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Management ofChemotherapy-Induced Thrombocytopenia:Current Status of Thrombopoietic Agents

Saroj Vadhan-Raj

Myelosuppression, one of the most common toxicities of chemotherapy, results in varying degreeof cytopenias. While neutropenia and anemia have been reduced with the currently approvedhematopoietic growth factors, thrombocytopenia remains a significant clinical problem with anunmet medical need. Although platelet transfusions can provide a temporary solution, they do notaddress the underlying cause of thrombocytopenia. Management of chemotherapy-associatedthrombocytopenia often involves dose reductions or treatment delays. Thrombocytopenia can alsoaffect quality of life and significantly increase healthcare costs. With the introduction of severalnovel antineoplastic agents with an increased propensity to cause thrombocytopenia, a furtherincrease in the incidence of thrombocytopenia can be expected. Despite the extensive efforts inthe clinical development of thrombopoietic agents in the past decade, recombinant interleukin-11(IL-11) is the only agent currently approved by the US Food and Drug Administration for throm-bocytopenia induced by chemotherapy. The use of this agent is limited due to its narrowtherapeutic index. While promising biologic activity was observed with recombinant thrombopoi-etins (TPOs) in nonmyeloablative clinical settings, further clinical development was halted due toevidence of neutralizing antibodies to pegylated recombinant human megakaryocyte growth anddevelopment factor (PEG-rHuMGDF). Recently, a number of novel TPO receptor agonists havebeen developed with promising clinical activity and a lesser potential for immunogenicity. Severalof these second-generation platelet-stimulating agents are currently in clinical development, includ-ing peptide (romiplostim, formerly AMG-531) and nonpeptide (eltrombopag and AKR501) mimet-ics. The clinical trials of romiplostim and eltrombopag are currently ongoing to optimize their doseand schedule in ameliorating chemotherapy-induced thrombocytopenia.Semin Hematol 46:S26-S32. © 2009 Published by Elsevier Inc.

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hemotherapy-induced myelosuppression re-sults in various degrees of neutropenia, anemia,and thrombocytopenia and related complica-

ions that can lead to hospitalization, an impaired qual-ty of life, and an increase in healthcare costs. While

yeloid growth factors have reduced neutropenia andhe incidence of neutropenic fever, and erythropoieticgents have reduced anemia and transfusions, theretill remains an unmet need for treatment of chemo-

ection of Cytokines and Supportive Oncology, University of TexasM.D. Anderson Cancer Center, Houston, TX.

TATEMENT OF CONFLICT OF INTEREST: Saroj Vadhan-Raj, MD,discloses the following: Investigator: Amgen, GSK.

ddress correspondence to Saroj Vadhan-Raj, MD, Chief, Section ofCytokines and Supportive Oncology, Professor of Medicine, Univer-sity of Texas M.D. Anderson Cancer Center, Houston, TX 77030,E-mail: svadhanr@mdanderson.org

037-1963/09/$ - see front matter2009 Published by Elsevier Inc.

toi:10.1053/j.seminhematol.2008.12.007

Seminars in Hem26

herapy-induced thrombocytopenia (CIT). Thrombocy-openia increases the risk for bleeding complications,he need for platelet transfusions, and the frequency ofhemotherapy dose reductions and/or treatment de-ays, which may compromise the treatment outcome.1,2

latelet transfusions are also limited by cost, supply,nd associated risks, such as transfusion reactions,ransmission of infection, and alloimmunization andlatelet refractoriness. Alternate strategies are evaluat-

ng pharmacologic options to stimulate platelet produc-ion and to overcome CIT.

Megakaryopoiesis, the process of development ofegakaryocytes and production of platelets, involves aighly complex cascade of events, from differentiation of

mmature progenitors to maturation of megakaryocytesnd release of platelets into the bone marrow sinusoids.ytokines present within specialized bone marrowiches contribute to survival, proliferation, and differen-iation of megakaryocytes.3 In addition to TPO, an essen-

ial growth factor for platelet production, there are sev-

atology, Vol 46, No 1, Suppl 2, January 2009, pp S26-S32

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ral other growth factors and cytokines, such asnterleukin (IL)-1, IL-3, IL-6, IL-11, and stem cell factorSCF), that contribute towards megakaryopoiesis at differ-nt stages of development and maturation.4-6 In the lastecade, a number of these cytokines have been evaluatedor the prevention and treatment of thrombocytopenia.nfortunately, none has yet provided a commerciallyvailable agent with a high therapeutic index.

