1
The following protocol information is provided solely to describe how the authors
conducted the research underlying the published report associated with the following
article:
Randomized trial of myeloablative conditioning regimens: busulfan plus
cyclophosphamide versus busulfan plus fludarabine
Lee, et al
DOI: 10.1200/JCO.2011.40.2362
The information provided may not reflect the complete protocol or any previous
amendments or modifications. As described in the Information for Contributors
(http://jco.ascopubs.org/site/ifc/protocol.xhtml) only specific elements of the most
recent version of the protocol are requested by JCO. The protocol information is not
intended to replace good clinical judgment in selecting appropriate therapy and in
determining drug doses, schedules, and dose modifications. The treating physician or
other health care provider is responsible for determining the best treatment for the
patient. ASCO and JCO assume no responsibility for any injury or damage to persons or
property arising out of the use of these protocol materials or due to any errors or
omissions. Individuals seeking additional information about the protocol are encouraged
to consult with the corresponding author directly.
2
COOPERATIVE GROUP A FOR HEMATOLOGY (COSAH)
Title: Randomized comparison of once-daily intravenous busulfan plus
cyclophosphamide versus fludarabine as a conditioning regimen for
allogeneic
hematopoietic
cell
transplantation
in
leukemia
and
myelodysplastic syndrome
Principal Investigator: Je-Hwan Lee, M.D., Asan Medical Center
Participating institute
Investigators
Asan Medical Center, Seoul, Korea
Kyoo-Hyung Lee, Je-Hwan Lee,
Seong-Jun Choi, Jung-Hee Lee,
Young-Shin Lee, Miee Seol, KeunHee Kim
Busan Paik Hospital, Busan, Korea
Young-Don Joo, Won-Sik Lee
Daegu Catholic University Hospital, Daegu, Korea
Hun Mo Ryoo , Sung Hwa Bae
Daegu Fatima Hospital, Daegu, Korea
Jung Lim Lee
Hallym Sacred Heart Sacred Heart Hospital, Anyang,
Dae Young Zang, Hyo Jung Kim
Korea
Kyeongsang National University Hospital, JinJu, Korea
Kyeong Won Lee
Ulsan University Hospital, Ulsan, Korea
Jae-Hoo Park, Young Joo Min,
Hawk Kim
Yeungnam University College of Medicine, Daegu, Korea
Myung Soo Hyun, Min Kyung Kim
3
=Abstract=
Randomized comparison of once-daily intravenous busulfan plus cyclophosphamide
versus fludarabine as a conditioning regimen for allogeneic hematopoietic cell
transplantation in leukemia and myelodysplastic syndrome
PROTOCOL ID

COSAH-005
PROTOCOL TYPE

Treatment
OBJECTIVES

Compare the regimen related toxicities of two different conditioning regimens, intravenous
once-daily busulfan plus cyclophosphamide (BuCy) vs. fludarabine (BuFlu) for allogeneic
hematopoietic cell transplantation (HCT) in leukemia and myelodysplastic syndrome.
PROTOCOL ENTRY CRITERIA

Patients with acute leukemia, chronic myelogenous leukemia, other uncommon leukemia,
and myelodysplastic syndrome.

Written informed consent must be obtained.

Patients should have an HLA-identical or one-locus mismatched sibling, family or unrelated
donor.

Patients should be 15 years of age or older, but younger than 70 years.

The performance status of the patients should be 70 or over by Karnofsky performance
scale.

Patients should not have major illness or organ failure.

Patients must have adequate hepatic function (bilirubin less than 3.0 ㎎/㎗, AST and ALT
less than three times the upper normal limit).

Patients must have adequate renal function (creatinine less than 2.0 ㎎/㎗).

Patients must have adequate cardiac function (ejection fraction > 45% on radionuclide scan
or echocardiogram).

Patients must not have a psychiatric disorder or mental deficiency severe as to make
compliance with the treatment unlike, and making informed consent impossible.

Patients must not be in pregnancy.
4
PROTOCOL OUTLINE

This is a prospective, randomized, nonblind study.

Conditioning therapy

BuCy regimen:

®
Intravenous busulfan (Busulfex ; Orphan Medical, Minnetonka, MN) 3.2 ㎎/㎏ in
normal saline 500 ㎖ i.v. over 3 hours on days -7 to -4


Cyclophosphamide 60 ㎎/㎏ in D5W 200 ㎖ i.v. over 1-2 hours on days -3 and -2
BuFlu regimen:

Intravenous busulfan 3.2 ㎎/㎏ in normal saline 500 ㎖ i.v. over 3 hours on days 7 to -4

®
Fludarabine (Fludara , Schering AG, Berlin, Germany) 30 ㎎/㎡ i.v. over 30
minutes in D5W 100 ㎖ on days -6 to -2
STRATIFICATION

Status at HCT: standard risk vs. high risk

Stem cell donor: related vs. unrelated
END POINTS

Incidence of regimen related toxicities
PROJECTED ACCRUAL

A total of 130 eligible patients will be accrued for this study.

