of Thrombopoietic Growth Factors

Transcription

1 Opportunities for the Use of Thrombopoietic Growth Factors CHARLES A. SCHIFFER Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA Key Words. Thrornbopoietin Platelet transfusion, Platelet donation Acute rnyeloid leukemia ' Hernatopoietic growth factors Platelets ABSTRACT Highly lineage specific thrombopoietic factors are now available which can produce substantial increments in platelet counts and attenuate the severity of therapy induced thrombocytopenia in preclinical models a:id early trials in patients. These striking findings are not equivalent to proving clinical benefit to patients, however, and studies are now in progress in a variety of clinical settings. Methodologic issues which could influence the interpretation of studies using thrombopoietin to mitigate thrombocytopenia in patients treated for acute myeloid leukemia and following stem cell transplantation are discussed. Studies in thrombocytopenic patients with myelodysplasia, aplastic anemia, immune throm- bocytopenic purpura, as well as selected platelet and stem cell donors, are also of interest. It is unclear, however, whether patients with impaired marrow function can benefit from further exogenous stimulation, and side effects must be very carefully monitored in studies with normal donors. Stem Cells 1998;16(suppl2): INTRODUCTION Although death from hemorrhage is a rare event in patients receiving intensive or myeloablative chemotherapy, more minor episodes of bleeding are common and there are many complications from repeated platelet transfusion. These side effects include febrile or allergic transfusion reactions [I], fluid overload, the occasional occurrence of bacteremia due to inadvertent contamination of the platelet product at the time of collection [2], and the development of alloimmunization with refractoriness to platelet transfusions. Compatible donors for alloimmunized patients can be difficult to locate, leaving the patient at risk of bleeding. Furthermore, the costs of transfusion are considerable, with additional hidden expenses including the loss in time from employment and other tasks incurred by apheresis donations. With the exception of the rate of alloimmunization, the frequency of these problems is related to the number of platelet transfusions administered [3]. Any means by which the need for platelet transfusions can be eliminated or significantly reduced would be of clinical benefit; hence, the long-standing interest in the identification of thrombopoietic stimulating factors. As described elsewhere in this volume, lineage-specific preparations of thrombopoietin are now available which produce marked elevations of megakaryocyte mass and platelet count after subcutaneous dosing, without apparent side effects [4, 51. Preclinical models suggest amelioration of severe thrombocytopenia and the need for platelet transfusion after administration of high-dose radiation or chemotherapy [6-91. Thrombopoietin: From Molecule to Medicine STEM CELLS 1998;16(suppl2): OAlphaMed Press. All rights reserved.

2 250 Clinical Uses for Thrombopoietin Trials in humans with these recombinant preparations are in progress. Early trials have shown a dose-dependent rise in platelet count beginning a few days after administration of the thrombopoietin without changes in the RBC or neutrophil counts, the production of morphologically and functionally normal platelets, mobilization of hematopoietic colony-forming units into the peripheral blood, attenuation of thrombocytopenia after chemotherapy (albeit in clinical circumstances in which the level of myelosuppression does not require platelet transfusion), and an absence of significant side effects in recipients [ Demonstration of these marked thrombopoietic effects is not the same as proving clinically meaningful benefit, however. Because fatal or serious hemorrhage is uncommon even at very low platelet counts, it would be difficult to demonstrate a favorable impact of the use of thrombopoietin by assessments of the rate of major hemorrhage [17]. It is also difficult to quantify more minor degrees of bleeding; thus, the potential benefit of a thrombopoietin should be evaluated primarily by a shorter duration of severe thrombocytopenia, a reduction in the number of platelet transfusions, and by inference, a decreased likelihood of some of the complications of transfusion. It is therefore critical to identify groups of patients who reproducibly require significant numbers of platelet transfusions as part of their treatment. There are wide variations in clinical practice with regard to criteria for administrating prophylactic platelet transfusion [IS]. Two recent randomized trials in patients with acute leukemia have demonstrated the safety of a lo,ooo/yl threshold [19, 201 for transfusion in stable patients, and most physicians are now comfortable in observing clinically stable patients at lower counts without immediately administering platelet transfusion. In our practice, the decision to administer platelets is individualized according to the patient s unique clinical circumstances [ 171. We frequently will not administer prophylactic platelet transfusions to patients who are clinically stable without active hemorrhage (e.g., patients with aplastic anemia, chronic myelodysplasia, etc.), even at platelet counts of 5,0OO/pl or below. It is likely that wider adoption of a lower transfusion trigger will decrease the number of transfusions required for many patients, and this change in practice should be considered in the design and interpretation of clinical trials. Randomized clinical trials evaluating thrombopoietins are being initiated in patients with acute myeloid leukemia (AML) and following myeloablative therapy. The methodologic issues inherent in these trials are similar to those addressed in randomized trials of myeloid growth factors [21]. It is critical that all such trials be double-blind and placebo-controlled in order to objectively evaluate side effects of therapy such as stimulation of leukemia cell growth as well as controlling for potential biases which could influence the decision to prescribe platelet transfusions, particularly towards the end of the aplastic period. Preferably, there should be some standardization of the dose of platelets administered and possibly some guidelines about ABO compatibility and the duration of storage. In addition, G- or GM-CSF are used commonly in patients receiving very high-dose therapy. Therapeutic or toxic interactions between the myeloid and thrombopoietic growth factors will therefore also have to be considered in the study design. There are some unique issues in trials in patients with AML. During induction treatment, patients require approximately platelet transfusions [22]. Most of these transfusions are administered during the first few weeks of treatment, either during the period of chemotherapy administration or while the marrow is aplastic, i.e., prior to any expected effect of thrombopoietin. Thus, as was apparent in trials of myeloid growth factors in this patient population, there is a relatively small window during the last week of marrow regeneration for a thrombopoietic factor to decrease the need for transfusion. In addition, patients who do not achieve remission, usually because of persistence of drug-resistant leukemia, are not informative in terms of platelet recovery. Indeed, these problems were noted in a pilot trial in which patients with AML received thrombopoietin after the completion of induction therapy without an obvious reduction in the duration of thrombocytopenia or in the number of platelet transfusions received [ 121. The situation may be somewhat more favorable following post-remission consolidation therapy. Intensive post-remission chemotherapy with sequential courses of high-dose cytarabine can be curative