Despite very promising thrombopoietic activity, thelinical development of first-generation recombinantPOs was halted due to immunogenicity concerns.his led to the development of TPO agonists with noomology to TPO that can bind the TPO receptors andctivate signaling, leading to increase in platelet pro-uction. As with erythropoietin and granulocyte colony-timulating factor, the role of TPO receptor agonists islso undergoing careful evaluation. The initial resultsndicate that the second-generation TPO receptor ago-ists may play an important role in stimulating plateletroduction in various disorders of thrombocytopenia.

HEMOTHERAPY-INDUCEDHROMBOCYTOPENIA

Thrombocytopenia can be caused by myelosuppres-ive or myeloablative chemotherapy and/or radiation.1

IT occurs most commonly in patients receiving inten-ive chemotherapy, as in the setting of hematologicalignancies, pediatric malignancies, and stem cell

ransplantation, and with certain regimens used in che-osensitive malignancies. In patients with solid tu-ors, it is typically seen as more of a cumulative toxicity.IT is associated with dose-intensive chemotherapy in the

nitial cycles and palliative chemotherapy after multipleycles or regimens7 and is typically observed 6 to 14ays after a treatment cycle.1

Cancer patients with CIT generally have a higherost of healthcare. In a study among patients withymphoma or solid tumors who had treatment cycles

ith and without thrombocytopenia,8 treatment cyclesuring which patients had thrombocytopenia were sig-ificantly more costly than cycles during which theame patients had platelet counts of about 50,000/�L.he increase in cost was predominantly related to these of platelet transfusions for the prophylaxis andreatment of thrombocytopenia.

A number of chemotherapeutic agents and regimensave been associated with thrombocytopenia.1,2,7 Theiming and kinetics of platelet nadir may be differentepending on the mode of action. Some regimens,uch as ICE (ifosfamide, carboplatin, etoposide), AImesna, doxorubicin, ifosfamide), or MAID (mesna,oxorubicin, ifosfamide, dacarbazine), are associatedith earlier nadirs than others, such as carboplatin,elphalan, or nitrosoureas, which can cause a delayedadir. In addition to traditional chemotherapeutic

gents and regimens, several novel targeted agents can t

ontribute to thrombocytopenia (eg, bortezomib andenalidomide) in the combination regimens.

It is important to understand the underlying biologyf thrombocytopenia in order to more effectively inte-rate treatments to alleviate it. Although there are sev-ral different causes for thrombocytopenia, includingeficiency in platelet production, excessive platelet de-truction, and sequestration of platelets in the spleen, theredominant reason for a low platelet count in canceratients receiving chemotherapy is a deficiency in plate-

et production. Each class of chemotherapeutic drugsay have a different type of effect on megakaryocyte

evelopment. For example, drugs like busulfan andarboplatin have an antimitotic effect on stem cells,hich leads to decreased platelet production and

hrombocytopenia that can potentially be more pro-onged and more refractory to treatment. In contrast,everal common cytotoxic agents have an antimitoticffect on progenitor cells in later stages of develop-ent than the stem cells. Therefore, thrombocytopenia

esulting from treatment with the common cytotoxicgents tends to be shorter in duration and more cumu-ative in nature. In contrast, agents such as proteasomenhibitors, eg, bortezomib, inhibit activation of nuclearactor �B (NF-�B), which affects the ability of matureegakaryocytes to shed platelets, leading to a decrease inlatelet count. In a study of multiple myeloma patientseceiving bortezomib, the severity of thrombocytopeniaas correlated with the pretreatment platelet count, andatients with higher pretreatment platelet counts had a

ower incidence of grade 3 or grade 4 thrombocytope-ia.9 Furthermore, the thrombocytopenia was cyclic,ith a platelet nadir occurring around day 14, after which

he platelet count rapidly recovered. With each subse-uent treatment cycle, the platelet nadir levels rose, andlatelet transfusions were not necessary in later cycles.herefore, understanding the mechanism of thrombo-ytopenia is important for its appropriate management.