About 3 years of accrual will be required.
5
1.0 OBJECTIVES
1.1
Compare the regimen related toxicities of two different conditioning regimens, intravenous
once-daily busulfan plus cyclophosphamide (BuCy) vs. fludarabine (BuFlu) for allogeneic
hematopoietic cell transplantation (HCT) in leukemia and myelodysplastic syndrome.
1.2
The other end points of the study include incidence of GVHD, non-relapse mortality,
event-free survival, overall survival, and relapse incidence.
2.0 BACKGROUND INFORMATION
2.1
High-dose oral busulfan in combination with cyclophosphamide has been widely used as
a conditioning regimen for allogeneic HCT. Busulfan-based combinations are important
alternatives to total body irradiation (TBI)-based therapy, and numerous clinical trials have
demonstrated their efficacy (Clift et al, 1994; Bensinger et al, 2004). Non-TBI containing
regimens have some advantages, over TBI-based regimens, such as convenience, lower
cost, and avoidance of the long-term sequelae of TBI, including cataracts, second
malignancies, growth and development problems in children, and myelodysplasia.
However, regimen related toxicities leading to non-relapse mortalities are still major
obstacles to successful HCT. With our experience, of 181 patients who were treated with
oral busulfan plus cyclophosphamide for allogeneic HCT, the incidences of severe
regimen-related toxicities were very high and non-relapse mortality was 24.4% (Kim et al,
2005). Many efforts have been tried to reduce regimen related toxicities after allogeneic
HCT. One of them is the development of i.v. busulfan. Because of variable absorption of
busulfan in the gastrointestinal tract, there is marked interindividual variation in oral
busulfan pharmacology, variations that may reach 10-fold or larger (Grochow et al, 1989).
To circumvent both the erratic, unpredictable intestinal busulfan absorption and the
hepatic first-pass effect that might contribute to hepatic veno-occlusive disease,
intravenous busulfan was developed. In clinical trials with intravenous busulfan, it showed
complete bioavailability and reliable systemic drug exposure with more predictable blood
levels (Andersson et al, 2000). The results of clinical transplantation have demonstrated
lower incidences of regimen related toxicities and lower non-relapse mortality using
intravenous busulfan over oral busulfan (Kashyap et al, 2005; Kim et al, 2005; Lee et al,
2005). Most experience with iv busulfan has been with the traditional 4-times-daily dosing,
but recent studies showed that daily dosing of busulfan was associated with low inter-
6
dose variation of busulfan plasma pharmacokinetics (PK) and no accumulation over the 4
days of administration (Russell et al, 2002; de Lima et al, 2004).
2.2
Cyclophosphamide is common to many transplantation conditioning regimens with a high
incidence of fatal veno-occlusive disease (McDonald et al, 1993). There have also been
several clinical reports of hepatotoxicity after administration of cyclophosphamide alone
(Modzelewski et al, 1994). In our previous report, we observed hypercoagulability and a
high incidence of VOD after allo-SCT in aplastic anemia patients conditioned with
cyclophosphamide plus antithymocyte globulin (Lee et al, 2000). A substantial literature
links acrolein (a metabolite formed simultaneously with phosphoramide mustard through
the initial oxidation of cyclophosphamide) to hepatotoxicity via mechanisms dependent on
glutathione. Cyclophosphamide is much more toxic to sinusoidal endothelial cells than to
hepatocytes when the two are incubated in co-culture. In one recent study, there was
large interpatient variability in 4-hydroxycyclophosphamide exposure at fixed dose of
cyclophosphamide and a correlation between exposure rates to metabolites of
cyclophosphamide and veno-occlusive disease (Slattery et al, 1996). In addition to
hepatic veno-occlusive disease, cyclophosphamide is frequently associated with the
occurrence of hemorrhagic cystitis in the early post transplant period (Seber et al, 1999).
Other recent study demonstrated that high exposure to a specific metabolite of
cyclophosphamide was associated with major toxicities and increased non-relapse
mortality after conditioning with cyclophosphamide and TBI (McDonald et al, 2003).
Above observations provide the rationale for replacing cyclophosphamide with other less
