Pharmacologic treatment options in patients with thrombocytopenia

Pharmacologic Treatment Options in Patients With Thrombocytopenia George D. Demetri Thrombocytopenia that results from chemotherapy has become an increasingly important issue in the treatment of cancer and remains a difficult clinical problem. The identification of a safe and effective platelet growth factor could significantly improve the management of severe chemotherapy-induced thrombocytopenia. Over the past decade, a number of hematopoietic growth factors with thrombopoietic activity have been identified, including stem-cell factor (c-kit ligand), interleukin (IL)-1, 11-3, IL-6, and IL-11, as well as thrombopoietin (TPO) and its derivatives. Only a few of these agents have shown acceptable tolerability and sufficient ability to stimulate thrombopoiesis to justlfy testing in randomized clinlcal trials. Currently, IL-11 is the only cytokine licensed In the United States for treatment of chemotherapy-induced thrombocytopenia. However, Its thrombopoietic activity is modest and its use is often associated with unfavorable side effects. Identification of TPO, the c-Mpl ligand, as the primary physiologic regulator of megakatyocyte and platelet development offers important promise for treatment of thrombocytopenia. Preliminary clinical studies of recombinant human TPO (rhTPO), a full-length glycosylated molecule, indicate that it is safe and biologically active in reducing severe chemotherapy-induced thrombocytopenia. In addition to rhTP0, the future may see the development of novel genetically englneered, high-afflnity cytokine receptor agonists and c-Mpl ligand mimetic peptides. Semin Hematol37(suppl4):ll-18. Copyright 0 2000 by W.B. Saunders Company.

M

YELOSUPPRESSION AND ASSOCIATED anemia, neutropenia, and thrombocytopenia are common dose-limiting and clinically problematic sequelae of radiation therapy and chemotherapy. Although growth factors such as erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF) have improved the management of chemotherapy-induced anemia’s2and neutropenia,3t4 an unmet medical need remains for mitigation of severe chemotherapy-induced thrombocytopenia. Although thrombocytopenia associated with conventional dose chemotherapy regimens rarely requires intervention, it remains a serious clinical problem in patients undergoing dose-intensive chemotherapy, induction and consolidation therapy of hematologic malignancies, and chemotherapy following multiple prior regimens. Platelet transfusion therapy is currently the only acute treatment for severe thrombocytopenia. Although temporarily effective in controlling severethrombocytopenia, platelet transfusion therapy is associatedwith several problems, including refractoriness and alloimmunization,>-a transmission of infectious agents,9T10 and transfusion reactions.ll The limited supply Seminars

in Hematology,

of blood products and increased cost associated with complications of platelet transfusions can also be problematic. l2 Furthermore, the need for therapeutic platelet transfusions limits outpatient treatment. Consequently, the clinical availability of safe and effective platelet growth factors is eagerly awaited.

Cytokines

with Thrombopoietic Effects

The search for a thrombopoietic growth factor has led to the identification of a number of cytokines and growth factors that can influence thrombopoiesis including thrombopoietin (TPO), stem-cell factor (c-kit ligand), interleukin (IL)-1, IL-3, IL-6, IL-l 1, and GM-CSF (Table 1). Preclinical studies of IL-l, IL-3, IL-6, and IL-l 1 indicated that these cytokines could stimulate megakaryocyte growth and producFrom the Center for Sarcoma and Bone Oncology, Farber Cancer Institute, Sarcoma Center, Boston, MA. Address reprint requests to George D. Demetri, MD,

DanaCenter

for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Sarcoma Center, 44 Binney St, Boston, MA, 02115-6084. Copyright 0 2000 by W.B. Saunders Company 003 7-l 963/00/3 702-4004$10.00/0 doi:lO.lO~3/sh.2000.7388

Vol 37, No 2, SuppI 4 (Apd),

2000:

pp 1 l-18

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George D. Demtri

Table

1. Cytokine

Approaches

to Thrombopoiesis

Pleiotropic cytokines IL-1 IL-3 IL-6 IL-11 c-Mpl llgands Peg-rHuMGDF rhTP0 Abbreviations: IL, interleukin; cyte growth and development human thrombopoietln.