ANAGEMENT OF CIT

hemotherapy Dose Reductions/Delays

The most common interventions to manage CIT are toelay the next cycle of chemotherapy or to reduce theose or number of chemotherapy cycles. The goal ofhese measures is to allow bone marrow hematopoieticecovery. In a study of 609 solid tumor and lymphomaatients with CIT, dose delay or reduction was necessary

n 22% of treatment cycles due to bleeding and in 30% ofycles due to thrombocytopenia.2 Recommended treat-ent modifications depend on the agent used and the

everity of the thrombocytopenia. For grade 1 or 2 throm-ocytopenia, treatment is typically delayed for 1 or 2eeks, but significant thrombocytopenia (�50,000/�L)ay also require chemotherapy dose reductions. While

he value of dose-intensity has not been well established,

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ubtherapeutic doses of chemotherapy have been associ-ted with compromised treatment outcome in certainalignancies, such as lymphoma and breast cancer.10,11

hen chemotherapy dose was decreased to less than5% of the target dose in breast cancer patients,verall and relapse-free survival were significantlyecreased.10 It is unclear what proportion of theseatients received lower doses related to thrombocy-openia.

latelet Transfusions

Platelet transfusions have been shown to be the mostffective rapid treatment for patients with severe throm-ocytopenia,1,12 but they are also associated with several

ssues. The use of transfusion is limited by the plateletupply and the high cost-impact utility, and, as the de-and for platelet transfusions has steadily increased over

he past four decades,13 the ability of the platelet supplyo handle the demand of transfusions is in question. Ac-ording to the American Red Cross, there has been a 4%o 6% increase in the use of platelet transfusions over theast decade. Older patients (�65 years of age) are much

ore likely to receive platelet transfusions,14 and, as theopulation in the United States ages, the number of plate-

et transfusions will increase. Additionally, cancer patientsre being treated with more aggressive therapies, result-ng in more cases of CIT, and, accordingly, increasingemand for platelet transfusion to decrease bleeding ando promote effectiveness of treatment. Between one halfnd three quarters of all platelet transfusions in the Unitedtates are prophylactic in nature,15 and half of these pa-ients receive �6 units of platelets. In addition to feasibil-ty issues, there are several physical complications associ-ted with platelet transfusions. Patients can be refractoryo the transfused platelets1,16 or can experience immuno-enic reactions after transfusion.12,16 Platelet transfusionsre also associated with a risk of transmitting infection.16

The platelet level at which platelet transfusionhould be initiated has been unclear for decades, buthe conventional threshold for platelet transfusion hasong been 20,000/�L. This threshold is often creditedo a study from almost 5 decades ago on the relation-hip of thrombocytopenia to hemorrhage.17 In thistudy in patients with leukemia and thrombocytopenia,leeding increased as the platelet count decreased;owever, the study could not determine a specifichreshold for a prophylactic platelet transfusion. Sub-equent studies took a more direct approach to definehe clinically meaningful threshold for platelet transfu-ions, injecting radioactive iron into patients to mea-ure gastrointestinal blood loss through radioactivity intools.18 Significant gastrointestinal blood loss occurredhen platelet counts declined below 5,000/�L, which

uggested that the threshold for platelet transfusionould potentially be lowered. Another more recent

tudy of the relationship between thrombocytopenia o

nd bleeding in solid tumor patients2 showed that thencidence of bleeding doubled from 10% at a levelelow 20,000/�L to 20% when the platelet count waselow 10,000/�L. These results further indicate that alatelet count below 10,000/�L is associated with an

ncreased risk of bleeding.In the past decade, a number of studies have exam-

ned threshold for the prophylactic platelet transfusionn patients with mostly hematologic malignancies.hese studies have indicated that a prophylactic thresh-ld of 10,000/�L is, in general, well tolerated andssociated with reduction in the platelet usage withoutncreasing severe bleeding complications.19 In patientsdentified as higher risk for bleeding, a higher thresholdan be applied to reduce the risk. Guidelines from themerican Society of Clinical Oncology call for a platelet

hreshold of 10,000/�L for patients with solid tumorsuring CIT and a 20,000/�L threshold should be con-idered for patients with bladder cancer receiving ag-ressive therapy or demonstrated necrotic tumors.12

Finally, transfusion is only a temporary solution untilndogenous platelet recovery, and transfusion does notddress the underlying cause of thrombocytopenia. Al-hough the process for platelet preparation, storage,nd transfusion has been streamlined, there is a needor alternative therapies to effectively treat the under-ying cause of thrombocytopenia in these patients.