toxic immunosuppressive agents capable of achieving sustained engraftment after
allogeneic HCT.
2.3
Fludarabine is a chemotherapeutic drug that has been shown to inhibit DNA replication
and repair effectively by binding and inhibiting DNA polymerase C, DNA primase and
DNA ligase I, as well as by inhibiting RNA synthesis and inducing apoptosis of cells
belonging predominantly to the lymphocytic series. Fludarabine has been shown to be
therapeutically efficacious against lymphoid malignancies. The compound has shown
minimal extramedullary toxicity at doses between 90 and 125 ㎎/㎡ per course, although
central nervous system toxicity may occur at higher doses. Fludarabine has lack of
hepatotoxicity and does not cause hemorrhagic cystitis. Previous clinical trials have well
demonstrated the immunosuppressive properties of fludarabine and engraftment of
allogeneic hematopoietic cells when used in combination with reduced doses of alkylating
agents or TBI (Slavin et al, 1998; Khouri et al, 1998; Giralt et al, 2001). Fludarabine may
possibly play a role in reducing the incidence and severity of graft-versus-host disease.
7
Recently, the combination of 250 ㎎/㎡ fludarabine with standard doses of intravenous or
targeted oral busulfan has been associated with a low rate of non-relapse mortality
(Russell et al, 2002; Borhauser et al, 2003; de Lima et al, 2004)
2.4
In our study, we will test whether fludarabine can safely replace cyclophosphamide in a
combination with once-daily intravenous busulfan for allogeneic HCT, related or unrelated.
3.0 ELIGIBILITY CRITERIA
3.1
Patients with acute leukemia, chronic myelogenous leukemia, myelodysplastic syndrome,
and other hematologic malignancies.
3.2
Written informed consent must be obtained.
3.3
Patients should have an HLA-identical or one-locus mismatched sibling, family or
unrelated donor.
3.4
Patients should be 15 years of age or older, but younger than 70 years.
3.5
The performance status of the patients should be 70 or over by Karnofsky performance
scale (see Appendix I).
3.6
Patients should not have major illness or organ failure.
3.7
Patients must have adequate hepatic function (bilirubin less than 3.0 ㎎/㎗, AST and ALT
less than three times the upper normal limit).
3.8
Patients must have adequate renal function (creatinine less than 2.0 ㎎/㎗).
3.9
Patients must have adequate cardiac function (ejection fraction > 45% on radionuclide
scan or echocardiogram).
3.10 Patients must not have a psychiatric disorder or mental deficiency severe as to make
compliance with the treatment unlike, and making informed consent impossible.
8
3.11 Patients must not be in pregnancy.
4.0 REGISTRATION AND RANDOMIZATION
4.1
The eligible patients will be registered to Research Nurse, Yae-Eun Jang, R.N.
4.2
At the same time of registration, patients will be randomized to one of the two
conditioning therapy groups; Arm I (intravenous busulfan plus cyclophosphamide; BuCy)
or Arm II (intravenous busulfan plus fludarabine; BuFlu).
4.3
4.3.1
Randomization will be a stratified permuted-block design.
The patients will be stratified into standard risk vs. high risk group, and related vs.
unrelated donor. Standard risk group will be defined as follows: patients with acute
leukemia in first remission, CML in chronic phase, and MDS (RA or RARS categories).
High risk group will be defined as follows: patients with acute leukemia in relapse or in
second or subsequent remission, CML in accelerated or blastic phase, and MDS
(CMMoL or RAEB categories).
4.3.2
Pre-assigned block size is 8.
5.0 TREATMENT PLAN
5.1
The patients will be admitted to laminar air flow room.
5.2
The patients will have triple lumen Hickman central venous catheter (CVC) placed.
Vancomycin 1 gm IV immediately prior to CVC placement and 1 gm q 12 hours for 3
doses. Chest X-ray should be taken after CVC placement to confirm the location of CVC
and absence of pneumothorax.
5.3
Lumbar puncture will be done and intrathecal preservative free methotrexate 10 ㎎/㎡
(not to exceed 12 ㎎ total) will be given. Folinic acid 15 ㎎ will be given po or IV 24
hours after intrathecal methotrexate and q 6 hours for a total of 4 doses.
5.4
Menstruating women will be given norethindrone (Norlutate) 10 ㎎ po daily.
9
5.5
5.5.1
The preparatory regimen is as follows:
