Managing Thrombocytopenia Associated With Cancer...

Managing Thrombocytopenia Associated With Cancer ChemotherapyPublished on Cancer Network (http://www.cancernetwork.com)

Managing Thrombocytopenia Associated With CancerChemotherapyReview 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 cancerpatients, including thrombopoietin treatment in patients receiving non-myeloablativechemotherapy.

Introduction

Thrombocytopenia is a common problem in patients with cancer. It can result from chemotherapy orradiation 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 proceduresare often complicated by bleeding. At platelet counts < 100,000/µL, chemotherapy and radiationtherapy are administered with caution for fear of worsening the thrombocytopenia and increasingthe risk of bleeding.[1] Therapeutic and prophylactic platelet transfusions create the additional riskof infusion complications. Thrombocytopenia can also occur with any infection or adverse drugreaction associated with cancer treatment. Finally, a diagnosis of thrombocytopenia exacerbates thepatient’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 intensityof chemotherapy or radiation is common; more effective regimens with thrombocytopenic toxicitymay be avoided; and treatment may even be precluded. For some patients, treatment of theunderlying cause of thrombocytopenia (eg, stopping therapy with the offending antiviral drug) maywork. Platelet transfusion is often the only readily available treatment.With the discovery of thrombopoietin in 1994, great expectations were generated that it would playa role in preventing or treating thrombocytopenia in cancer patients, just as erythropoietin andgranulocyte colony-stimulating factor (G-CSF) have played roles in reducing anemia andneutropenia, respectively.[2] The first-generation recombinant thrombopoietins reducedchemotherapy-related thrombocytopenia in early clinical trials, but their subsequent developmentwas halted due to antibody formation against endogenous thrombopoietin.[3] While twosecond-generation thrombopoietin receptor agonists have now been developed that are potentstimulators of platelet production, neither has yet been tailored for treating thrombocytopenia inpatients with cancer.[2,4]This review will focus on the general approach to, and treatment of, thrombocytopenia in cancerpatients, including thrombopoietin treatment in patients receiving non-myeloablative chemotherapy.The use of thrombopoietin in myeloablative settings (stem cell transplantation and induction therapyfor 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 withcancer, other etiologies should be considered in all patients. In general, the following evaluationshould be considered when platelet counts are < 100,000/µL.Is the underlying disease the cause of the thrombocytopenia? Tumor metastatic to bone marrow iscommon in patients with breast and lung cancer, as well as in those with primary hematologicmalignancies such as lymphoma. Many such patients also demonstrate pancytopenia, and thesecytopenias 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%) ofpatients with other non-Hodgkin lymphomas (NHLs)[7] develop a secondary ITP. These patientsrespond 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 moreeffective.[7]Has there been a recent infection? While infection may produce consumptive coagulopathies (eg,disseminated intravascular coagulation [DIC]), some bacteria release neuraminidase that actuallyreduces platelet survival by removing the sialic acids coating platelets and thereby increasing theirclearance by the Ashwell-Morell receptor in the liver.