3 Schiffer 25 1 in a substantial fraction of adults with AML [22]. In an evaluation at our center incorporating four sequential courses of high-dose cytarabine [23], 27 patients receiving 54 courses of treatment received an average of 4.9 platelet transfusions (range 1-44, 95% CI ) per course. Because patients start with remission marrows and the mortality rate is low, essentially all recover normal blood counts. In addition, it has been shown that other growth factors can be effective in this situation; G-CSF significantly shortens the duration of neutropenia and can occasionally eliminate the development of severe neutropenia when given following the completion of post-remission chemotherapy [24, 251. Because of the smaller number of transfusions required, however, variations in criteria for administering prophylactic transfusion could be critical. It might also be difficult to demonstrate a statistically significant reduction in the number of transfusions because of the small number of transfusions required unless there was a large patient sample size. Given the probable cost of the thrombopoietin, there is likely to be debate about the cost relative to the clinical significance of a possible savings of only one or two platelet transfusions. The same question will arise in the stem cell transplant setting since the increased use of cytokine stimulated peripheral blood as the source of stem cells has dramatically decreased the platelet transfusion needs following autologous transplantation. It is possible that any additional benefit afforded by thrombopoietin plus or minus other cytokines will be a need for fewer apheresis collections rather than an important shortening of the duration of thrombocytopenia following ablative therapy. Furthermore, the mpl ligand for thrombopoietin is expressed on myeloid blasts from most patients with AML with some evidence that thrombopoietin can enhance leukemia cell growth in vitro [26, 271. Although it is reassuring that large numbers of clinical trials using G-CSF and GM-CSF after the completion of induction chemotherapy did not demonstrate a higher rate of treatment failure due to drugresistant leukemia [28], it is critical to monitor trials in patients with AML for the emergence of either obvious leukemic growth or an unexpectedly low complete response rate. Patients receiving standard-dose regimens for solid tumors and lymphomas infrequently require platelet transfusion, and when they do, it is uncommon that more than one or two transfusions are administered per course. Although a small randomized clinical trial evaluating interleukin 11 (IL- 1 1) demonstrated a reduction in the use of subsequent platelet transfusions in a subset of patients identified as being at risk by virtue of having required transfusions during previous courses of chemotherapy [29], this is an uncommon clinical situation; it is likely that if a threshold of lo,ooo/yl for transfusion is used, the need for transfusions in this circumstance will be decreased further. OTHER POTENTIAL USES OF THROMBOPOIETIN MyelodysplasidAplastic Anemia In many patients with these bone marrow failure states, severe thrombocytopenia is a major cause of morbidity and altered quality of life. Because there is an inverse relationship between the platelet count and endogenous thrombopoietin levels [28], it is predictable that most such patients will have high endogenous levels and perhaps already be maximally stimulated. This is analogous to the situation with erythropoietin levels and response to treatment, although a small percentage of patients with myelodysplastic syndrome (MDS) can respond to pharmacologic doses of erythropoietin [30]. Similarly, some patients with MDS or aplastic anemia have increased neutrophil counts when stimulated with G- or GM-CSF, providing at least transient benefit in terms of combating infection [31]. It would be of great interest to evaluate thrombopoietins in selected patients with hemorrhagic problems, with assessment of pretreatment levels to determine whether there are some patients, presumably those with lower endogenous production, who might benefit. This is particularly true because of the possibility of a convenient weekly schedule of administration of the thrombopoietin [l 11. Obviously, patients with MDS and aplastic anemia have markedly impaired marrow function and decreased ability to respond to growth factors. There is also concern about stimulation of transformation to acute leukemia, particularly in patients with MDS.

