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Managing Thrombocytopenia Associated With Cancer Chemoth
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Managing Thrombocytopenia Associated With Cancer
Chemotherapy
Review Article [1] | April 15, 2015 | Oncology Journal [2], Cancer Complications [3]
By David J. Kuter, MD, DPhil [4]
This review will focus on the general approach to, and treatment of, thrombocytopenia in cancer
patients, including thrombopoietin treatment in patients receiving non-myeloablative
chemotherapy.
Introduction
Thrombocytopenia is a common problem in patients with cancer. It can result from chemotherapy or
radiation treatment, or from the underlying disease itself.
Thrombocytopenia creates a number of problems in the care of a cancer patient. At platelet counts <
10,000/µL, spontaneous bleeding is increased. At platelet counts < 50,000/µL, surgical procedures
are often complicated by bleeding. At platelet counts < 100,000/µL, chemotherapy and radiation
therapy are administered with caution for fear of worsening the thrombocytopenia and increasing
the risk of bleeding.[1] Therapeutic and prophylactic platelet transfusions create the additional risk
of infusion complications. Thrombocytopenia can also occur with any infection or adverse drug
reaction associated with cancer treatment. Finally, a diagnosis of thrombocytopenia exacerbates the
patient’s sense of anxiety and fear beyond that associated with the cancer diagnosis itself.
Clinicians’ responses to thrombocytopenia in a cancer patient vary. Reduction of the dose intensity
of chemotherapy or radiation is common; more effective regimens with thrombocytopenic toxicity
may be avoided; and treatment may even be precluded. For some patients, treatment of the
underlying cause of thrombocytopenia (eg, stopping therapy with the offending antiviral drug) may
work. Platelet transfusion is often the only readily available treatment.
With the discovery of thrombopoietin in 1994, great expectations were generated that it would play
a role in preventing or treating thrombocytopenia in cancer patients, just as erythropoietin and
granulocyte colony-stimulating factor (G-CSF) have played roles in reducing anemia and
neutropenia, respectively.[2] The first-generation recombinant thrombopoietins reduced
chemotherapy-related thrombocytopenia in early clinical trials, but their subsequent development
was halted due to antibody formation against endogenous thrombopoietin.[3] While two
second-generation thrombopoietin receptor agonists have now been developed that are potent
stimulators of platelet production, neither has yet been tailored for treating thrombocytopenia in
patients with cancer.[2,4]
This review will focus on the general approach to, and treatment of, thrombocytopenia in cancer
patients, including thrombopoietin treatment in patients receiving non-myeloablative chemotherapy.
The use of thrombopoietin in myeloablative settings (stem cell transplantation and induction therapy
for acute myeloid leukemia) has recently been discussed.[5]
Clinical Approach to Thrombocytopenia in Patients With Cancer
Although chemotherapy and radiation are the major causes of thrombocytopenia in patients with
cancer, other etiologies should be considered in all patients. In general, the following evaluation
should be considered when platelet counts are < 100,000/µL.
Is the underlying disease the cause of the thrombocytopenia? Tumor metastatic to bone marrow is
common in patients with breast and lung cancer, as well as in those with primary hematologic
malignancies such as lymphoma. Many such patients also demonstrate pancytopenia, and these
cytopenias generally occur when over 80% of the bone marrow is infiltrated.
Is there an associated immune thrombocytopenia (ITP)? Up to 1% of Hodgkin disease patients,[6,7]
2% to 10% of patients with chronic lymphocytic leukemia,[8-10] and 0.76% (range, 0–1.8%) of
patients with other non-Hodgkin lymphomas (NHLs)[7] develop a secondary ITP. These patients
respond to steroids, rituximab, splenectomy, and thrombopoietin receptor agonists in the same way
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as patients with primary ITP, although treatment of the underlying lymphoma may be more
effective.[7]
Has there been a recent infection? While infection may produce consumptive coagulopathies (eg,
disseminated intravascular coagulation [DIC]), some bacteria release neuraminidase that actually
reduces platelet survival by removing the sialic acids coating platelets and thereby increasing their
clearance by the Ashwell-Morell receptor in the liver.[11,12] Viral infection (eg, with
cytomegalovirus) in compromised patients may inhibit bone marrow production of platelets. Such
thrombocytopenias improve with adequate treatment of the infection.