[11,12] Viral infection (eg, withcytomegalovirus) in compromised patients may inhibit bone marrow production of platelets. Suchthrombocytopenias improve with adequate treatment of the infection.Has the patient received a new medication? Heparin-induced thrombocytopenia should beconsidered. Antibiotics (eg, vancomycin,[13] linezolid[14]) and antiviral agents (eg,ganciclovir[15,16]) commonly induce thrombocytopenia by direct bone marrow toxicity ordrug-dependent antibody clearance.[13,17]Has there been a recent transfusion? Post-transfusion purpura (PTP) is a rare complication oftransfusion of red blood cells (RBCs) and platelets, with the platelet count usually dropping below10,000/µL. PTP occurs in the 1% of patients who lack the common platelet antigen PLA1, also knownas human platelet antigen (HPA)-1a, and in this group, PTP usually is observed in women previouslysensitized by pregnancy. Upon transfusion of HPA-1a–positive platelets into sensitizedHPA-1a–negative patients, antibody destroys the transfused platelets, and by a still unclearmechanism also destroys the patient’s own HPA-1a–negative platelets. This under-recognizedcomplication of transfusion responds readily to intravenous immunoglobulin (IVIG).Does the patient have a coagulopathy? In addition to infection, some tumors (eg, gastric andpancreatic adenocarcinomas) can produce chronic DIC.[18,19] Such thrombocytopenic patientsusually have elevated D-dimer and low fibrinogen levels, but often have minimally prolongedprothrombin 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 effectivetreatment of the underlying tumor.Is there a chemotherapy- or transplant-related thrombotic microangiopathy? Mitomycin-C andgemcitabine have been found to induce endothelial injury, with a resultant thromboticmicroangiopathy whose major manifestation is renal failure and thrombocytopenia; this is bestreferred to as a chemotherapy-related hemolytic uremic syndrome.[21] These patients usually havenormal activity levels of the protein ADAMTS13 but have abundant schistocytes in the peripheralblood smear and an elevated lactate dehydrogenase level; most improve with supportive care anddiscontinuation 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 normallifespan of 8 to 10 days. After many types of chemotherapy, the platelet count generally starts todrop 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 ofthrombocytopenia 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 withthe chemotherapy regimen. Most non-myeloablative chemotherapy regimens were developed tominimize thrombocytopenia and the need for platelet transfusions. Thus, most standard regimensare associated with relatively low rates of dose-limiting thrombocytopenia; when thrombocytopeniaoccurs, 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 plateletcount < 100,000/μL was seen in 21.8% of all subjects; these were unaccompanied by othercytopenias in 6.2%.[25] Grade III thrombocytopenia (platelet count, 25,000–49,000/μL) was seen in3.6% and grade IV thrombocytopenia (platelet count, < 25,000/μL) in 3.3%. Thrombocytopeniaoccurred in 82% of those receiving only carboplatin, and in 58%, 64%, and 59% of those receivingcombination therapies with carboplatin, gemcitabine, or paclitaxel, respectively. In an analysis of43,995 patients receiving 62,071 chemotherapy regimens,[26] 6.5% had grade III and 4.1% hadgrade IV thrombocytopenia with platinum-based regimens; 3.0% had grade III and 2.2% grade IVthrombocytopenia with anthracycline-based regimens; 7.8% had grade III and 3.4% grade IVthrombocytopenia with gemcitabine-based regimens; and 1.4% had grade III and 0.5% grade IVthrombocytopenia with taxane-based regimens. Among the 10,582 regimens for which data wereavailable, platelet transfusions occurred in 2.5% of patients (in 1.0% of those treated withplatinum-based regimens, 0.6% of those who received anthracycline-based treatment, 1.8% ofpatients 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 thrombocytopeniaassociated with various current chemotherapy regimens.

