 after transplantation) aspergillosis.290,291 Neutrophil
dysfunction as a result of GVHD and treatment with corticosteroids is assumed to be the principal mechanism for this in-
crease in risk.292 Lastly, although widespread use of fluconazole (400 mg/day) prophylaxis since the early 1990s has led
to a significant decline in the morbidity and mortality associated with invasive candidiasis in BMT recipients,291 the incidence of infections due to fluconazole-resistant Candida
species, such as C. krusei and C. glabrata as well as the incidence of IA has increased substantially as a result of this practice.290,293,294
A.W. is receiving corticosteroid treatment for GVHD and
is taking fluconazole as antifungal prophylaxis. These factors
increase his risk for developing invasive aspergillosis.
TREATMENT
42. A.W. undergoes a bronchoalveolar lavage in an attempt to
identify the organism responsible for his infection. Pathologic examination of the fluid obtained reveals septate, branching hyphae, and results from a culture of the fluid confirm a diagnosis
of Aspergillus fumigatus infection. CT scans confirm the presence of lung nodules but are negative for any other sites of disease. A.W. is started on amphotericin B lipid complex (Abelcet)
at 300 mg IV daily. How is aspergillosis usually diagnosed and
what are the acceptable alternatives for treating this infection?
In practice, the ability to definitively diagnose, and thus appropriately treat IA, is quite challenging. Although early diagnosis and institution of aggressive antifungal therapy may
reduce the high mortality rate of patients with IA, rapid diagnosis is difficult and relies on obtaining tissue or fluid from an
infected site.295 Although the lower respiratory tract is frequently the primary focus of infection, Aspergillus may invade blood vessels and spread hematogenously to other organs including the brain, liver, kidneys, spleen, and skin.296
Head, chest, abdomen, and pelvic CT scans are performed to
assess the extent of disease as the findings may influence
management and overall prognosis. Also, the medical condition of many HCT recipients prohibit obtaining a biopsy of
the infected tissue; some biopsies suffer from low specificity
for detecting Aspergillus Moreover, Aspergillus grows slowly
in culture.296 With these techniques, many clinicians have
adopted the European Organization for Research and Treatment of Cancer’s (EORTC) criteria for diagnosis of proven,
probable, and possible IA (Table 92-11).297
Promising newer diagnostic techniques including detection
of fungal nucleic acids using PCR and detection of a component of the aspergillus cell wall called galactomannan (GM)
using an enzyme-linked immunosorbent assay (EIA) are being developed.298,299 An Aspergillus Galactmannan enzyme
immunoassay (GM-EIA) was FDA approved in spring of
1999300; prospective screening for GM allows for earlier diagnosis than conventional diagnostic criteria based on data in
European allogeneic HCT recipients.301 Currently, GM-EIA
may be considered in a neutropenic HCT recipient when IA is
suspected or as a surveillance tool during the at-risk period
(e.g., days 60 to 100).