Has the patient received a new medication? Heparin-induced thrombocytopenia should be
considered. Antibiotics (eg, vancomycin,[13] linezolid[14]) and antiviral agents (eg,
ganciclovir[15,16]) commonly induce thrombocytopenia by direct bone marrow toxicity or
drug-dependent antibody clearance.[13,17]
Has there been a recent transfusion? Post-transfusion purpura (PTP) is a rare complication of
transfusion of red blood cells (RBCs) and platelets, with the platelet count usually dropping below
10,000/µL. PTP occurs in the 1% of patients who lack the common platelet antigen PLA1, also known
as human platelet antigen (HPA)-1a, and in this group, PTP usually is observed in women previously
sensitized by pregnancy. Upon transfusion of HPA-1a–positive platelets into sensitized
HPA-1a–negative patients, antibody destroys the transfused platelets, and by a still unclear
mechanism also destroys the patient’s own HPA-1a–negative platelets. This under-recognized
complication of transfusion responds readily to intravenous immunoglobulin (IVIG).
Does the patient have a coagulopathy? In addition to infection, some tumors (eg, gastric and
pancreatic adenocarcinomas) can produce chronic DIC.[18,19] Such thrombocytopenic patients
usually have elevated D-dimer and low fibrinogen levels, but often have minimally prolonged
prothrombin time and partial thromboplastin time.[20] Treatment of chronic DIC is often difficult.
Heparin may improve the coagulopathy, but most patients do not improve without effective
treatment of the underlying tumor.
Is there a chemotherapy- or transplant-related thrombotic microangiopathy? Mitomycin-C and
gemcitabine have been found to induce endothelial injury, with a resultant thrombotic
microangiopathy whose major manifestation is renal failure and thrombocytopenia; this is best
referred to as a chemotherapy-related hemolytic uremic syndrome.[21] These patients usually have
normal activity levels of the protein ADAMTS13 but have abundant schistocytes in the peripheral
blood smear and an elevated lactate dehydrogenase level; most improve with supportive care and
discontinuation of the chemotherapy. Plasma exchange, rituximab, or steroids are not indicated.[22]
It is unclear whether complement inhibition with eculizumab is of benefit.[23]
When was the last chemotherapy or radiation therapy administered? The platelet has a normal
lifespan of 8 to 10 days. After many types of chemotherapy, the platelet count generally starts to
drop by day 7 and reaches its nadir at day 14, with a gradual return back to baseline by day 28 to 35
(Figure 1). [24] Depending upon the dose and duration of radiation therapy, the onset of
thrombocytopenia is generally at days 7 through 10. The duration of thrombocytopenia is longer,
and sometimes continues for 30 to 60 days.
What chemotherapy was given? The incidence, severity, and duration of thrombocytopenia vary with
the chemotherapy regimen. Most non-myeloablative chemotherapy regimens were developed to
minimize thrombocytopenia and the need for platelet transfusions. Thus, most standard regimens
are associated with relatively low rates of dose-limiting thrombocytopenia; when thrombocytopenia
occurs, it is often of short duration (4 to 6 days). Most patients respond well to platelet transfusion.
In a recent review of different chemotherapy regimens in 614 patients with solid tumors, a platelet
count < 100,000/μL was seen in 21.8% of all subjects; these were unaccompanied by other
cytopenias in 6.2%.[25] Grade III thrombocytopenia (platelet count, 25,000–49,000/μL) was seen in
3.6% and grade IV thrombocytopenia (platelet count, < 25,000/μL) in 3.3%. Thrombocytopenia
occurred in 82% of those receiving only carboplatin, and in 58%, 64%, and 59% of those receiving
combination therapies with carboplatin, gemcitabine, or paclitaxel, respectively. In an analysis of
43,995 patients receiving 62,071 chemotherapy regimens,[26] 6.5% had grade III and 4.1% had
grade IV thrombocytopenia with platinum-based regimens; 3.0% had grade III and 2.2% grade IV
thrombocytopenia with anthracycline-based regimens; 7.8% had grade III and 3.4% grade IV
thrombocytopenia with gemcitabine-based regimens; and 1.4% had grade III and 0.5% grade IV
thrombocytopenia with taxane-based regimens. Among the 10,582 regimens for which data were
available, platelet transfusions occurred in 2.5% of patients (in 1.0% of those treated with
platinum-based regimens, 0.6% of those who received anthracycline-based treatment, 1.8% of
patients treated with gemcitabine-based therapy, and 0.3% of those who received taxane-based
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treatment). The Table provides an overview of the reported frequencies of thrombocytopenia
associated with various current chemotherapy regimens.