Pathophysiology of Chemotherapy-Induced Thrombocytopenia

Not all chemotherapy drugs cause thrombocytopenia in the same way. In reviewing the mechanismof thrombocytopenia, it is helpful to understand how platelets are made (Figure 2). Stem cellsdifferentiate into cells committed to megakaryocyte differentiation (megakaryocyte colony-formingcells [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 thecell. This gives rise to polyploid precursor cells with 2, 4, 8, 16, or 32 times the normal diploid DNAcontent. These polyploid megakaryocyte precursor cells then stop DNA synthesis and mature intolarge, morphologically identifiable megakaryocytes.Mature megakaryocytes then produce platelets by a mechanism that is still poorly defined. In itssimplest iteration, mature megakaryocytes extrude long cytoplasmic processes through endothelialcells, and large strands of platelet material (proplatelets) are released into the circulation, eventuallybecoming mature platelets, possibly through fragmentation in the lung.[27] If not consumed inhemostasis, 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 calledBcl-x(L), a protein that restrains the pro-apoptotic proteins Bax and Bak.[28-31] When levels ofBcl-x(L) decline, Bax and Bak activity increase and trigger platelet apoptosis. The apoptotic plateletsare cleared by the reticuloendothelial cell system; the spleen plays only a limited role in normalplatelet homeostasis.[32]Different chemotherapy drugs affect the megakaryocyte and platelet production pathway at differentsteps (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 aldehydedehydrogenase, but affects later megakaryocyte progenitors.[35] Bortezomib has no effect on stemcells[36] or megakaryocyte maturation but does inhibit nuclear factor kappa B, a critical regulator ofplatelet shedding.[37] This probably explains the relatively short duration of thrombocytopeniafollowing its administration.[37]Not all chemotherapy drugs reduce platelet production; some can actually increase the rate ofplatelet destruction. Indeed, platelet survival itself may be altered by some agents. Theexperimental chemotherapy agent ABT-737 reduces the activity of the platelet clock Bcl-x(L) andrapidly induces platelets to undergo apoptosis.[29,38] After a single dose of ABT-737, platelet levelsdropped to 30% of baseline by 2 hours, dropped to 5% of baseline by 6 hours, started to recover to10% of baseline by 24 hours, and returned to baseline after 72 hours.[38] This was not due toplatelet activation; rather, caspase-mediated apoptosis was induced, with a rapid appearance ofphosphatidylserine on the platelet surface and clearance of these cells from the circulation by thereticuloendothelial system in the liver. Although this mechanism has not been evaluated for moststandard 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 ofmany lymphomas, administration of single-agent fludarabine has been noted to produce an immunethrombocytopenia in up to 4.5% of patients.[39] This ITP typically responds to rituximab.[40] Plateletdestruction is also increased when chemotherapy drugs produce a drug-dependent secondaryimmune 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. Inanimals or humans deficient in thrombopoietin or its receptor, the platelet count is 10% to 15% ofnormal values.[41,42] Megakaryocyte, erythroid, and myeloid precursor cells are all reduced in suchknock-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 ofdesialylated platelets may slightly increase hepatic thrombopoietin production.[44] Once in thecirculation, most thrombopoietin is cleared by avid thrombopoietin receptors on platelets andpossibly on bone marrow megakaryocytes. These cells bind, internalize, and then degradethrombopoietin. The small residual amount of thrombopoietin in the circulation accounts for thebasal 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 ofthrombopoietin production. With severe thrombocytopenia caused by chemotherapy, hepaticthrombopoietin mRNA levels are unchanged despite a 10- to 20-fold increase in the concentration ofthrombopoietin.[45] Hepatic damage results in a proportional decrease in thrombopoietinproduction.[46]Circulating thrombopoietin levels are inversely related to the rate of platelet production.[47] Withthe reduction in platelet production as a result of chemotherapy, thrombopoietin clearance isreduced and levels rise (see Figure 1). There is a log-linear relationship between the rise inthrombopoietin 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 isnormal, and levels do not rise. This primitive form of regulation of a hematopoietic growth factor issimilar to that by which the basal levels of G-CSF and macrophage colony-stimulating factor aredirectly maintained by the circulating mass of neutrophils and monocytes, respectively. The onlyexception seems to be erythropoietin, levels of which are determined by a hypoxia-inducedfactor–mediated renal sensor of the hemoglobin concentration.