ANTIFUNGALS
Outcomes for IA patients, particularly after HCT, are poor,
with approximately 20% of IA patients alive after 1 year.290
Outcomes depend not only on the use of intensive antifungal
therapy, but also on recovery of the host’s immune system and
reduction of immune suppression.295,302 In fact, studies have
HEMATOPOIETIC CELL TRANSPLANTATION
Table 92-11
•
92-29
Diagnostic Criteria for Fungal Infections
Category
Type of infection
Proven invasive fungal infections
Deep tissue infections
Fungemia
Probable invasive fungal infections
Possible invasive fungal infections
Description
Histopathologic or cytopathologic examination showing hyphae or yeast cells from needle aspiration or biopsy
specimen with evidence of associated tissue damage; or positive culture result for sample obtained by sterile
procedure from normally sterile and clinically or radiographically abnormal site consistent with infection, excluding urine and mucous membranes
Blood culture that yields fungi, excluding Aspergillus species and Penicillium species other than Penicillium marneffei, or Candida species accompanied by temporally related clinical signs and symptoms compatible with relevant organism
At least 1 host factor criterion and 1 microbiologic criterion; and 1 major or 2 minor clinical criteria from abnormal site consistent with infection (see below)
At least 1 host factor criterion; and 1 microbiologic or 1 major (or 2 minor) clinical criteria from abnormal site
consistent with infection
Host Factor Criteria
• ANC 500 cells/mm3 for 10 days
• Persistent fever for 96 hr despite broad-spectrum antibiotics
• Temperature 38°C and any of the following:
Prolonged neutropenia in past 60 days
Use of immunosuppressive agents in past 30 days
History of fungal infection
• Signs/symptoms of GVHD
• Prolonged use of corticosteroids in past 60 days
Microbiologic Criteria
• Positive culture or microscopic evaluation for fungi from sputum, BAL fluid samples, or sinus aspirate
• Positive findings of cytologic or direct microscopic examination for fungal elements in sterile body fluid samples
• Positive result of blood culture for Candida species
Clinical Criteria
Major
• CT imaging demonstrating halo sign, air crescent sign, or cavity within area of consolidation
• Radiologic evidence of invasive infection in sinuses or CNS
Minor
• Symptoms of lower respiratory tract infection (cough, chest pain, hemoptysis, dyspnea); physical finding of a pleural rub; any new infiltrate not fulfilling major criterion
• Upper respiratory symptoms (nasal discharge, stuffiness); maxillary tenderness
• Focal neurologic symptoms and signs including seizures, hemiparesis, and cranial nerve palsies; mental status changes; meningeal irritation findings
ANC, absolute neutrophil count; BAL, bronchoalveolar lavage; CNS, central nervous system; CT, computed tomography; GVHD, graft-versus-host disease.
From Ascioglu S. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002; 34:7–14.
found that the single most important predictor of mortality for
IA in the allogeneic HCT recipients is high total doses of corticosteroids.302
Traditionally, conventional amphotericin B (c-AmB) at a
minimum dose of 1 mg/kg per day has been the gold standard
antifungal therapy for any IA infection. Depending on the
severity of the underlying immune suppression, complete and
partial response rates for single agent c-AmB range from 28%
to 51%; however, 65% of responders eventually die of their
infection.295 In addition, toxicity associated with c-AmB is
significant and frequently limits dose and duration of therapy.
(Refer to case 43 for further discussion of amphotericin toxicity). Recently, newer agents including liposomal derivatives
of amphotericin B, broad-spectrum triazoles, and a new class
of antifungals called the echinocandins have become available. These alternatives offer a promising spectrum of therapeutic options for fungal disease.
Since the mid 1990s, three liposomal formulations of amphotericin have been developed that may be used in place of
c-AmB to manage fungal disease and for empiric therapy in
neutropenic patients at high risk for nephrotoxicity. These include amphotericin B lipid complex (Abelcet, ABLC), liposomal amphotericin B (Ambisome, L-Amb) and amphotericin
B colloidal dispersion (Amphotec, ABCD). (Refer to Chapter
68, Prevention and Treatment of Infections I Neutropenic
Cancer Patients, for a complete review of these products.)
Practice guidelines are available for the use of these agents for
treatment of fungal infections in HCT patients.303 Overall,
studies of single-agent liposomal formulations of amphotericin B for patients with IA who have failed or are intolerant to c-Amb therapy reveal response rates in the range of
23% to 71%, regardless of the agent used. However, no randomized studies have confirmed that these liposomal formulations result in better outcomes compared with c-Amb for the
92-30
•
NEOPLASTIC DISORDERS
treatment of IA.302 Various doses of the liposomal formulations were given in these trials, most commonly 5 mg/kg per
day for ABLC and L-Amb and 4 to 6 mg/kg per day for
ABCD. Although lower doses, particularly of L-Amb (1 to 3
mg/kg per day) have been studied for empirical use in neutropenic patients with persistent fever, it remains to be determined whether such doses are efficacious in the treatment of
IA.304,305 A notable difference between the liposomal formulations and c-Amb described is the decreased risk for nephrotoxicity when liposomal products are used.
An additional factor that limits widespread use of the liposomal products is their high cost compared with c-Amb.