Pathophysiology of Chemotherapy-Induced Thrombocytopenia
Not all chemotherapy drugs cause thrombocytopenia in the same way. In reviewing the mechanism
of thrombocytopenia, it is helpful to understand how platelets are made (Figure 2). Stem cells
differentiate into cells committed to megakaryocyte differentiation (megakaryocyte colony-forming
cells [Mk-CFCs]). At some stage, these cells stop their mitotic divisions and enter a process called
“endomitosis,” in which DNA replication occurs without subsequent division of the nucleus or the
cell. This gives rise to polyploid precursor cells with 2, 4, 8, 16, or 32 times the normal diploid DNA
content. These polyploid megakaryocyte precursor cells then stop DNA synthesis and mature into
large, morphologically identifiable megakaryocytes.
Mature megakaryocytes then produce platelets by a mechanism that is still poorly defined. In its
simplest iteration, mature megakaryocytes extrude long cytoplasmic processes through endothelial
cells, and large strands of platelet material (proplatelets) are released into the circulation, eventually
becoming mature platelets, possibly through fragmentation in the lung.[27] If not consumed in
hemostasis, the mature platelet undergoes programmed cell death (apoptosis), determined by a
“platelet clock.”[28] This platelet clock depends on the presence of an anti-apoptotic protein called
Bcl-x(L), a protein that restrains the pro-apoptotic proteins Bax and Bak.[28-31] When levels of
Bcl-x(L) decline, Bax and Bak activity increase and trigger platelet apoptosis. The apoptotic platelets
are cleared by the reticuloendothelial cell system; the spleen plays only a limited role in normal
platelet homeostasis.[32]
Different chemotherapy drugs affect the megakaryocyte and platelet production pathway at different
steps (see Figure 2). Alkylating agents such as busulfan affect pluripotent stem cells.[33,34]
Cyclophosphamide spares hematopoietic stem cells because of their abundant levels of aldehyde
dehydrogenase, but affects later megakaryocyte progenitors.[35] Bortezomib has no effect on stem
cells[36] or megakaryocyte maturation but does inhibit nuclear factor kappa B, a critical regulator of
platelet shedding.[37] This probably explains the relatively short duration of thrombocytopenia
following its administration.[37]
Not all chemotherapy drugs reduce platelet production; some can actually increase the rate of
platelet destruction. Indeed, platelet survival itself may be altered by some agents. The
experimental chemotherapy agent ABT-737 reduces the activity of the platelet clock Bcl-x(L) and
rapidly induces platelets to undergo apoptosis.[29,38] After a single dose of ABT-737, platelet levels
dropped to 30% of baseline by 2 hours, dropped to 5% of baseline by 6 hours, started to recover to
10% of baseline by 24 hours, and returned to baseline after 72 hours.[38] This was not due to
platelet activation; rather, caspase-mediated apoptosis was induced, with a rapid appearance of
phosphatidylserine on the platelet surface and clearance of these cells from the circulation by the
reticuloendothelial system in the liver. Although this mechanism has not been evaluated for most
standard chemotherapy drugs, etoposide also increases platelet apoptosis by reducing Bcl-x(L)
activity.[38]
Finally, chemotherapy may enhance platelet clearance by immune mechanisms. In the treatment of
many lymphomas, administration of single-agent fludarabine has been noted to produce an immune
thrombocytopenia in up to 4.5% of patients.[39] This ITP typically responds to rituximab.[40] Platelet
destruction is also increased when chemotherapy drugs produce a drug-dependent secondary
immune thrombocytopenia, but this effect is uncommon.