[51] There is no such sensor of theplatelet count.Thrombopoietin binds to its receptor on many hematopoietic cells and exerts its effect on moststages of megakaryocyte growth (see Figure 2). Thrombopoietin is necessary for the viability ofhematopoietic stem cells; when the thrombopoietin receptor is absent, humans are born withthrombocytopenia and develop pancytopenia over subsequent years.[52-54] Thrombopoietinstimulates mitosis of Mk-CFCs. Its major effect (at exceedingly low concentrations) is to increasemegakaryocyte endomitosis and increase megakaryocyte ploidy, greatly expanding themegakaryocyte pool. Thrombopoietin then stimulates megakaryocyte maturation. It is unclearwhether thrombopoietin plays any role in platelet shedding.[55] An underappreciated property ofthrombopoietin is that it prevents apoptosis of early and late megakaryocytes,[56] an effect thatmay play a major protective role in patients receiving radiation and chemotherapy (as discussedbelow).Inflammatory cytokines such as interleukin (IL)-6 and IL-11 may also stimulate platelet production bymechanisms 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 recentthrombopoietin receptor agonists.[2]With the discovery of thrombopoietin in 1994, two recombinant thrombopoietin molecules weredeveloped (Figure 3). Recombinant human thrombopoietin (rhTPO) was a fully glycosylatedthrombopoietin protein made in CHO (Chinese hamster ovary) cells. The other, pegylatedrecombinant human megakaryocyte growth and development factor (PEG-rhMGDF), was anon-glycosylated protein comprising the first 163 amino acids of thrombopoietin coupled topolyethylene glycol. Both molecules were potent stimulators of platelet production, with half-lives ofabout 40 hours. In healthy volunteers, both agents demonstrated the same time course of plateletresponse after a single dose: by day 3, megakaryocyte ploidy increased; by day 5, platelet countsstarted to rise; by days 10 through 14, a peak platelet count was obtained; and by day 28, plateletcounts returned to their baseline values.Between 1995 and 2000, both recombinant thrombopoietins underwent extensive clinicaldevelopment in oncology settings.[3] Development of both was stopped due to concerns overneutralizing antibody formation against PEG-rhMGDF.[59] Despite differences between the structureof PEG-rhMGDF and that of rhTPO, antibody formation against PEG-rhMGDF might have been due tothe route of administration. After early studies suggested that rhTPO might induce antibodyformation when given by a subcutaneous route, rhTPO was thereafter given intravenously, with nosubsequent antibody formation. In contrast, PEG-rhMGDF was given only subcutaneously, and inseveral studies patients developed neutralizing antibody to the recombinant protein.[60,61] In 525healthy volunteers given up to three monthly doses of PEG-rhMGDF, 13 (2.5%) developedthrombocytopenia due to the formation of antibodies to PEG-rhMGDF that cross-reacted withendogenous thrombopoietin, creating thrombopoietin deficiency and thrombocytopenia. All subjectsrecovered, but some required immunosuppressive treatment.[60,61]Despite the failure of one of these recombinant thrombopoietin molecules, interest turned todeveloping 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 identifiedthat had no sequence homology to thrombopoietin but bound to the thrombopoietin receptor; whendimerized, 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 ahalf-life of 120 hours (see Figure 3).[63] When injected into healthy volunteers, romiplostimproduced 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, aneightfold 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 thrombopoietinreceptor. One of these, eltrombopag, bound the thrombopoietin receptor in the transmembraneregion, an area different from where thrombopoietin or romiplostim bound, and activated thethrombopoietin 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, andboth increased the platelet count in over 85% of patients with ITP.[1,4,68-71] Both have beenapproved in many countries for the treatment of ITP; prolonged use of both has produced sustainedincreases 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 Cinfection requiring antiviral treatment[73] and in patients with aplastic anemia in whomimmunosuppressive therapy has failed.[74,75] In the latter disease, treatment was also associatedwith an increase in WBCs and RBCs.