Peg-rHuMGDF, factor: rhTP0,

megakarye recombinant

tion both in vitro and in animal models of severe radiation- and chemotherapy-induced thrombocytopenia. However, the thrombopoietic activity observed in vitro often has not translated into a significant clinical effect, and many of the first thrombopoietic cytokines tested had unacceptable toxicities.

Initial Thrombopoietic

Cytokines

In phase I/II studies, IL-3 functioned as a multilineage hematopoietic growth factor and produced dose-dependent effects on peripheral platelet counts. i3-16 However, these promising results were not confirmed in phase III studies, which showed no significant clinical benefit from adding IL-3 to supportive care in reducing the number of platelet transfusions required or incidence of severe grade 4 thrombocytopenia.17x1sMoreover, IL-3 appeared to have little effect on overall hematopoietic cell recovery in patients with lymphoma undergoing autologous bone marrow transplantation19 and in patients with myelodysplastic syndrome.*O Similarly, variable clinical effect on platelet recovery was observed with stem-cell factor. In a small phase I study of patients with nonsmall-cell lung cancer, stem-cell factor appeared to enhance recovery of neutrophils and platelets after chemotherapy.*’ However, stemcell factor appeared to have no effect on platelet counts in breast cancer patients receiving more dose-intensive therapy.** The pleiotropic biologic effects of the thrombopoietic cytokines also raised concern about their clinical application. Although interleukins such as IL-l and IL-6 have thrombopoietic

activity in vitro, *K** they are associated with a spectrum of in vivo effects, including fever25 and induction of acute-phase proteins.26-29 In clinical studies, the potential therapeutic role of IL- 1(Y in attenuating chemotherapy-induced thrombocytopenia was limited by toxicities, including fever, chills, hypotension, and headache.30J1 Extensive toxiciries observed in patients with solid tumors3* and little efficacy in patients with bone marrow failure also limited the use of recombinant human (rh)IL-1P.33 Similarly, IL-6 has been shown to stimulate murine megakaryocytopoiesis in vivo by acting on early megakaryocyte differentiation.** Although this cytokine appeared to accelerate platelet recovery following chemotherapy with minimal toxicity in patients with ovarian cancer,3* other clinical trials of IL-6 in cancer patients have reported only modest thrombopoietic efficacy and significant toxicity, including hyperbilirubinemia, rapid induction of anemia, fever, and fatigue.29,35v36Thus, moderate efficacy and high toxicity may limit the clinical use of IL-6.

Interleukin-

11

The ability of rhIL-11 (Neumega; Genetics Institute, Cambridge, MA) to indirectly promote the proliferation and maturation of megakaryocytic cells in vitro3’-39 and to accelerate the recovery of platelets in myelosuppressed animals40~41stimulated interest in this cytokine as a potential thrombopoietic agent. In phase I clinical studies conducted in breast cancer patients, administration of rhIL-11 was associated with dose-dependent increases in mean platelet counts, increased bone marrow megakaryocyte and progenitor cell numbers, and reduced incidence of severe thrombocytopenia compared with expectations.**,*3 Similar results were observed in a randomized study of rhIL-11 in breast cancer patients undergoing dose-intensive chemotherapy.** Toxicities associated with rhIL-11 in these studies included fatigue, myalgia, edema, and cardiovascular events.*3~** The ability of rhIL-11 (25 pg/kg and 50 pg/kg) to prevent the need for platelet transfusions compared with placebo was studied in 93 cancer patients who required platelet transfusions in the chemotherapy cycle imme-

Treatment Option

diately before randomization. In this study, rhIL-11 (50 pg/kg) significantly decreased the requirement for platelet transfusions in 30% (eight of 27) of patients (P < .05).45 Based on these results, rhIL-11 was licensed in the United States for the treatment of severe chemotherapy-induced thrombocytopenia. In the autologous transplant setting, rhIL-11 did not reduce the requirement for platelet transfusions and was associated with mild edema and higher incidence of cardiovascular events.46 Thus, despite its ability to ameliorate thrombocytopenia in a subset of patients treated with conventional dose chemotherapy, its moderate toxicity and indirect effect on megakaryocytopoiesis make rhIL-11 a less than ideal thrombopoietic agent.