The Role of Thrombopoietin in Platelet Production
The hematopoietic growth factor thrombopoietin is the key regulator of platelet production. In
animals or humans deficient in thrombopoietin or its receptor, the platelet count is 10% to 15% of
normal values.[41,42] Megakaryocyte, erythroid, and myeloid precursor cells are all reduced in such
knock-out animals, but the white blood cell (WBC) and RBC counts are normal.[43]
Thrombopoietin is usually made in a constant (“constitutive”) rate in the liver, lacks a storage form,
and is released into the circulation. At non-physiological levels in animals, large quantities of
desialylated platelets may slightly increase hepatic thrombopoietin production.[44] Once in the
circulation, most thrombopoietin is cleared by avid thrombopoietin receptors on platelets and
possibly on bone marrow megakaryocytes. These cells bind, internalize, and then degrade
thrombopoietin. The small residual amount of thrombopoietin in the circulation accounts for the
basal rate of platelet production. Thrombocytopenia does not increase the hepatic thrombopoietin
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production rate, and no other physiologic stimulus has been shown to alter the rate of
thrombopoietin production. With severe thrombocytopenia caused by chemotherapy, hepatic
thrombopoietin mRNA levels are unchanged despite a 10- to 20-fold increase in the concentration of
thrombopoietin.[45] Hepatic damage results in a proportional decrease in thrombopoietin
production.[46]
Circulating thrombopoietin levels are inversely related to the rate of platelet production.[47] With
the reduction in platelet production as a result of chemotherapy, thrombopoietin clearance is
reduced and levels rise (see Figure 1). There is a log-linear relationship between the rise in
thrombopoietin concentration and the fall in the platelet count after chemotherapy.[48] In contrast,
in most ITP patients, the platelet production rate is not reduced,[49,50] thrombopoietin clearance is
normal, and levels do not rise. This primitive form of regulation of a hematopoietic growth factor is
similar to that by which the basal levels of G-CSF and macrophage colony-stimulating factor are
directly maintained by the circulating mass of neutrophils and monocytes, respectively. The only
exception seems to be erythropoietin, levels of which are determined by a hypoxia-induced
factor–mediated renal sensor of the hemoglobin concentration.[51] There is no such sensor of the
platelet count.
Thrombopoietin binds to its receptor on many hematopoietic cells and exerts its effect on most
stages of megakaryocyte growth (see Figure 2). Thrombopoietin is necessary for the viability of
hematopoietic stem cells; when the thrombopoietin receptor is absent, humans are born with
thrombocytopenia and develop pancytopenia over subsequent years.[52-54] Thrombopoietin
stimulates mitosis of Mk-CFCs. Its major effect (at exceedingly low concentrations) is to increase
megakaryocyte endomitosis and increase megakaryocyte ploidy, greatly expanding the
megakaryocyte pool. Thrombopoietin then stimulates megakaryocyte maturation. It is unclear
whether thrombopoietin plays any role in platelet shedding.[55] An underappreciated property of
thrombopoietin is that it prevents apoptosis of early and late megakaryocytes,[56] an effect that
may play a major protective role in patients receiving radiation and chemotherapy (as discussed
below).
Inflammatory cytokines such as interleukin (IL)-6 and IL-11 may also stimulate platelet production by
mechanisms independent of thrombopoietin.[57,58]
Clinical Development of Thrombopoietin Molecules
The development of clinically relevant thrombopoietin molecules has occurred in two phases:
creation of the early recombinant thrombopoietins and then development of the recent
thrombopoietin receptor agonists.[2]
With the discovery of thrombopoietin in 1994, two recombinant thrombopoietin molecules were
developed (Figure 3). Recombinant human thrombopoietin (rhTPO) was a fully glycosylated
thrombopoietin protein made in CHO (Chinese hamster ovary) cells. The other, pegylated
recombinant human megakaryocyte growth and development factor (PEG-rhMGDF), was a
non-glycosylated protein comprising the first 163 amino acids of thrombopoietin coupled to
polyethylene glycol. Both molecules were potent stimulators of platelet production, with half-lives of
about 40 hours. In healthy volunteers, both agents demonstrated the same time course of platelet
response after a single dose: by day 3, megakaryocyte ploidy increased; by day 5, platelet counts
started to rise; by days 10 through 14, a peak platelet count was obtained; and by day 28, platelet
counts returned to their baseline values.
Between 1995 and 2000, both recombinant thrombopoietins underwent extensive clinical
development in oncology settings.[3] Development of both was stopped due to concerns over
neutralizing antibody formation against PEG-rhMGDF.[59] Despite differences between the structure
of PEG-rhMGDF and that of rhTPO, antibody formation against PEG-rhMGDF might have been due to
the route of administration. After early studies suggested that rhTPO might induce antibody
formation when given by a subcutaneous route, rhTPO was thereafter given intravenously, with no
subsequent antibody formation. In contrast, PEG-rhMGDF was given only subcutaneously, and in
several studies patients developed neutralizing antibody to the recombinant protein.[60,61] In 525
healthy volunteers given up to three monthly doses of PEG-rhMGDF, 13 (2.5%) developed
thrombocytopenia due to the formation of antibodies to PEG-rhMGDF that cross-reacted with
endogenous thrombopoietin, creating thrombopoietin deficiency and thrombocytopenia. All subjects
recovered, but some required immunosuppressive treatment.[60,61]
Despite the failure of one of these recombinant thrombopoietin molecules, interest turned to
developing newer thrombopoietin molecules (now called thrombopoietin receptor agonists) with
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novel properties and less risk of antibody formation. In 1997, a 14-amino-acid peptide was identified
that had no sequence homology to thrombopoietin but bound to the thrombopoietin receptor; when
dimerized, it had the same activity as rhTPO.[62] To overcome its short half-life in the circulation,
this peptide was inserted into an IgG4 heavy chain to produce romiplostim, a “peptibody” with a
half-life of 120 hours (see Figure 3).[63] When injected into healthy volunteers, romiplostim
produced a dose-dependent platelet count rise that began at day 5 and peaked by day 14.[64]
Single doses of 10 µg/kg produced peak platelet counts of 1,600,000/µL in healthy volunteers, an
eightfold increase over baseline. There was no effect on the number of WBCs or RBCs.