Effect of rhTPO and PEG-rhMGDF in Cancer Patients ReceivingChemotherapy

Before considering the use of thrombopoietin agents in patients with cancer, it is important to notethat solid tumors appear not to possess functional thrombopoietin receptors.[76,77] In one studyusing reverse-transcription polymerase chain reaction (RT-PCR) on 39 human cell lines and 20primary normal and malignant human tissues, thrombopoietin receptor (c-mpl) transcripts werefound in all megakaryocytic cell lines tested (DAMI, CMK, CMK-2B, CMK-2D, SO), in the CD34-positiveleukemia cell line KMT-2, and in the hepatocellular carcinoma cell line Hep3B.[77] While fetal liverand brain cells had detectable levels of c-mpl mRNA, none was found in primary tumors. In a moreextensive study, microarray testing detected thrombopoietin receptor mRNA in 0 of 118 breasttumors and at very low levels in 14 of 29 lung tumors.[76] Low but detectable thrombopoietinreceptor mRNA was found by quantitative real-time PCR (QT-PCR) in some normal (14%–43%) andmalignant (3%–17%) breast, lung, and ovarian tissues, but none of these tissues showed detectablethrombopoietin receptor protein by immunohistochemistry. Culture of breast, lung, and ovariancarcinoma 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 bythe 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 abstractform. In general, thrombopoietin produced an earlier but higher nadir platelet count, shortened theduration of thrombocytopenia, reduced platelet transfusions, and enabled chemotherapy to be givenon schedule.When PEG-rhMGDF was administered to lung cancer patients for up to 16 days after treatment withcarboplatin 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; mediantime to nadir was 7 days vs 15 days (P < .001). The platelet count recovered to baseline in a medianof 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 placebogroup 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 carboplatinchemotherapy 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 vs20,000/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 aplatelet 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 at600 mg/m2 and cyclophosphamide at 1,200 mg/m2 in their first cycle. In subsequent cycles they alsoreceived PEG-rhMGDF for 1, 3, or 7 days after chemotherapy. Compared with cycle 1, those receivingthe 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 wassignificantly shorter (0 vs 3 days; P = .004). However, there was no difference in the time to plateletrecovery. 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 thetreatment of patients with relapsed NHL with ifosfamide, carboplatin, and etoposide (ICE)chemotherapy, maintenance of dose intensity and dose density correlates with improved survival. Ina study of 38 NHL patients randomized to placebo (n = 16) or PEG-rhMGDF (n = 22), ICE was givenon schedule to 42% of those on placebo and to 75% of those on PEG-rhMGDF (P = .008) with overallsurvivals of 31% and 59% (P = .06), respectively, after a median follow-up of 8.5 years. Patients onplacebo were 4.4 times more likely to have a dose delay; in 83% of cases, the dose delay was due tothrombocytopenia. Grade IV thrombocytopenia was seen in 35% of the placebo group vs 15% ofPEG-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% ofPEG-rhMGDF cycles (P = .04).There were no human radiotherapy studies with PEG-rhMGDF or rhTPO, but one important series ofprimate studies suggested that thrombopoietin might have a radioprotective effect.[82-86] Whenrhesus 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 theirradiation 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 radiationtherapy but without thrombopoietin, and 739,000/µL ± 165,000/µL with both radiation therapy andthrombopoietin. Assays for precursor cells of all lineages showed marked increases in viability whenrhTPO was administered.

Effects of Thrombopoietin Receptor Agonists in Cancer Patients ReceivingChemotherapy