ABLC and ABCD are approximately 15 times more expensive than c-Amb, whereas L-Amb is 30 times more expensive
when compared with doses used to treat IA. Drug acquisition
cost should be balanced with the potentially greater cost of
managing c-Amb nephrotoxicity in the hospital. A recent
pharmacoeconomic evaluation comparing hospital costs for
neutropenic patients with persistent fever treated with L-Amb
or c-Amb revealed that overall costs were significantly higher
for patients receiving L-Amb.306 Furthermore, this difference
in cost was principally attributable to the higher acquisition
cost of L-Amb. Thus, establishing cost-effective strategies for
the appropriate use of these agents is imperative. Most HCT
centers have developed criteria for appropriate use based on
the patient’s risk for nephrotoxicity and the severity of the infection being treated.
Two newer broad-spectrum triazoles have been licensed for
the treatment of fungal infections in patients who fail or are
intolerant of amphotericin B therapy. Itraconaozle (Sporonox)
was the first to become available. In a compassionate use trial
in patients with aspergillosis unresponsive to amphotericin B,
27% of patients were found to have a complete response to
itraconazole and another 35% experienced improvement in
their infection.307 Patients in this trial who had undergone
HCT had responses similar to those patients who were less
immunocompromised. Itraconazole is available for both oral
and intravenous use. Unfortunately, oral itraconazole exhibits
erratic absorption, and the IV formulation is complicated by
the risk of precipitation of the drug in the IV line.295
More recently, voriconazole (Vefend) has been approved
by the FDA for treatment of fungal infections unresponsive to
alternative agents. An advantage of voriconazole is its 96%
oral bioavailability, which makes this oral drug an attractive
and less expensive alternative. Voriconazole has been compared directly with c-Amb for treatment of primary IA.308 The
primary objective of this trial was to demonstrate the noninferiority of voriconazole compared with c-Amb after 12
weeks of therapy in patients with definite or probable IA. Patients received either voriconazole 6 mg/kg IV Q 12 hr 2
doses followed by 4 mg/kg IV Q 12 hr for at least 7 days at
which point they could switch to oral voriconazole 200 mg Q
12 hr or c-Amb 1 to 1.5 mg/kg per day. Patients who couldn’t
tolerate or failed to respond to initial therapy could receive alternate licensed antifungal therapy (itraconazole, liposomal
formulations of amphotericin B). Of 144 evaluable patients
who received voriconazole, 76 (52.8%) had either a complete
or partial response compared with 42 of 133 (31.6%) of patients treated with c-Amb. The median duration of therapy for
patients treated with voriconazole was 77 days and 52 of 144
patients switched to an alternate antifungal drug. In contrast,
the median duration of therapy for patients receiving c-Amb
was 10 days and 107 of 133 patients switched to another agent
(most commonly a liposomal derivative of amphotericin B).
In addition, the survival rate in the voriconazole group was
70.8% compared with 57.9% in the c-Amb group. The authors concluded that voriconazole was not inferior to c-Amb
in the treatment of IA. In fact, initial therapy with voriconazole appeared to be superior to initial therapy with c-Amb.
Finally, extensive research using a novel class of antifungals called the echinocandins in the treatment of fungal disease is underway. Echinocandins have a novel target for their
antifungal activity, -1,3 glucan synthase, an enzyme that
produces an important component of the fungal wall. Of this
class, caspofungin (Cancidas) is the first such product licensed for use. It is indicated for treatment of IA refractory to
alternate therapy. Caspofungin may be administered only IV
because its oral bioavailability is 2%.309 An open-label, noncomparative trial evaluated the efficacy of caspofungin in 69
patients with IA who had not responded to or were intolerant
of a minimum of 7 days of standard antifungal therapy.309 Patients received 70 mg IV on day 1 of therapy followed by 50
mg IV daily. Of the 63 evaluable patients, 26 (43%) had a favorable response to treatment. When outcomes were assessed
in patients who had received a minimum of 7 days of therapy,
26 of 52 patients (50%) had a favorable response. To date,
there have been no randomized controlled trials comparing
caspofungin with amphotericin B products for the treatment
of IA.