A separate approach identified small molecules that bound and activated the thrombopoietin
receptor. One of these, eltrombopag, bound the thrombopoietin receptor in the transmembrane
region, an area different from where thrombopoietin or romiplostim bound, and activated the
thrombopoietin receptor in a different fashion.[65-67] When given to healthy volunteers for 10 days,
eltrombopag produced a 50% increase in the platelet count with no effect on the WBC or RBC count.
Both of these thrombopoietin receptor agonists have undergone extensive clinical development, and
both increased the platelet count in over 85% of patients with ITP.[1,4,68-71] Both have been
approved in many countries for the treatment of ITP; prolonged use of both has produced sustained
increases in platelet counts for years, with minimal or no adverse events.[69,72] Additionally,
eltrombopag is now approved for the treatment of thrombocytopenia in patients with hepatitis C
infection requiring antiviral treatment[73] and in patients with aplastic anemia in whom
immunosuppressive therapy has failed.[74,75] In the latter disease, treatment was also associated
with an increase in WBCs and RBCs.
Effect of rhTPO and PEG-rhMGDF in Cancer Patients Receiving
Chemotherapy
Before considering the use of thrombopoietin agents in patients with cancer, it is important to note
that solid tumors appear not to possess functional thrombopoietin receptors.[76,77] In one study
using reverse-transcription polymerase chain reaction (RT-PCR) on 39 human cell lines and 20
primary normal and malignant human tissues, thrombopoietin receptor (c-mpl) transcripts were
found in all megakaryocytic cell lines tested (DAMI, CMK, CMK-2B, CMK-2D, SO), in the CD34-positive
leukemia cell line KMT-2, and in the hepatocellular carcinoma cell line Hep3B.[77] While fetal liver
and brain cells had detectable levels of c-mpl mRNA, none was found in primary tumors. In a more
extensive study, microarray testing detected thrombopoietin receptor mRNA in 0 of 118 breast
tumors and at very low levels in 14 of 29 lung tumors.[76] Low but detectable thrombopoietin
receptor mRNA was found by quantitative real-time PCR (QT-PCR) in some normal (14%–43%) and
malignant (3%–17%) breast, lung, and ovarian tissues, but none of these tissues showed detectable
thrombopoietin receptor protein by immunohistochemistry. Culture of breast, lung, and ovarian
carcinoma cell lines with thrombopoietin receptor agonists showed no stimulation of growth. Finally,
in none of the human clinical studies described next was there any stimulation of tumor growth by
the administration of the recombinant thrombopoietins.
The recombinant thrombopoietins were studied in a wide variety of non-myeloablative settings.
Unfortunately, the results of many of these studies have never been reported other than in abstract
form. In general, thrombopoietin produced an earlier but higher nadir platelet count, shortened the
duration of thrombocytopenia, reduced platelet transfusions, and enabled chemotherapy to be given
on schedule.
When PEG-rhMGDF was administered to lung cancer patients for up to 16 days after treatment with
carboplatin and paclitaxel, the median platelet count nadir was 188,000/µL (range,
68,000–373,000/µL) vs 111,000/µL (range, 21,000–307,000/µL; P = .013) in the placebo group
(Figure 4). The nadir platelet count occurred earlier in the patients treated with PEG-rhMGDF; median
time to nadir was 7 days vs 15 days (P < .001). The platelet count recovered to baseline in a median
of 14 days in the PEG-rhMGDF patients as compared with > 21 days in those receiving placebo (P <
.001).[78] There was no effect on platelet transfusions or bleeding; only one patient in the placebo
group required a platelet transfusion. The incidence of thrombosis was not increased.