Novel Strategies: PIXY32 1, Syntbokine, and Combination Therapy Strategies to improve the specificity and activity of thrombopoietic factors have led to the development of several novel factors (Table 2), including the fusion protein PIXY321 and a highly mutated genetically engineered analog of IL-3 referred to as synthokine. PIXY321 is a bifunctional cytokine produced by the fusion of the cDNAs for GM-CSF and IL-3. Results of nonrandomized phase I/II studies of PIXY321 indicated a potential role for this novel agent in attenuating cumulative chemotherapy-induced myelosuppression47-49and in increasing hematologic recovery after autologous bone marrow transplantation.50J1 However, as with the cytokines mentioned previously, favorable preliminary clinical results observed with PIXY321 in phase I/II studies were not confirmed in larger randomized phase III studies5*z53 Furthermore, the development of neutralizing antibodies to PIXY321 abrogated its hematologic effects after multiple exposures.53 Synthokine, a high-affinity IL-3 receptor ligand, also showed greater activity in stimulat-

Table

2. Synthetic

Cytokine

Approaches

PIXY321 IL-3 synthokine c-Mpl ligand mimetic peptides GW395058 Promegapoietin (thrombopoietin

to Thrombopoiesis

plus IL-3 synthokine)

fw

13

Tbrmbocytopenia

ing hematopoiesis of human bone marrow progenitor cells in vitro than did native IL-3.54,55 In a nonhuman primate model of radiationinduced myelosuppression, synthokine at a dose of 100 pg/kg/d significantly reduced the duration of thrombocytopenia compared with control animals.55 However, clinical evaluation of this agent has been discontinued due to lack of sufficient activity to improve thrombocytopoiesis in patients. The role of combined cytokine treatment after cytotoxic therapy has also been investigated. Results of underpowered phase I/II studies evaluating the combination of IL-3 with G-CSF or GM-CSF suggested that this combination was well tolerated and could produce a clinically significant increase in platelet counts in patients receiving myelosuppressive chemotherapy.5”-58 A recent randomized, doubleblind, phase II study evaluated the efficacy of combining IL-6 with G-CSF compared with placebo plus G-CSF in patients receiving standard chemotherapy for ovarian cancer.59 Patients who received IL-6 (1 pglkg) and G-CSF (5 pg/kg) had higher platelet nadirs in the first cycle than did the placebo group. However, no statistically significant difference in cycle treatment delays, carboplatin dose delivered, number of patients with grade 4 thrombocytopenia, or platelet transfusion was observed between the treatment groups. Again, the pattern emerges of initial encouragement from small feasibility studies being trumped by negative results from appropriately powered, randomized studies-a not uncommon theme in the annals of drug development.

Thrombopoeitin

and c-Mpl

Ligands

The cDNA for the c-Mpl ligand was isolated and cloned in 1994,60-64and subsequent studies showed that the c-Mpl ligand is indeed the long sought after TPO. 63,65,66 In both in vitro and in vivo experimental studies, TPO stimulated increasesin megakaryocyte number, ploidy, and platelet count.62,67Thus, TPO appears to be the primary regulator for both the proliferation and differentiation of most stages of megakaryocytopoiesis, although it may not be a critical factor in the final platelet budding from mature

14

George D. Dtmtri

megakaryocytes .68,69 The major recombinant forms of TPO that have been developed for clinical studies include rhTP0 the full-length, glycosylated molecule (Genentech, Inc, San Francisco, CA) and PEG-rHuMGDF the truncated, pegylated derivative of the molecule (Amgen Inc, Thousand Oaks, CA).

Megakaryocyte Growth and Development Factor PEG-rHuMGDF, the most broadly studied variant of TPO, has produced dose-dependent increases in platelet counts in patients with advanced malignancies70 and significantly attenuated chemotherapy-induced thrombocytopenia.71*72Administration of PEG-rHuMGDF to healthy platelet donors increased platelet counts and apheresis yields. These increases, in turn, were associated with significantly larger absolute platelet increments in transfusion recipients. ‘3 However, PEG-rHuMGDF has been associated with adverse events, most importantly the development of neutralizing antibodies.T4 Because of these side effects, the manufacturer (Amgen Inc) withdrew the product from clinical trials in the United States in September 1998.