In summary, the spectrum of agents available to manage
IA has expanded greatly in the past few years. Although it remains to be determined which agent(s) will ultimately lead to
the best outcomes, the similar efficacy profiles of the liposomal formulations of amphotericin B, itraconazole, voriconazole, and caspofungin allow clinicians to tailor therapy to the
individual patient based on response, tolerability, and cost.
ANTIFUNGAL TOXICITIES
43. Despite premedication with acetaminophen and diphenhydramine, A.W. experiences significant chills and rigors with his
Abelcet infusions. In addition, he is having daily temperatures
exceeding 39°C. On day 5 of therapy, morning laboratory tests
reveal a SrCr of 1.4 mg/dL, K of 2.7 mEq/L and Mg of 1.4
mg/dL. What expected adverse reactions of conventional amphotericin B–based therapy does A.W. demonstrate?
[SI units: SrCr, 106.8 mol/L; K, 2.7 mmol/L; Mg, 0.57 mmol/L]
The most troublesome side effect of amphotericin B therapy is nephrotoxicity. Depending on the definition of renal
toxicity used, up to 80% of patients receiving c-Amb will experience an episode of altered renal function during treatment.310 The mechanisms of amphotericin B nephrotoxicity
are complex and may involve vasoconstriction resulting in
cortical ischemia and a subsequent decrease in GFR as well as
tubular defects in acid secretion. Several risk factors for
nephrotoxicity have been identified. Notably, concomitant
administration of other nephrotoxic agents such as aminoglycosides, cyclosporine, cisplatin, or radiocontrast dye significantly increases risk. Concomitant cyclosporine administration was found to be the most significant risk factor for
developing severe nephrotoxicity in HCT patients.310 Additional risk factors include longer mean duration of ampho-
HEMATOPOIETIC CELL TRANSPLANTATION
tericin B therapy, history of chronic renal disease, male gender, and a mean daily dose 35 mg.311
Liposomal derivatives of amphotericin B were developed
with the specific intent of reducing nephrotoxicity. Indeed,
each of the liposomal products has demonstrated significantly
lower incidences of renal toxicity compared with cAmb.303,304,312–314 Furthermore, patients treated with c-Amb
who experience nephrotoxicity and who are then switched to
a liposomal formulation frequently show improvement in renal function. It is difficult to determine the true incidence of
nephrotoxicity associated with the liposomal derivatives because most trials evaluate their use in patients who have received prior c-Amb therapy. In addition, many trials do not
control for other factors known to reduce the risk of nephrotoxicity including salt loading and fluid boluses administered
before c-Amb infusions. However, clinical experience supports the reduced incidence of nephrotoxicity with these products, and they are recommended as first-line therapy for patients at high risk for nephrotoxicity or in whom baseline
renal function is impaired.
Additional toxicities of c-Amb include infusion-related reactions (fever, chills, rigors, hypotension, hypoxia), electrolyte wasting, nausea, and anemia. Generally, premedications such as acetaminophen, diphenhydramine, meperidine,
and/or hydrocortisone are administered before each dose to
ameliorate these infusion-related events with variable degrees
of success. Moreover, patients may become tolerant to these
effects over time. There appears to be a reduced incidence of
infusion-related reactions when liposomal products are used.
Electrolyte wasting, especially potassium and magnesium,
secondary to amphotericin B therapy (either conventional or
liposomal) can be significant and persist well beyond discontinuation of the drug. Most patients require daily potassium
and magnesium supplementation, particularly if they require
prolonged amphotericin therapy.
LENGTH OF ANTIFUNGAL THERAPY AND COMBINATION ANTIFUNGAL
THERAPY
44. In response to A.W.’s rise in SrCr, his physician elects to
discontinue Abelcet and begin voriconazole 6 mg/kg IV Q 12 hr
2 doses followed by 4 mg/kg IV Q 12 hr and caspofungin 70
mg IV on day 1 and 50 mg IV QD thereafter. What side effects
should be monitored for with this new regimen and what is the
rationale for combination therapy for A.W.? How long should
A.W. receive antifungal therapy for his aspergillosis?