In another study, rhTPO was administered on days 2, 4, 6, and 8 after a second cycle of carboplatin
chemotherapy for patients with gynecologic malignancy (Figure 5). Compared with the first cycle,
during which no rhTPO was administered, the mean platelet count nadir was higher (44,000/µL vs
20,000/µL; P = .002); the number of days with platelet count < 20,000/µL was lower (1 vs 4 days; P
= .002); and the number of days with a platelet count < 50,000/µL was lower (4 vs 7 days; P = .006).
The need for platelet transfusion in the group receiving rhTPO was reduced from 75% of patients in
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cycle 1 to 25% of patients in cycle 2 (P = .013). Administration of rhTPO improved recovery to a
platelet count ≥ 100,000/µL (20 days for rhTPO in cycle 2 vs 23 days without rhTPO in cycle 1; P <
.001).[79]
In the third major study,[80] patients with advanced malignancy were treated with carboplatin at
600 mg/m2 and cyclophosphamide at 1,200 mg/m2 in their first cycle. In subsequent cycles they also
received PEG-rhMGDF for 1, 3, or 7 days after chemotherapy. Compared with cycle 1, those receiving
the same chemotherapy dose on a subsequent cycle had a significantly higher platelet nadir
(47,500/µL vs 35,500/µL; P = .003), and the duration of grade III or IV thrombocytopenia was
significantly shorter (0 vs 3 days; P = .004). However, there was no difference in the time to platelet
recovery. Administration of PEG-rhMGDF prior to chemotherapy did not show any benefit.
One study has suggested a possible survival benefit from treatment with PEG-rhMGDF.[81] In the
treatment of patients with relapsed NHL with ifosfamide, carboplatin, and etoposide (ICE)
chemotherapy, maintenance of dose intensity and dose density correlates with improved survival. In
a study of 38 NHL patients randomized to placebo (n = 16) or PEG-rhMGDF (n = 22), ICE was given
on schedule to 42% of those on placebo and to 75% of those on PEG-rhMGDF (P = .008) with overall
survivals of 31% and 59% (P = .06), respectively, after a median follow-up of 8.5 years. Patients on
placebo were 4.4 times more likely to have a dose delay; in 83% of cases, the dose delay was due to
thrombocytopenia. Grade IV thrombocytopenia was seen in 35% of the placebo group vs 15% of
PEG-rhMGDF patients (P = .02), with platelet count nadirs of 20,000/µL and 49,000/µL (P = .008),
respectively. Platelet transfusions were administered in 23% of placebo cycles and in 8% of
PEG-rhMGDF cycles (P = .04).
There were no human radiotherapy studies with PEG-rhMGDF or rhTPO, but one important series of
primate studies suggested that thrombopoietin might have a radioprotective effect.[82-86] When
rhesus monkeys were sublethally irradiated, all blood lines were reduced 10 days later.
Administration of rhTPO in a critical time period anywhere from 2 hours before until 4 hours after the
irradiation markedly ameliorated the pancytopenia; in the study, platelet counts were 1,123,000/µL
± 89,000/µL without radiation therapy or thrombopoietin, 144,000/µL ± 62,000/µL with radiation
therapy but without thrombopoietin, and 739,000/µL ± 165,000/µL with both radiation therapy and
thrombopoietin. Assays for precursor cells of all lineages showed marked increases in viability when
rhTPO was administered.
Effects of Thrombopoietin Receptor Agonists in Cancer Patients Receiving
Chemotherapy
Although 6 years have elapsed since the approval of thrombopoietin receptor agonists for treatment
of ITP, surprisingly few studies of these agents have been conducted in cancer patients undergoing
chemotherapy. Only a small number of case reports[87] and small series of patients with cancer
have been published in this area.[88-91]
In one retrospective study, cancer patients were selected who had a platelet count < 100,000/µL and
who had > 4-week delay in their chemotherapy or had dose reductions/modification in > 2 prior
cycles.[88] These patients were treated with romiplostim at 2 µg/kg weekly. Platelet counts
improved in all of them, and 19 of 20 had platelet counts ≥ 100,000/µL. A total of 15 patients
resumed chemotherapy, and all but one continued for 2 or more cycles without dose modifications.
Three of 20 patients developed deep vein thrombosis (DVT).