Conditioning therapy will start on day –7 in patients who are randomized to receive
intravenous
busulfan
(Busulfex®;
Orphan
Medical,
Minnetonka,
MN)
plus
cyclophosphamide. Busulfex 3.2 ㎎/㎏ will be administered once daily for 4 days
(days –7 to –4) followed by cyclophosphamide 60 ㎎/㎏ in D5W 200 ㎖ i.v. over 1-2
hours on days –3 and –2. Busulfex will be diluted in normal saline 500 ㎖ and infused
over 3 hours by pump through a central venous catheter The doses of Busulfex and
cyclophosphamide will be calculated using following guideline: 1) if actual body weight
(ABW) of the patient is less or equal to ideal body weight (IBW), ABW will be used. 2)
if ABW is greater than IBW but by less than 20%, then IBW will be used. 3) if ABW is
greater than IBW by more or equal to 20 %, then the dose will be based on; IBW +
25 % (ABW-IBW). IBW is calculated as follows: 50 ㎏ + 2.3 ㎏ (Height in inch – 60)
in male, and 45.5 ㎏ +2.3 ㎏ (Height in inch –60) (1 inch= 2.54 ㎝).
5.5.2
Conditioning therapy will start on day –7 in patients who are randomized to receive
Busulfex plus fludarabine (Fludara®, Schering AG, Berlin, Germany). Busulfex 3.2
㎎/㎏ will be administered once daily for 4 days (days –7 to –4) and fludarabine 30
㎎/㎡ will be infused intravenously over 30 minutes in D5W 100 ㎖ for 5 consecutive
days (days –6 to –2). The dose of Busulfex will be calculated using above-mentioned
guideline (see 5.5.1). The dose of fludarabine will be calculated using ABW.
5.6
5.6.1
GVHD prophylaxis
All patients will receive cyclosporine 1.5 ㎎/㎏ in NS 100 ㎖ i.v. over 2-4 hours q 12
hrs (dose of cyclosporine rounded to nearest 5 ㎎) starting day –1 at 9 a.m.
Cyclosporine dose will be adjusted to provide appropriate level and according to the
change of renal function (see Appendix II).
5.6.2
When the patients can tolerate oral medications, cyclosporine can be given p.o. 3
㎎/㎏ (or two times the i.v. dose) q 12 hrs.
5.6.3
Cyclosporine dose will be decreased by 10 % every month starting day 60 of BMT
provided that there is no clinical evidence of GVHD.
5.6.4
In addition to cyclosporine, methotrexate 15 ㎎/㎡ will be given intravenously on day
1 and 10 ㎎/㎡ on days 3, 6, and 11. The dose of methotrexate will be decreased or
omitted according to the guideline provided in Appendix III.
10
5.6.5
Methotrexate will not be given to patients with acute leukemia or MDS who will receive
hematopoietic cell graft from an HLA-matched sibling donor
5.7
5.7.1
Bone marrow cell infusion
For ABO matched or minor mismatched transplantation, premedication with Avil 45.5
㎎ i.v. push and tylenol 600 ㎎ p.o. will be given. Stem cell will be infused over 1-2
hrs.
5.7.2
For major ABO mismatched transplantation, premedication with Avil 45.5 ㎎ i.v. push,
tylenol 600 ㎎ p.o., 10 % mannitol 100 g i.v. over 4 hrs will be started 30 min before
stem cell infusion, and hydrocortisone 250 ㎎ i.v. will be given immediately before
and 30 min of stem cell infusion.
5.8
5.8.1
Supportive cares.
Dilantin 15 ㎎/㎏ (ABW) in NS 200 ㎖ i.v. over 1 hour for loading on day –8, then 200
㎎ p.o. bid through day –5.
Dilantin dose should be adjusted to provide therapeutic
level.
5.8.2
Allopurinol 300 ㎎/day p.o. qd day –8 to –2.
5.8.3
Nystatin powder to groin, axilla, and perianal area bid from day –8 until absolute
neutrophil count (ANC) > 3,000/㎕.
5.8.4
Sodium bicarbonate/saline mouthwash qid until mucositis is resolved.
5.8.5
Fluconazole 100 ㎎/day p.o. qd until ANC > 3,000/㎕.
5.8.6
Ciprofloxacin 500 ㎎ p.o. bid (for selective bowel decontamination) until ANC >
3,000/㎕. With the first fever spike, ciprofloxacin will be discontinued and broad
spectrum antibiotics will be begun.
5.8.7
Hydration will be done with 0.9 % NS at 100 ㎖/hour while the patients are receiving
busulfan.
5.8.8
IV Immunoglobulin 500 ㎎/㎏ (ABW) i.v. over 6 hours every other week starting day –
7 until day 120, then every month until day 180.
5.8.9
Prophylaxis against Herpes simplex virus will include acyclovir 250 ㎎/㎡ in D5W 100
㎖ i.v. q 8 hours starting at day –7.
When the patient can tolerate oral medication,
11
acyclovir will be given 200 ㎎ p.o. tid until day 180.
5.8.10
Prophylaxis against Pneumocystis carinii will include Bactrim SS 2 tablets p.o. bid with
folinic acid 7.5 ㎎ p.o. bid, 2 days weekly, starting after engraftment through day 360.
5.8.11
Amoxacillin 250 ㎎ p.o. bid starting at day 70 through day 360.