Although 6 years have elapsed since the approval of thrombopoietin receptor agonists for treatmentof ITP, surprisingly few studies of these agents have been conducted in cancer patients undergoingchemotherapy. Only a small number of case reports[87] and small series of patients with cancerhave been published in this area.[88-91]In one retrospective study, cancer patients were selected who had a platelet count < 100,000/µL andwho had > 4-week delay in their chemotherapy or had dose reductions/modification in > 2 priorcycles.[88] These patients were treated with romiplostim at 2 µg/kg weekly. Platelet countsimproved in all of them, and 19 of 20 had platelet counts ≥ 100,000/µL. A total of 15 patientsresumed 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 orcarboplatin (12 patients) were randomized to receive eltrombopag or placebo on days −5 to −1 anddays 2 through 6, starting from cycle 2; no study drug was administered for cycle 1.[89] For patientsreceiving gemcitabine alone, the nadir platelet count for cycles 2 through 6 was 143,000/µL foreltrombopag 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 and50% of placebo patients required dose reductions or delays in cycles 3 through 6. No DVTs werereported, 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 samebeneficial effects in chemotherapy treatment as did the recombinant thrombopoietins, studies arechallenging in this area for many reasons, namely:• Most standard chemotherapy regimens do not produce very high rates of thrombocytopenia, andwhen 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 areusually experimental; it remains unclear whether platelet production support with a thrombopoietinreceptor agonist during chemotherapy is beneficial for the overall cancer outcome, which may bemore limited by the chemotherapy than by the supportive care.• Study design in this setting is also a concern. Although it is unlikely that concurrent administrationof a thrombopoietic agent during chemotherapy would have any adverse effect, the doses andschedules for these agents have certainly not been established. It is unclear whether treatment witha thrombopoietin receptor agonist before or after chemotherapy is superior or whetheradministration of thrombopoietin at both times is required.• Animal chemotherapy models would be of help to assess the dose and schedule of treatment withthrombopoietin receptor agonists. Unfortunately, eltrombopag is only active in chimpanzees andhumans; romiplostim is active in most species, but there are no animal studies to inform humantreatment.Good clinical studies that address the dose and schedule for the thrombopoietin receptor agonistsare essential. These should probably be conducted in patients who have developed significantthrombocytopenia during prior chemotherapy cycles. Pharmacokinetic/pharmacodynamic modelingsuggests that the ideal schedule for eltrombopag might be 5 days before and 5 days afterchemotherapy.[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 inguidelines, and there are no studies to guide the appropriate approach to management of patientswith this condition. Much depends upon the underlying treatment goals of the individual cancerpatient; different levels of risk assessment need to be brought into play for patients being treated forcure vs those being treated for palliation. Overall, it is reasonable when confronted withchemotherapy-induced thrombocytopenia first to assess the underlying need for chemotherapy andthe goals of treatment for that particular patient. A clinical assessment of bleeding risk for patients isalso important to undertake, especially if patients are receiving anticoagulant drugs or othertherapies that might increase bleeding. What follows is a synthesis of the data and the author’spersonal 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 ifchemotherapy is not standard or not of curative intent.• Platelet transfusion support should be used if maintenance of dose intensity is vital for response orsurvival. 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 outpatientsetting, however, this transfusion trigger needs to be reconsidered; transfusing at higher plateletcounts on the Friday before a long weekend has its advantages.• Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid have been used insome thrombocytopenic cancer patients to decrease the bleeding risk when platelet transfusions didnot work.[95-97] Total daily doses of 2–24 g (mean, 6 g) of epsilon-aminocaproic acid given in 3 or 4divided doses have been used.[96] Tranexamic acid doses of 4–6 g/d given as 3 or 4 divided doseshave also been studied.[97] However, the use of such agents in cancer patients is fraught withdifficulty 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 platelettransfusions and for whom the maintenance of dose intensity is crucial for remission or survival. Inthis setting, this author has used romiplostim at 2–3 µg/kg weekly, or 50–75 mg of eltrombopag dailyto maintain platelet counts over 100,000/µL, in order to allow continuation of chemotherapy (Figure6). Thrombopoietin receptor agonists would be started only when the patient’s platelet count hadfailed 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 theplatelet count only begins to rise 5 days after TPO administration, with maximal effect 10–14 dayslater, platelet transfusions should not be withheld if they are indicated.• The use of vincristine, rituximab, prednisone, IVIG, splenectomy, or anti-D immunoglobulin is rarelyjustified in patients with chemotherapy-induced thrombocytopenia, despite their widespread use andefficacy 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 hadbeen 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 ithas 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. Forexample, a platelet transfusion costs about $3,000 per event (calculated as the cost of a singleapheresis product or a pool of six random donor concentrates) and a transfused unit of RBCs costsabout $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 treatmentwith 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 itstreatment in patients with cancer. The simple issues of chemotherapy delay and dose reductioncarry with them costs in material and space utilization, while the larger issue of reduced doseintensity in some settings translates into the costs of life lost.While guidelines exist to guide the rational administration of platelet transfusions, there are few dataand no established guidelines to guide rational reduction in chemotherapy dose or frequency, whichis 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 factorcan be modified, the only treatments are platelet transfusion and dose modification of chemotherapyor radiation therapy. Future studies should target methods to mitigate thrombocytopenia byprotection of the bone marrow or the rational use of thrombopoietic agents. Guidelines need to bedeveloped that carefully assess the risks and benefits of current and future treatments for ourpatients with thrombocytopenia.Financial Disclosure: Dr. Kuter is a consultant to 3SBio, Amgen, Kirin, and Pfizer. He receivesresearch funding from Bristol-Myers Squibb, GlaxoSmithKline, and Ono.

Figure 1: The Relationship Between the PlateletCount (Open Circles) a...

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Table: Frequencies of Thrombocytopenia WithSelected Chemotherapy Regimens

Figure 2: The Production of Platelets From BoneMarrow Stem Cells

Figure 3: Structures of the RecombinantThrombopoietin (TPO) Molecules...

Figure 4: PEG-rhMGDF Increases the PlateletCount in Patients Undergoi...

Figure 5: rhTPO Reduces the Need for PlateletTransfusions in Patients...

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Figure 6: Use of Romiplostim to Increase thePlatelet Count in a Cance...

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