HROMBOPOIETIC AGENTS

ytokines

The process of megakaryocytopoiesis and plateletroduction is controlled by a number of cytokines.tem cell factor or c-KIT ligand and IL-3 or multi–olony-stimulating factor act at early stages and stimu-ate proliferation and differentiation of progenitor cellsnto megakaryocyte (MK) lineage. The multifunctionalytokines, such as IL-1, IL-6, and IL-11, act as costimu-ating factors in concert with early acting growth fac-ors and have effects at later stages in development.

In contrast, TPO, a potent megakaryocyte colony-stim-lating factor, has a broader activity, stimulating growthnd maturation of MK progenitor cells into mature MKs.arious thrombopoietic cytokines, including IL-1, IL-3,

L-6, IL-11, stem cell factor, and fusion molecules, such asIXY321 and promegapoietin (IL-3/C-mpl receptor ago-ist), have been investigated. These cytokines mediateultiple biologic effects and have increased platelet

ounts in preclinical and clinical studies.Based on their thrombopoietic activity, clinical trials

ave examined the potential of these agents in reduc-ng CIT. IL-1, IL-3, IL-6, and IL-11 were independentlynvestigated in clinical trials, and, although they allhowed promising thrombopoietic activity, their use haseen limited due to their toxicity profile.20 IL-11 was the

nly cytokine tested that was granted approval by the US

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ood and Drug Administration for this indication, basedargely on a relatively small, phase II, randomized clinicalrial in patients who had required platelet transfusion atevels of �20,000/�L for CIT. Placebo or rhIL-11 wasdministered subcutaneously once daily for 14 to 21 days.dose of 50 �g/kg of IL-11 reduced the need for trans-

usion in eight of 27 patients in the subsequent cycle,ompared to one of 27 who were given placebo (P �.05).ith the lower dose of 25 �g/kg of IL-11, five of 28

atients avoided transfusion, but this number did noteach statistical significance when compared to placebo.he toxicity profile with IL-11 is significant, includingdema in more than 50% of patients, dyspnea, atrial ar-hythmias, syncope, and fatigue.21

A more recent study in younger patients receivingntensive chemotherapy showed that there was a trendowards shortened time to platelet recovery and reduc-ion in the number of platelet transfusions with IL-11.owever, the toxicity profile was similar to the phase

I study described above, with the addition of perios-eal bone changes. As these toxicities are not favorableor a supportive care agent, less toxic and more effec-ive agents are necessary.22

PO Agents in CIT

The first-generation thrombopoietic agents were re-ombinant versions of TPO. Recombinant human TPOrhTPO) was a full-length molecule, PEG-rHuMGDFas a truncated, pegylated (PEG) version of recombi-ant human megakaryocyte growth and developmentactor (MGDF), and promegapoietin was a chimericonstruct of IL-3 and Mpl ligand.23 The clinical devel-pment of all three agents was halted after neutralizingntibodies against PEG-MGDF and promegapoietinere found in healthy subjects. However, extensive

linical investigations were completed with two ofhese agents, rhTPO and PEG-rHuMGDF.7 Some of therinciples learned from these studies can provide in-ight into biology and potential clinical applicationsnd directions with novel thrombopoietic agents.

In general, efficacy is observed with these agentshen a population of megakaryocytes and precur-

ors is available to respond to TPO, but clinicalctivity has not been demonstrated where there is aaucity of target cells available to stimulate, such as

n the setting of highly myelosuppressive or myeloa-lative chemotherapy, as used in acute myeloid leu-emia induction and consolidation or stem cell trans-lantation. There is no impact on platelet nadir, time toecovery (�20,000/�L), or platelet transfusions in pa-ients who received either of these agents followingtem cell transplant.7 However, clinical activity is dem-nstrated in CIT in a schedule-dependent manner, inlatelet apheresis (both normal donors and cancer pa-ients), in stem cell mobilization, and in treating myelo-

ysplastic syndromes and immune thrombocytopenic g

urpura in limited experience. The clinical experiencen CIT with TPO molecules will be briefly reviewed tonderscore the complexity in the development ofhrombopoietic agents in CIT setting.