5.8.12
G-CSF administration.
5.8.12.1
Starting day 5, G-CSF 300 ㎍ in 100 ㎖ of D5W will be given i.v. over 3 hours
daily until ANC > 3,000/㎕.
5.8.12.2
If ANC drops below 1,000/㎕, G-CSF administration will resume and continue until
ANC > 3,000/㎕.
5.9
In patients with acute leukemia or CML in blastic crisis, intrathecal methotrexate
administration will be resumed after the patient recovered platelet count to over 50,000/㎕.
Methotrexate 10 ㎎/㎡ (not to exceed 12 ㎎ total) will be given intrathecally once every
2 weeks for three times (total four doses including one given before preparatory regimen).
Folinic acid 15 ㎎ will be given p.o. or i.v. 24 hours after intrathecal methotrexate and q 6
hours for a total of 4 doses.
6.0 PROTOCOL REQUIREMENTS AND TOXICITIES TO BE MONITORED
6.1
Pre-transplant work-up for donor and recipient will be done as Appendix IV.
6.2
Hematologic and coagulation tests will be measured as follows:
6.2.1
Complete blood counts (CBC) including reticulocyte counts daily; chemistry including
electrolytes and magnesium twice a week; prothrombine time (PT), activated partial
thromboplastin time (aPTT), fibrinogen once a week; isoagglutinin titers in case of
ABO-mismatched transplantation once a week. After discharge, these tests will be
measured per visit through day 100.
6.2.2
Blood levels of various hemostatic parameters such as protein C, antithrombin III,
tissue plasminogen activator, and plasminogen activator inhibitor-1 will be measured
serially before initiation of preparative regimen, on the day of marrow infusion, and
days 7, 14, and 21 of transplantation (Lee et al, 1998).
6.2.3
If engraftment is established, perform bone marrow aspirate and biopsy with
12
cytogenetics and appropriate disease markers such as bcr-abl transcript in CML,
AML1-ETO transcript in AML with t(8;21), MLL-AF4 transcript in ALL with t(4;11), or
PML-RARα transcript in APL.
6.3
The status of mixed chimerism will be evaluated by PCR analysis of short tandem repeat
(STR) of one of six polymorphic introns. The chimerism status will be analyzed from the
peripheral blood of the patients monthly for the first 3 months, then every 3 month for
another 9 months or until relapse (Day 30, 60, 90, 180, 270, and 360).
6.4
Assays for appropriate disease markers such as bcr-abl transcript in CML, AML1-ETO
transcript in AML with t(8;21), MLL-AF4 transcript in ALL with t(4;11), or PML-RARα
transcript in APL will be done analyzed from the peripheral blood of the patients at Day 30,
60, 90, then every 3 months until relapse or progression.
6.5
T cell subsets, NK cell, Ig G/M/A/E, and Ig G subclasses will be evaluated at Day 30, 60,
90, 180, 365.
6.6
Monitoring of cytomegalovirus (CMV) infection, pre-emptive therapy for CMV infection,
and treatment of CMV disease.
6.6.1
Blood CMV antigenemia assay will be done weekly starting day –7 until discharge,
then q visit through day 100.
6.6.2
Pre-emptive therapy for CMV infection with ganciclovir will be started as soon as blood
CMV antigenemia assay become positive if peripheral blood ANC is over 3,000/㎕
and the patient is independent of platelet transfusion: ganciclovir 5 ㎎/㎏ i.v. every 12
hours for 7 days then once daily until day 100.
6.6.3
If CMV disease is documented, ganciclovir will be given 5 ㎎/㎏ i.v. every 12 hours
for 14 days, then once daily for 12 weeks or until control of CMV disease. CMV
immunoglobulin (CMV Ig) may be added.
6.7
6.7.1
Graft-versus-host disease (GVHD).
The diagnosis and grading of acute and chronic GVHD will be made according to the
criteria in Appendix V (Armitage et al, 1994; Przepiorka et al, 1995).
6.8
6.8.1
Veno-occlusive disease (VOD) of the liver.
The diagnosis of VOD will be made according to the McDonald’s criteria (see
Appendix VI) (McDonald et al, 1993).
13
6.9
Regimen related toxicities (RRT)
6.9.1
RRT will be scored as defined by the criteria of Bearman et al (1988) (Appendix VII).
6.9.2
Post-HCT toxicities within 100 days after HCT will also be graded according to NCI
Common Terminology Criteria for Adverse Events (CTCAE) v3.0, which classifies
each toxicity as grades I through V. In this study, grades III to V toxicities will be
defined as severe abnormalities.
7.0 STATISTICAL CONSIDERATIONS
7.1
This study is designed as a prospective, randomized, nonblind study.
7.2