4 252 Clinical Uses for Thrombopoietin Immune Thrombocytopenic Purpura (ITP) Patients with ITP are thrombocytopenic because their antibody-mediated platelet destruction rate exceeds the rate of platelet production. Although platelet production is already markedly expanded in most patients with ITP, it is unknown whether production can be further enhanced by pharmacologic doses of thrombopoietin, particularly in the subgroup of ITP patients in whom thrombopoietin levels are lower than predicted by the level of thrombocytopenia. Trials in the small minority of patients with severe refractory ITP and in individuals with higher counts scheduled for elective surgery would be of interest. Platelet Donation This topic is reviewed extensively in another chapter in this symposium; therefore, only a few points will be raised. The yield of platelets obtained via apheresis is directly related to the donor s platelet count [ 141. Although there is interest in utilizing thrombopoietin in more routine platelet collection settings, there are issues related to the cost of the drug, and the necessity for the donor to come to the center twice (to receive the injection, and subsequently for apheresis), with at least the theoretic background concern of thrombotic events in normal volunteer donors. There are, however, selected circumstances in which higher yields can be quite beneficial, including collections from HLA compatible donors for alloimmunized recipients or from patients scheduled to receive intensive therapy from whom autologous platelets can be obtained and cryopreserved for subsequent transfusion during periods of aplasia [32]. It would be appropriate to consider this maneuver in patients who are undergoing collection of stem cells. It is conceivable that platelets could be harvested either simultaneously with the stem cells or at a subsequent apheresis with storage either in the liquid or frozen state, depending on the interval between stem cell collection and treatment and thrombocytopenia. CONCLUSIONS As noted, there are multiple potential clinical applications of thrombopoietin, either alone or in combination with other cytokines. Indeed, the explosive growth of recent publications and symposia dealing with thrombopoietins attest to the intense interest and research activity in this area. Although there has been a dramatic increase in our understanding of thrombopoiesis in the past few years due in part to the availability of this new reagent, it has also become apparent that proof of clinical benefit will not be straightforward, particularly when thrombopoietin is used to attenuate thrombocytopenia. It is likely that the next series of trials will evaluate alternative scheduling of the drug, combinations of cytokines, and pretreatment with thrombopoietin to assess whether beginning chemotherapy with higher platelet counts will shorten the duration of clinically relevant thrombocytopenia. Ultimately, clinical usage will be determined by the clinician s perception of the benefits of this new cytokine, balanced by its eventual costs. REFERENCES 1 Heddle JM, Klama L, Singer J et al. The role of plasma from platelet concentrates in transfusion reactions. N Engl J Med 1994;331: Buchholz DH, Young VM, Friedman NR et al. Bacterial proliferation in platelet products stored at room temperature. N Engl J Med 1971; Dutcher J, Schiffer CA, Aisner J et al. AUoitnmunhtion following platelet transfusion: the absence of a dose response relationship. Blood 1980;57: Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood 1995; 86: de Sauvage FJ, Hass PE, Spencer SD et al. Stimulation of megakaryoc ytopoiesis and thrombopoiesis by the c-mpl ligand. Nature, 1994;369: Ulich T, del Castillo J, Yin S et al. Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Blood 1995;86: Farese AM, Hunt P, Boone TC et al. Recombinant factor stimulates thrombocytopoiesis in normal non-human primates. Blood 1995;86: Andrews RG, Winkler A, Woogerd P et al. Recombinant human megakaryocyte growth and development factor (rhumgdf) stimulates thrombopoiesis in normal baboons and accelerates platelet recovery after chemotherapy. Blood 1995;86(suppl 1):371a.

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