Initial studies with both rhTPO24 and PEG-HuMGDF25,26 showed a dose-dependent increase inlatelet counts without chemotherapy. In a studyith advanced cancer patients, treatment with PEG-

HuMGDF substantially increased platelet counts, buthe kinetics of response show that the peak effect wasetween day 16 to day 18.25 This time factor has led toifficulty encountered in CIT, as most cytotoxic drugsause a platelet count nadir earlier, around day 10 toay 14. In a study of rhTPO in patients with sarcoma, aose-related increase in platelet counts was observedfter a single dose. The peak effect occurred at day 12r day 13, and this delay in peak response causesroblems when these agents are integrated postchemo-herapy.24

In a setting where the platelet nadir occurs late,round day 16, as with carboplatin, efficacy in CIT wasemonstrated. In a study of 29 patients with ovarianancer treated with high-dose carboplatin (area underhe curve [AUC] 11), patients did not receive plateletrowth factor until cycle 2, when carboplatin wasollowed by rhTPO every other day for four doses.27

ompared to the control cycle (cycle 1) without TPO,atients experienced a reduction in degree and dura-ion of thrombocytopenia and faster platelet recoveryn cycle 2 with rhTPO (Figure 1). This led to a reduc-ion in the need for platelet transfusion, from 75% inhe control cycle to 25% in cycle 2 with rhTPO atiologically active dose. Therefore, for CIT induced byn agent such as carboplatin, which causes a late plate-et nadir, treatment with rhTPO was very effective ineducing thrombocytopenia.

As mentioned earlier, treatment of CIT is problem-tic with chemotherapy agents that cause an earlylatelet nadir, between day 10 and day 12. To over-ome this problem, administration of rhTPO prior tohemotherapy was examined to determine whetherllowing the biologic effects of rhTPO to stimulateegakaryocyte development before chemotherapy

ould offset the platelet nadir.28 Multiple cohorts of sixatients with sarcoma (n � 66) were treated sequen-ially with doxorubicin and ifosfamide (AI regimen) andarying schedules of four fixed doses (1.2 �g/kg) ofhTPO in cycle 2 and subsequent cycles. The plateletadir for AI occurs early, around day 12. Therefore, itas felt that earlier administration of rhTPO prior to

hemotherapy may overcome the nadir. The cohortsncluded two doses prechemotherapy and two dosesostchemotherapy; three doses pre and one dose post;ne dose pre and three doses post; all four dosesostchemotherapy; and all four doses of rhTPO preche-optheary. The best results were obtained with the

roup of patients who received three rhTPO doses

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rior to chemotherapy, starting 5 days prechemo-herapy, and one dose after chemotherapy (Figure 1).esults from the subsequent cohorts treated with aingle pre-dose administered 5 days before and a singleose postchemotherapy demonstrated similar efficacy

n attenuating platelet nadir with this regimen.These studies highlight the importance of timing in

rder to optimize the use of thrombopoietic agents in theIT setting. In both the carboplatin study and the AItudy, there was a reduction in thrombocytopenia with aaster platelet recovery using different schedules.29 Opti-al TPO schedule depends on the length of the chemo-

herapy regimen and kinetics of platelet nadir; with ahort chemotherapy regimen and/or delayed platelet na-ir, postchemotherapy dosing with rhTPO may be suffi-ient, but, with a long regimen and/or early nadir, earlyosing of rhTPO both before and after chemotherapy maye required to impact the nadir and transfusions.

It is plausible that this strategy may not be applicablen all CIT settings. In a study with acute myeloid leu-emia patients, two different doses of PEG-rHuMGDF2.5 �g/kg/d or 5 �g/kg/d) were given in patientseceiving chemotherapy with daunorubicin and cytar-bine.30 The platelet recovery was very high, reachingreater than 700,000/�L, but the nadir was not af-ected. It is possible that in settings where there are noarget cells available or not enough time to stimulatelatelet production, such as in the transplant setting orith highly myelosuppressive chemotherapy regimensf longer duration, these agents may not effective inhe traditional way.

igure 1. Schedule-dependent reduction in thrombocytolatin; Pre, prechemotherapy; Post, postchemotherapy; rh

mportance of schedule of rhTPO with early nadir v late nadiven as all four doses postchemotherapy with carboplaostchemotherapy with AI (early nadir). The right panel shoith AI (early nadir). Reprinted with permission from Cuueso-Ramos C. Thrombopoietic growth factors and cytok