The primary endpoint of this study is regimen-related toxicities.
7.3
Chi-square test and t-test will be used to compare the categorical and continuous
variables in the two conditioning therapy groups, respectively. Survival curves will be
computed according to the Kaplan-Meier method, and differences in survival will be
compared with the log-rank test. A Cox proportional hazard model will be used to
determine the effects of different variables survivals.
7.4
The primary criterion for assessing regimen related toxicities will be the incidence of any
severe hepatotoxicity after transplantation. Severe hepatotoxicity is defined as grade III-V
hepatotoxicity, which occurs within 100 days after transplantation. Hepatotoxicity is
chosen because the toxicity can be graded by objective laboratory tests such as serum
bilirubin, albumin, etc. In our previous study, severe hepatotoxicity occurred in about 50%
of the patients who were conditioned with intravenous busulfan plus cyclophosphamide
(Kim et al, 2005). A target accrual of 130 eligible patients is calculated to provide a
probability (power) of 0.8 of detecting an decrease in the occurrence of hepatic venoocclusive disease from 50% to 25% using a two-sided test at the P=0.05 level of
significance. Accrual to the randomized part of the study is anticipated to be 45 per year.
Three years of accrual and one additional year of follow-up will be required.
7.5
Formal interim analyses will be performed at years 1, 1.5, 2, and 2.5. Early stopping will
be considered if results are sufficiently positive (P < 0.00001 at 1 year, P < 0.0013 at 1.5
years, P < 0.008 at 2 years, or P < 0.023 at 2.5 years) or if they are sufficiently negative.
Reporting shortly after closure of the study will be considered if results are significant at
the 0.01 level. Otherwise results will be reported after one year of follow-up, and this final
14
analysis will be performed at the 0.041 level (O’Brein et al, 1979). These stopping and
reporting guidelines will result in an overall level of 0.05 for the trial.
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15
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busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell
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with
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plus
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factor, and factor VIII for the development of hepatic veno-occlusive disease in patients
undergoing allogeneic bone marrow transplantation: a prospective study. Bone Marrow
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Lee JH, Lee KH, Choi SJ, et al. Veno-occlusive disease of the liver after allogeneic bone
marrow transplantation for severe aplastic anemia. Bone Marrow Transplant 26:657, 2000
Lee JH, Choi SJ, Lee JH, et al. Decreased incidence of hepatic veno-occlusive disease and
fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults
conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann
Hematol 84:321, 2005
McDonald GB, Hinds MS, Fisher LB, et al. Venocclusive disease of the liver and multiorgan
failure after bone marrow transplantation: A cohort study of 355 patients. Ann Intern Medi
118:255, 1993
McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and
mortality following hematopoietic stem cell transplantation. Blood 101:2043, 2003
Modzelewski JR, Daeschner C, Joshi VV, et al. Veno-occlusive disease of the liver induced by
low dose cyclophosphamide. Mod Pathol 7:967, 1994
O’Brein PC, Fleming RT. A multiple testing procedure for clinical trials. Biometrics 35:549, 1979
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conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical
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Appendix I. Karnofsky Scale for Rating Activity Status.
Able to carry on normal activity.
100
Normal; no complaints; no evidence of disease; no
special care is needed.
Unable to work; able to live at
90
Able to carry on normal activity.
80
Normal activity with effort.
70
Cares for self; unable to carry on normal activity or
home, care for most personal
needs; a varying amount of
to do active work.
60
assistance in needed.
Requires occasional assistance but is able to care
for most needs.
50
Requires considerable assistance and frequent
medical care.
17
Unable to care for self; requires