Recombinant Human Thrombopoietin In clinical studies, rhTP0 has also produced a dose-dependent increase in platelet counts in patients with sarcomas75and gynecologic malignancies76 who were at risk for developing severe chemotherapy-induced thrombocytopenia. In these studies, treatment with rhTP0 was well tolerated and without serious adverse events. Studies of rhTP0 in the treatment of chemotherapy-induced thrombocytopenia continue. To date, the development of neutralizing antibodies in patients treated with rhTP0 has not been reported, which may be due in part to the intravenous route of administration used for rhTP0 compared with the subcutaneous route used for PEG-rHuMGDF. It is postulated that subcutaneous administration may allow dendritic cells in the skin to process PEGrHuMGDF and increase its antigenicity. Further studies of rhTP0 in the clinical setting are all proceeding with the intravenous route of administration to minimize this risk.

Synthetic c-Mpl Ligands Synthetic peptides that share no homology with TPO can be designed to compete with TPO for binding to the c-Mpl receptor. These molecules include the TPO mimetic peptide GW395058 and promegapoietin (Table 2). GW395058 is a pegylated, peptide TPO receptor agonist under evaluation for the treatment of chemotherapyinduced thrombocytopenia.77 Because it can share epitopes, its potential for immunogenicity is a significant concern. However, recent experimental studies suggest that its potential for the production of neutralizing antibodies is low, although the PEG-rHuMGDF experience reinforces the fact that only clinical data will be able to fully answer this important concern.” Promegapoietin, a genetically engineered chimerit growth factor, has agonist activity at both the IL-3 and c-Mpl receptors.78 However, clinical development of this molecule was discontinued in November 1998, again due to concerns of antibody development when given by the subcutaneous route.

Conclusion Platelet transfusions remain the standard of care for the treatment of patients with life-threatening thrombocytopenia. Platelets, however, are a limited and costly resource, and their use is associated with inconvenience, expense, transmissible infections and antibody development. Consequently, significant medical resources have been expended in the search for cytokines and hemacopoietic growth factors to treat and prevent thrombocytopenia. Many of the thrombopoietic cytokines and growth factors identified have failed to produce significant clinical activity. This may be a result of the complex intrinsic biology of platelet production. Although IL-1 1 is approved for the secondary prophylaxis of chemotherapy-induced thrombocytopenia, it is a pleiotropic factor with modest clinical activity and is frequently associated with unacceptable systemic toxicities. Thus, there is room for improvement in cytokine support of thrombopoiesis. The ideal factor must have an outstanding safety and tolerability profile and be effective and reliable in increasing platelet counts. rhTP0 appears to be

Trtutmt

Option

the most specific and effective growth factor identified to date for the treatment of therapyinduced thrombocytopenia. Preliminary clinical evidence indicates that rhTP0 may be a promising adjunct to the conventional approach of platelet transfusion therapy and may become the agent of choice for the treatment of chemotherapy-induced thrombocytopenia in cancer patients.

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of platelet (PLT) donors with pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuPEG-RHUMGDF) increases circulating PLT counts (CTS) and PLT aphersis yields and increases platelet increments in recipients of PLT transfusions. Blood 90:579a, 1997 (suppl 1, abstr 2579) Crawford J, Glaspy J, Belani C, et al: A randomized, placebo-controlled, blinded, dose scheduling trial of pegylated recombinant human megakaryocyte growth and development factor (PEG-RHUPEGRHUMGDF) with filgrastim support in non-small cell lung cancer (NSCLC) patients treated with paclitaxel and carboplatin during multiple cycles of chemotherapy. Proc Am Sot Clin Oncol 17:73a, 1998 (abstr 285) Vadhan-Raj S, Murray LJ, Bueso-Ramos C, et al: Stimulation of megakaryocyte and platelet produc-

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