Common toxicities reported with voriconazole to date include infusion-related, transient visual disturbances (blurred
vision, altered color perception, photophobia, visual hallucinations), skin reactions (rash, pruritus, photosensitivity), elevations in hepatic transaminases and alkaline phosphatase,
nausea, and headache.308,315,316 Caspofungin appears to have
fewer adverse events. Most commonly, mild to moderate infusion reactions and headache have been reported. In addition, a smaller number of patients have experienced dermatologic reactions related to histamine release (flushing,
erythema, wheals). Caspofungin therapy has also been associated with elevations in hepatic transaminases in approximately 6% of patients.309 A.W. should be monitored for
changes in liver function and counseled regarding the potential visual side effects of voriconazole.
•
92-31
Data regarding combination therapy with newly available
triazoles, echinocandins, and polyenes in patients with fungal
disease are lacking. However, in vitro data suggest combinations of voriconazole with caspofungin or caspofungin with
polyenes may be synergistic.317,318 Furthermore, no evidence
of antagonism among these agents has been demonstrated in
vitro. Given the overall poor prognosis of IA in severely immunosuppressed patients, many practitioners are treating patients with combination therapy known to be synergistic in
vitro to maximize the chance of response. Thus, voriconazole
in combination with caspofungin is a reasonable alternative
for A.W., particularly considering the degree of toxicity he is
experiencing with Abelcet therapy.
Finally, the optimum duration of appropriate antifungal
therapy for treating IA is unknown.302 The appropriate duration largely depends on the individual’s reconstitution of their
immune system and their response to antifungal treatment.
Most clinicians continue aggressive antifungal therapy until
the infection has stabilized radiographically and may continue
with less aggressive “maintenance” therapy (such as singleagent oral voriconazole) until the degree of immune suppression is decreased. In general, it is not uncommon to require
several months of antifungal therapy to manage IA.
Prevention of Pneumocystis carinii Pneumonia
45. P.N. is receiving co-trimoxazole, 1 single-strength tablet
PO BID on Mondays, Wednesdays, and Fridays. What is the rationale for its use in P.N.?
Pneumocystis is a common cause of infection after allogeneic HCT and has a high mortality rate if left untreated (see
Chapter 70, Opportunistic Infections in HIV-Infected Patients, for description, diagnosis, and treatment). Pneumocystis carinii pneumonia (PCP) prophylaxis is routine after allogeneic HCT. Data are lacking as to the best regimen in HCT
and current practices primarily are based on the pediatric cancer literature. Most centers administer co-trimoxazole for PCP
prophylaxis.8 Dapsone or aerosolized pentamidine are alternatives for patients who are allergic to sulfa drugs or who do
not tolerate co-trimoxazole.
PCP most commonly occurs after engraftment. Therefore,
co-trimoxazole usually is begun after the counts have recovered to ANC 1,000 cells/mm3. However, some centers administer co-trimoxazole throughout the neutropenic period.
Because of the myelosuppressive effects of co-trimoxazole,
this practice is approached with some caution and, although
not proven, may delay or prevent engraftment. It is common
for co-trimoxazole prophylaxis to be held back after engraftment if WBC or platelet counts fall unexplainably. This occurs more often in patients receiving ganciclovir for CMV
prophylaxis or methotrexate for GVHD prophylaxis. Rash
may occur secondary to the sulfa component in co-trimoxazole and require its discontinuation. Co-trimoxazole usually is
avoided on days of methotrexate administration because of
the ability of sulfonamides to displace methotrexate from
plasma binding sites and decrease renal methotrexate clearance, resulting in higher methotrexate concentrations. Prophylaxis usually is continued for 6 months to 1 year after
transplantation.
Autologous HCT recipients with underlying hematologic
malignancies (e.g. lymphoma, leukemia) are also at risk).8
92-32
•
NEOPLASTIC DISORDERS
The routine use of PCP prophylaxis after autologous HCT is
controversial and practices vary widely among centers. Autologous HCT patients do not receive post-transplant immunosuppression. Thus, their risk of developing PCP is lower. PCP
prophylaxis is often used after autologous HCT for NHL,
Hodgkin’s disease, multiple myeloma, and lymphocytic
leukemias because of the immunosuppressive nature of the
underlying disease. PCP prophylaxis is not generally used after autologous transplantation for breast cancer.