40
Disabled; requires special care and assistance.
equivalent of institutional or
30
Severely disabled; hospitalization indicated,
hospital care; disease may be
although death not imminent.
progressing rapidly.
20
Very sick; hospitalization necessary.
10
Moribund; fatal process progressing rapidly.
0
Dead.
Appendix II. Guidelines of Dose Modification for Cyclosporine.
Mild
Grade
Serum Cr.
IA
IB
Moderate
Severe
Life-threatening
II
III
IV
x>3.0 of baseline
x1.25-1.5 of
x>1.5-2.0 of
x>2.0-2.5 of
x>2.5-3.0 of
baseline
baseline
baseline
baseline
0 - 25 %
0 - 50 %
25 - 75 %
25 - 100 %
Dose
reduction
50 - 100 %
18
APPENDIX III. GUIDELINES OF DOSE MODIFICATION FOR METHOTREXATE FOR DAYS
1, 3, 6 AND 11.
a) Renal
SWOG
Grade
Serum Cr.
Dose
reduction
Mild
I
X1.5-2.0 of
baseline
0 - 50 %
Moderate
II
x>2.0-2.5 of
baseline
25 - 75 %
Severe
III
x>2.5-3.0 of
baseline
100 %
Life-threatening
IV
x>3.0 of baseline
Severe
III
>20-30
Life-threatening
IV
>30
100 %
100 %
100 %
b) Bilirubin
IA
2.5-5
IB
>5-10
Moderate
II
>10-20
0-50 %
50-100 %
100 %
Mild
Grade
Bilirubin (㎎%)
Dose
reduction
c) AST
Grade
AST (SGOT)
I
200 - 399
II
400 - 699
III
>700
19
Dose reduction
50 - 100 %
100 %
100 %
d) Third spacing, edema, ascites, weight gain ( weight gain > 5 kg above baseline)
Day 1
Day 3
Day 6
Day 11
Dose reduction
50 - 100 %
50 - 100 %
50 - 100 %
100 %
e) Mucositis
SWOG
Stomatitis
Pharynx &
esophagus
Other mucositis
Dose reduction
I
painless ulcer;
mild erythema;
mild soreness
mild dysphasia
erythema;
mild pain;
no need of
treatment
0%
II
painful erythema;
ulcer;
can eat
can eat without
narcotics
patchy &
serosangui-nous
discharge;
require narcotics
0 – 50 %
III
Painful lesion;
cannot eat
IV
require parenteral
support
cannot eat
complete
obstruction
confluent fibrinous necrosis
mucositis;
require narcotics
100 %
100 %
Appendix IV. Pretransplant Work-Up for Recipients and Donors.
Recipient work-up (should be obtained within one month of BMT)
-
Appropriate disease staging.
MUGA scan or echocardiogram.
Dental consult and Panorex films.
ENT consult and PNS films.
PFT with DLCO .
-
Urinalysis, Chest X-ray, EKG.
Diagnostic LP, send fluid battery (cell count, glucose, protein, LD, fungal and
bacterial cultures, cytology, cytospin). Hematologic malignancy only.
Bone marrow aspirate and biopsy with cytogenetics and appropriate molecular
tests such as bcr-abl or PML-RAR.
-
HBsAg, HBsAb, HBcAb (IgG), HCV Ab, HIV Ab, VDRL, CMV (IgG, IgM), HSV (IgG,
IgM), EBV serology, Toxo titer (IgG), VZV (IgG).
ABGA.
20
-
Serum pregnancy test (-hCG) in females.
-
CBC with Reticulocyte, Chemical batt with BUN/P, Coagulation batt with
Fibrinogen, ABO and Rh type.
Blood CMV antigenemia and culture.
Isoagglutinin titers if ABO mismatched BMT
-
Donor work-up (should be obtained within one month of BMT)
HLA Typing
ABO/Rh
CBC, Reticulocyte, PBS
-
Chemistry, BUN/P, Electrolyte
Coagulation battery
Urinalysis with microscopy
EKG
Chest PA & Lat, Pelvis AP
HBsAg, HBsAb, HCV Ab
HIV Ab, VDRL
CMV (Ig G), HSV (Ig G), EBV serology, Toxo titer (Ig G), VZV (Ig G)
Send 10 mL of peripheral blood in heparinized tube to research lab for chimerism
-
study.
Appendix V.
Diagnosis and Scoring of Graft-Versus-Host Disease (GVHD).
1) Clinical staging of acute GVHD
Stage
1
2
3
4
Skin
Liver
Rash on < 25% of Skin
Bilirubin 2.0-3.0 ㎎/㎗
Rash 25-50% of Skin
Rash on > 50% of Skin
Generalized
Erythroderma with
bullous formation
Bilirubin 3.1-6.0 ㎎/㎗
Bilirubin 6.1-15.0 ㎎/㎗
Bilirubin, >15.0 ㎎/㎗
Gut
Diarrhea >500 ㎖/day or
persistent nausea*
Diarrhea >1,000 ㎖/day
Diarrhea >1,500 ㎖/day
Severe abdominal pain
with or without ileus
* Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
2) Clinical grading of acute GVHD
Overall
grade*
Stage
Skin
Liver
Gut
21
I
II
III
IV
Stage 1-2
Stage 3 or
Stage 4 or
None
Stage 1 or
Stage 2-3 or
Stage 4
None
Stage 1
Stage 2-4
-
*Criteria for grading as minimum degree of organ involvement required to confer that grade.
3) Clinicopathologic classification of chronic GVHD
Limited : Either or both
1. Localized skin involvement
2. Hepatic dysfunction due to chronic GVHD
Extensive :
Either
1. Generalized skin involvement, or
2. Localized skin involvement and/or hepatic dysfunction due to
chronic GVHD
Plus
a. Liver histology showing chronic aggressive hepatitis, bridging
necrosis, or cirrhosis, or
b. Involvement of eye (Schirmer's test with less than 5 mm wetting),