In another blinded, placebo-controlled study, patients with solid tumors and a platelet count ≤
300,000/µL receiving either gemcitabine alone (14 patients) or gemcitabine plus either cisplatin or
carboplatin (12 patients) were randomized to receive eltrombopag or placebo on days −5 to −1 and
days 2 through 6, starting from cycle 2; no study drug was administered for cycle 1.[89] For patients
receiving gemcitabine alone, the nadir platelet count for cycles 2 through 6 was 143,000/µL for
eltrombopag vs 103,000/µL for placebo; for those receiving gemcitabine plus cisplatin or carboplatin,
the nadir was 115,000/µL vs 53,000/µL for placebo. A total of 14% of all eltrombopag patients and
50% of placebo patients required dose reductions or delays in cycles 3 through 6. No DVTs were
reported, but 16 of 19 patients treated with eltrombopag developed platelet counts > 400,000/µL.
Although this author anticipates that the thrombopoietin receptor agonists will have the same
beneficial effects in chemotherapy treatment as did the recombinant thrombopoietins, studies are
challenging in this area for many reasons, namely:
• Most standard chemotherapy regimens do not produce very high rates of thrombocytopenia, and
when thrombocytopenia occurs, it is often short-lived.
• Platelet transfusions often resolve the thrombocytopenia and are usually needed for only 3 to 4
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days.
• Chemotherapy regimens commonly associated with increased rates of thrombocytopenia are
usually experimental; it remains unclear whether platelet production support with a thrombopoietin
receptor agonist during chemotherapy is beneficial for the overall cancer outcome, which may be
more limited by the chemotherapy than by the supportive care.
• Study design in this setting is also a concern. Although it is unlikely that concurrent administration
of a thrombopoietic agent during chemotherapy would have any adverse effect, the doses and
schedules for these agents have certainly not been established. It is unclear whether treatment with
a thrombopoietin receptor agonist before or after chemotherapy is superior or whether
administration of thrombopoietin at both times is required.
• Animal chemotherapy models would be of help to assess the dose and schedule of treatment with
thrombopoietin receptor agonists. Unfortunately, eltrombopag is only active in chimpanzees and
humans; romiplostim is active in most species, but there are no animal studies to inform human
treatment.
Good clinical studies that address the dose and schedule for the thrombopoietin receptor agonists
are essential. These should probably be conducted in patients who have developed significant
thrombocytopenia during prior chemotherapy cycles. Pharmacokinetic/pharmacodynamic modeling
suggests that the ideal schedule for eltrombopag might be 5 days before and 5 days after
chemotherapy.[92] The relevant endpoints for such studies would be:
• Avoid nadir platelet counts < 50,000/µL.
• Avoid platelet transfusions.
• Avoid bleeding events.
• Avoid chemotherapy dose reductions.
• Avoid chemotherapy delays.
Treatment of Chemotherapy-Induced Thrombocytopenia
The response to significant chemotherapy-induced thrombocytopenia has not been codified in
guidelines, and there are no studies to guide the appropriate approach to management of patients
with this condition. Much depends upon the underlying treatment goals of the individual cancer
patient; different levels of risk assessment need to be brought into play for patients being treated for
cure vs those being treated for palliation. Overall, it is reasonable when confronted with
chemotherapy-induced thrombocytopenia first to assess the underlying need for chemotherapy and
the goals of treatment for that particular patient. A clinical assessment of bleeding risk for patients is
also important to undertake, especially if patients are receiving anticoagulant drugs or other
therapies that might increase bleeding. What follows is a synthesis of the data and the author’s
personal experiences over the past 4 decades.
• If possible, treat any other underlying cause of thrombocytopenia: stop antibiotics, treat infection,
and control coagulopathy.
• Reduce chemotherapy dose and/or frequency or alter the chemotherapy regimen, especially if
chemotherapy is not standard or not of curative intent.
• Platelet transfusion support should be used if maintenance of dose intensity is vital for response or
survival. Prophylactic platelet transfusions are indicated if bleeding occurs or if platelet counts are <
10,000/µL (or with platelet counts < 20,000/µL if the patient is febrile).[93,94] In the outpatient
setting, however, this transfusion trigger needs to be reconsidered; transfusing at higher platelet
counts on the Friday before a long weekend has its advantages.
• Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid have been used in
some thrombocytopenic cancer patients to decrease the bleeding risk when platelet transfusions did
not work.[95-97] Total daily doses of 2–24 g (mean, 6 g) of epsilon-aminocaproic acid given in 3 or 4
divided doses have been used.[96] Tranexamic acid doses of 4–6 g/d given as 3 or 4 divided doses
have also been studied.[97] However, the use of such agents in cancer patients is fraught with
difficulty because antifibrinolytic agents can exacerbate the underlying increased risk of thrombosis.