Alternate strategies in these settings may include autol- d

gous platelet transfusions collected in remission or allo-eneic transfusion of platelets obtained from normal do-ors treated with TPO agents to stimulate platelets and

ncrease donation yield for subsequent transfusions. In atudy of patients with ovarian cancer, two doses of rhTPOere given before chemotherapy to raise the platelet

ount high enough for autologus donation. Platelets wereollected (an average of around 50 units in two collec-ions) and cryopreserved for later use.31 Patients werehen treated with high-dose carboplatin. A reproducibleise in platelet count occurred after every autologouslatelet transfusion, including in those patients who wereefractory to the first transfusion of single-donor alloge-eic platelets. These results were consistent over a periodf six cycles.

These cryopreserved autologous platelet transfu-ions appeared to be more effective than single-donor,resh platelets in select patients with alloimmunization.s shown in Figure 2, in the study above, a patientesponded to a cryopreserved autologous platelet trans-usion in the initial cycle. This patient experiencedrolonged thrombocytopenia, experienced bleeding,nd did not respond to the allogeneic, fresh, single-onor platelets in the subsequent cycle.31 However,his patient responded to another autologous cryopre-erved platelet transfusion, the bleeding stopped, andhe platelet count recovered, suggesting that this is aiable strategy in select clinical settings (Figure 2).

PO Agonists in Clinical Trials

The setback of immunogenicity (or antibody pro-

y rhTPO. AI, doxorubicin and ifosfamide; CBDCA, carbo-combinant human thrombopoietin. The figure shows theens. The left panel shows the effects of rhTPO (1.2 �g/kg)e nadir). The middle panel shows all four doses givendoses prechemotherapy and one dose postchemotherapy

matolology Reports, Vol. 4, Vadhan-Raj S, Cohen V, andges 137-144, Copyright 2005.

penia bTPO, reir regimtin (latws threerrent He

uction) to the first-generation thrombopoietic agent

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ed to the development of second-generation TPO mi-etics, both peptide and nonpeptide molecules, andPO agonist antibodies. Several novel thrombopoieticgents are in clinical trials, such as romiplostim, eltrom-opag, and AKR501. The kinetics of platelet responseith these agents are similar to TPO. The time to peaklatelet response is similar for all three agents: arounday 15 with romiplostim,32 around day 15–16 withltrombopag,33 and around day 15 with AKR501.34

herefore, some of the same issues as with recombi-ant TPOs will be encountered with these agents whenombined with chemotherapy.

An ongoing phase I/II study of romiplostimin inatients receiving high-dose carboplatin (a late nadiregimen) and AI regimen (an early nadir regimen) isnvestigating the optimal dose/schedule to reducehrombocytopenia and transfusions. Clinical trials arelso examining the use of eltrombopag in CIT. Onehase II study compared eltrombopag to placebo inatients with advanced solid tumors who received che-otherapy with carboplatin and paclitaxel.35 This

tudy has been completed and results will be forthcom-ng. A phase I study of eltrombopag in patients witharcoma who are receiving AI is currently ongoing.36

ONCLUSIONS

Treatment of thrombocytopenia induced by chemo-herapy still remains an unmet medical need. A numberf cytokines with pleiotropic biologic activity haveeen tested with modest efficacy but have an unfavor-ble toxicity profile. Recombinant TPO and PEG-HuMGDF have both shown potent biologic activity,ut immunogenicity has remained a concern. Treat-

igure 2. Utility of autologous cryopreserved platelets iransfusion. The figure shows the response to autologouslloimunized patient refractory to allogeneic single-donorrom The Lancet, Vol. 359, Vadhan-Raj S et al, Safety and efrom recombinant human thrombopoietin to support chross-over study, pages 2145-2152, Copyright 2002, with

ent biology with these agents is complex, and, there-

ore, optimization of scheduling was the main issue inhe development of their use in CIT. The new TPOimetics and TPO-receptor agonists clearly hold prom-

se. They have been found effective in immune throm-ocytopenic purpura and patients with hepatitis C–re-

ated cirrhosis receiving antiviral treatment. However,heir role in CIT remains to be defined, and trials arengoing to determine their clinical safety, optimalcheduling, and dosage.

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