or
c. Involvement of minor salivary glands or oral mucosa demonstrated
on labial biopsy, or
d. Involvement of any other target organ
Appendix VI.
Diagnostic Criteria for Veno-Occlusive Disease (VOD) of the Liver.
Occurrence of two of the following events within 20 days of transplantation.
1. Hyperbilirubinemia (total serum bilirubin  2.0 ㎎%).
2. Hepatomegaly or right upper quadrant pain of liver origin.
3. Unexplained weight gain (> 2% of baseline body weight) because of fluid accumulation.
No other explanation for these signs and symptoms could be present at the time of
diagnosis.
22
Appendix VII.
Regimen-Related Toxicity (RRT) According to Organ Systems
Grade I
Mild EKG abnormality, not
requiring medical intervention;
or noted heart enlargement on
chest radiograph, with no
clinical symptoms
Grade II
Moderate EKG abnormalities
requiring to medical
intervention; requiring
continuous monitoring without
treatment; or congestive heart
failure responsive to digitalis or
diuretics
Bladder
toxicity
Macroscopic hematuria after 2
days from last chemotherapy
dose, with no subjective
symptoms of cystitis and not
caused by infection
Renal
toxicity
Increase in creatinine up to twice
the baseline value (usually the
last recorded before the start of
conditioning)
Dyspnea without chest radiographic changes, not caused
by infection or congestive heart
failure; or chest radio-graphs
showing isolated infiltrate or
mild interstitial changes without
symptoms not caused by
infection or congestive heart
failure
Macroscopic hematuria after 7
days from last chemotherapy
dose not caused by infection;
or hematuria after 2 days, with
subjective symptoms of cystitis
not caused by infection
Increase in creatinine above
twice baseline but not requiring
dialysis
Cardiac
toxicity
Pulmonary
toxicity
Chest radiograph with extensive
localized infiltrated or moderate
interstitial changes combined
with dyspnea and not caused
by infection or congestive heart
failure; decrease of PO2 (>10%
from baseline), not requiring
mechanical ventilation, or >
50% oxygen on mask, and not
a
Grade III
Severe EKG abnormalities
with no or only partial
response to medical
intervention; heart failure
with no or only minor
response to intervention; or
decrease in voltage by more
than 50%
Hemorrhagic cystitis with
frank blood, necessitating
invasive local intervention
with installation of sclerosing
agents, nephrostomy, or
other surgical procedure
Requirement of dialysis
Interstitial changes requiring
mechanical ventilatory
support or > 50% oxygen on
mask, and not caused by
infection or congestive heart
failure
23
Hepatic
toxicity
CNS toxicity
Mild hepatic dysfunction with
bilirubin > 2.0 ㎎% and < 6.0
㎎%; weight gain > 2.5% and <
5% from baseline, of
noncardiac origin; or SGOT
increase more than two-fold but
less than fivefold from lowest
preconditioning
Somnolence, but patient is
easily arousable and is oriented
after arousal
Stomatitis
Pain or ulceration not requiring a
continuous IV narcotic drug
Gastrointestinal
toxicity
Watery stools>500 mL but
<2,000 mL every day not
related to infection
caused by infection or
congestive heart failure
Moderate hepatic dysfunction
with bilirubin > 6 ㎎% <20 ㎎%;
SGOT increase >fivefold from
preconditioning; clinical ascites
or image-documented ascites
>100 mL; or weight gain >5%
from baseline of noncardiac
origin
Somnolence with confusion after
arousal; or other new objective
CNS symptoms with no loss of
consciousness not more easily
explained by other medication,
bleeding, or CNS infection
Pain or ulceration requiring a
continuous IV narcotic drug
(morphine drip)
Watery stools>2,000 mL every
day not related to infection;
macroscopic hemorrhagic
stools with no effect on
cardiovascular status not
caused by infection; or subileus
not related to infection
Severe hepatic dysfunction
with bilirubin > 20 ㎎%;
hepatic encephalopathy; or
ascites compromising
respiratory function
Seizures or coma not
explained (documented) by
other medication, CNS
infection, or bleeding
Severe ulceration or
mucositis requiring
preventive intubation; or
resulting in documented
aspiration pneumonia with
or without intubation
Ileus requiring nasogastric
suction or surgery and not
related to infection; or
hemorrhagic enterocolitis
affecting cardiovascular
status and requiring
transfusion