• Despite the lack of US Food and Drug Administration (FDA) approval for these agents,
thrombopoietin receptor agonists can be considered in patients who cannot be supported by platelet
transfusions and for whom the maintenance of dose intensity is crucial for remission or survival. In
this setting, this author has used romiplostim at 2–3 µg/kg weekly, or 50–75 mg of eltrombopag daily
to maintain platelet counts over 100,000/µL, in order to allow continuation of chemotherapy (Figure
6). Thrombopoietin receptor agonists would be started only when the patient’s platelet count had
failed to recover to levels > 100,000/µL before the next scheduled chemotherapy.
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• Thrombopoietin receptor agonists should not be used in lieu of platelet transfusions. Since the
platelet count only begins to rise 5 days after TPO administration, with maximal effect 10–14 days
later, platelet transfusions should not be withheld if they are indicated.
• The use of vincristine, rituximab, prednisone, IVIG, splenectomy, or anti-D immunoglobulin is rarely
justified in patients with chemotherapy-induced thrombocytopenia, despite their widespread use and
efficacy in ITP.
• The use of IL-11 is rarely justified, given its significant side effects. Recombinant IL-11 (oprelvekin)
has been shown to reduce the need for platelet transfusions from 96% to 70% of patients who had
been transfused with platelets in a prior cycle and who then received additional chemotherapy.[98]
This drug has been FDA-approved for the prevention of thrombocytopenia with chemotherapy, but it
has too many adverse effects to make it an acceptable treatment for most patients.
Thrombocytopenia in the Cancer Patient: Costs of Treatment
The direct costs of treating thrombocytopenia in the cancer patient can be readily assessed. For
example, a platelet transfusion costs about $3,000 per event (calculated as the cost of a single
apheresis product or a pool of six random donor concentrates) and a transfused unit of RBCs costs
about $1,300–$3,500. A week of antifibrinolytic treatment with epsilon aminocaproic acid (6 g/d) is
$280, and with tranexamic acid (6 g/d) is $290. A week of thrombopoietin receptor agonist treatment
with romiplostim (2 µg/kg/wk) is about $1,400, and with eltrombopag (75 mg/d) is about $2,000.
(Data are from Partners Healthcare Center for Drug Policy.) Oprelvekin at 50 µg/kg daily costs
$2,366 (average wholesale price) for a week of treatment.
However, no attempt has been made to address the overall costs of thrombocytopenia and its
treatment in patients with cancer. The simple issues of chemotherapy delay and dose reduction
carry with them costs in material and space utilization, while the larger issue of reduced dose
intensity in some settings translates into the costs of life lost.
While guidelines exist to guide the rational administration of platelet transfusions, there are few data
and no established guidelines to guide rational reduction in chemotherapy dose or frequency, which
is often the first response to treating thrombocytopenia in the setting of cancer.
Conclusions
Treatment of the thrombocytopenic cancer patient remains a challenge. If no other underlying factor
can be modified, the only treatments are platelet transfusion and dose modification of chemotherapy
or radiation therapy. Future studies should target methods to mitigate thrombocytopenia by
protection of the bone marrow or the rational use of thrombopoietic agents. Guidelines need to be
developed that carefully assess the risks and benefits of current and future treatments for our
patients with thrombocytopenia.
Financial Disclosure: Dr. Kuter is a consultant to 3SBio, Amgen, Kirin, and Pfizer. He receives
research funding from Bristol-Myers Squibb, GlaxoSmithKline, and Ono.
Figure 1: The Relationship Between the Platelet
Count (Open Circles) a...
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Table: Frequencies of Thrombocytopenia With
Selected Chemotherapy Regimens
Figure 2: The Production of Platelets From Bone
Marrow Stem Cells
Figure 3: Structures of the Recombinant
Thrombopoietin (TPO) Molecules...
Figure 5: rhTPO Reduces the Need for Platelet
Transfusions in Patients...
Figure 4: PEG-rhMGDF Increases the Platelet
Count in Patients Undergoi...
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Published on Cancer Network (http://www.cancernetwork.com)
Figure 6: Use of Romiplostim to Increase the
Platelet Count in a Cance...
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Source URL:
http://www.cancernetwork.com/oncology-journal/managing-thrombocytopenia-associated-cancer-che
motherapy
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Managing Thrombocytopenia Associated With Cancer Chemoth
Published on Cancer Network (http://www.cancernetwork.com)
Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/oncology-journal
[3] http://www.cancernetwork.com/cancer-complications
[4] http://www.cancernetwork.com/authors/david-j-kuter-md-dphil
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