Issues of Survivorship After Hematopoietic Cell
Transplantation
46. H.O. is a 32-year-old woman who received a BU/CY
preparative regimen and an HLA-matched sibling BMT for
treatment of CML in chronic phase at age 21. H.O. received her
BMT over 10 years ago, is disease free, and has not had chronic
GVHD for 9-years. Her only medication is a one multivitamin
tablet PO QD. What issues of cancer survivorship are of concern
to H.O.?
A greater proportion of cancer patients are surviving their
cancer diagnosis without evidence of their primary malignancy, but they are at risk for long-term physical and emotional sequelae of their cancer treatments.319 These sequelae
are of paramount importance to HCT recipients because 5year disease-free survival after HCT is increasing and the
myeloablative preparative regimens put them at high risk for
long-term toxicities.203,320 HCT recipients are also at risk for
diseases common in the general population.320
Mortality for HCT recipients is higher than the general
population, with the principal causes of death being relapse,
GVHD, infection, a secondary malignant neoplasm, and endorgan failure.321 Immune function can take over 2 years to recover, even without immunosupressants.320 Treatment of
GVHD exacerbates immune system defects, necessitating
prophylaxis for and vigilant monitoring for infectious complications. Fevers should be rapidly assessed and treated
within HCT survivors to prevent a fatal infection. Recipients
of HCT also lose protective antibodies to vaccine-preventable
diseases. Therefore, HCT survivors need to be re-vaccinated
for selected infectious diseases and with due consideration for
the risk of vaccination. The CDC and European Group for
Bone Marrow Transplantation have issued recommendations
for immunization for HCT recipients, which have been summarized by Goldberg and colleagues.322
Survivors of HCT have a threefold higher risk for secondary malignant neoplasms.320,321,323 Long-term impairment
of end-organ function may be due to the preparative regimen,
infectious complications (either autologous or allogeneic
grafts) and post-transplantation immunosuppression (allogeneic grafts only).324 Endocrine dysfunction is common,
with hypothyroidism occurring in up to 25% of adults owing
to total body irradiation.324 Adrenal insufficiency can also result from long-term corticosteroids used to treat GVHD. Infertility is commonly observed after myeloablative HCT because of the high doses of alkylating agents and radiation
administered. Frequently, men are azoospermic and chemically induced menopause results in women. However, pregnancies have occurred after HCT. Up to 60% of HCT recipients have osteopenia, most likely resulting from gonadal
dysfunction and corticosteroid administration; avascular
necrosis due to corticosteroids can also occur.324 In addition,
a significant portion (15% to 40%) of HCT survivors have
pulmonary toxicity with variable symptoms (e.g., restrictive,
chronic obstructive lung disease) and multiple causes.324 Hepatitis infections can occur in HCT recipients, with the prevalence of chronic hepatitis C ranging from 5% to 70% in longterm HCT survivors.325 Because of this, cirrhosis and its
complications may become an important late complication of
HCT.192,325 Hepatic dysfunction can also result from iron overload, which may occur secondary to multiple PRBC transfusions administered during aplasia after myeloablative preparative regimens and before HCT.192 Alopecia is a common late
effect with BU/CY, as are cataracts with CY/TBI.117
H.O. should be routinely monitored for signs of relapse
and chronic GVHD. To lower the risk of infectious complications, she should be counseled to obtain prompt medical care
for fevers or signs of an infection, and she should be revaccinated if she has not done so since receiving her myeloablative HCT. Thorough evaluation of end-organ function,
including renal, hepatic, thyroid, and ovarian function, should
be assessed at regular intervals. In addition, her bone mineral
density should be determined, and H.O. should be counseled
on preventive measures for osteopenia (e.g., calcium supplementation). In addition to standard cancer screening tests,
H.O. should be closely monitored for secondary malignant
neoplasms.320
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