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© 2003 American Society for Clinical Oncology Importance of Predosing of Recombinant Human Thrombopoietin to Reduce Chemotherapy-Induced Early Thrombocytopenia
From the Departments of Bioimmunotherapy, Sarcoma Medical Oncology, Hematopathology, and Biostatistics, the University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Department of Microbiology and Immunology, the Walther Oncology Center and the Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN. Address reprint requests to Saroj Vadhan-Raj, MD, Department of Bioimmunotherapy, Box 422, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: svadhanr{at}mail.mdanderson.org.
Purpose: Recombinant human thrombopoietin (rhTPO) increases platelets, and the peak response of rhTPO is delayed and is, therefore, not uniformly effective when administered after chemotherapy. The purpose of this study was to identify an effective schedule of rhTPO to best attenuate early thrombocytopenia. Patients and Methods: Cohorts of six patients with sarcoma (66 assessable patients) were treated sequentially with doxorubicin and ifosfamide (AI), with rhTPO by a fixed dose and varying schedules being administered before and/or after chemotherapy in cycle 2 and subsequent cycles. Cycle 1 without rhTPO served as an internal control. Results: AI causes cumulative thrombocytopenia. The platelet nadir in cycle 2 was higher than in cycle 1 (mean nadir ± SEM, 119 ± 12 x 103/µL v 80 ± 7 x 103/µL, respectively; P < .001) in 24 (80%) of the 30 patients (P < .001) in whom rhTPO (1.2 µg/kg) was administered starting from 5 days before chemotherapy (pre/postdoses, three/one or one/one) compared with only four (17%) of 24 patients given rhTPO by other schedules (pre/postdoses, two/two, one/three, zero/four, or four/zero) and none of 15 historical control patients. The need for platelet transfusions in four cycles was significantly lower (13 [11%] of 114 cycles, P < .001) in patients who received rhTPO from day -5 (pre/post doses, three/one or one/one) compared with patients who received rhTPO at later time points (28 [47%] of 60 cycles). Bone marrow megakaryocytes increased markedly (four-fold) before chemotherapy with predosing rhTPO and remained elevated (two-fold) after chemotherapy, which may explain the possible mechanism for response. One patient developed subclavian vein thrombosis, and no patients developed neutralizing antibodies to rhTPO. Conclusion: These results demonstrate the importance of timing of rhTPO in relation to chemotherapy and indicate that, by optimizing the timing, only two doses of rhTPO (one before and one after chemotherapy) were required to significantly reduce the severity of chemotherapy-related early thrombocytopenia.
CHEMOTHERAPY-INDUCED THROMBOCYTOPENIA can increase the risk for bleeding complications and the need for platelet transfusions and limit the doses of cytotoxic agents in the treatment of certain malignancies. Currently, platelet transfusion is the primary treatment for management of severe thrombocytopenia.1–3 However, the potential drawbacks of platelet transfusion include increased risk for infections, alloimmunization, and increased health care costs. These limitations have led to the development of evidence-based guidelines for platelet transfusions4 and continued search for safe and effective strategies to reduce chemotherapy-induced thrombocytopenia. In the last decade, a number of thrombopoietic cytokines and growth factors have undergone clinical evaluations.5–10 Unfortunately, many have showed only modest activity and significant toxicity. Interleukin-11 has been approved for treatment of thrombocytopenia; however, its therapeutic index is limited.10,11 Thrombopoietin is a principal regulator of megakaryocyte development and platelet production.12–14 Early clinical trials of two forms of the recombinant protein (ie, the full-length molecule, recombinant human thrombopoietin [rhTPO], and a truncated, pegylated recombinant human megakaryocyte growth and development factor) have demonstrated a dose-dependent increase in circulating platelet count when given without chemotherapy.15–17 Administration of both of these molecules after chemotherapy has enhanced platelet recovery and has reduced thrombocytopenia after moderately myelosuppressive regimens.15,17–20 However, the clinical development of pegylated recombinant human megakaryocyte growth and development factor has been discontinued in the United States because of the development of neutralizing antibodies and severe thrombocytopenia in some cancer patients and normal donors. Furthermore, their use, when given as multiple postchemotherapy doses (up to 20 doses) after more intensive chemotherapy regimens, has not uniformly reduced the severity of thrombocytopenia or the need for platelet transfusions, except in patients receiving carboplatin.17–20 The positive effect of rhTPO after carboplatin administration may be related to the facts that carboplatin is administered over only 1 day and causes late platelet nadir (around day 16), allowing the required time lag for the formation of platelets from rhTPO-responsive precursor cells.20 Several observations indicated that administration of rhTPO before chemotherapy might be beneficial. For example, many regimens are given over 3 to 5 days and result in early platelet nadir (days 10 to 14).21,22 The increase in platelets after rhTPO peaks around day 12.16,17 Thus, rhTPO administered only after chemotherapy would not be expected to have optimum impact on the early nadir induced by many chemotherapy regimens. Therefore, we reasoned that, for the early acting regimens, predosing with rhTPO might increase the pool of mature megakaryocytes before chemotherapy, and these, in turn, would increase the number of platelets sufficiently to dampen the nadir. In addition, postdosing with rhTPO might accelerate the time to recovery and further off-set the nadir. On the basis of this biology-based schedule rationale, we performed a clinical trial of rhTPO in patients with sarcoma who were receiving dose-intensive chemotherapy and who were at increased risk for cumulative severe thrombocytopenia.18 The purpose of this trial was to identify an effective schedule of rhTPO that would attenuate the cumulative thrombocytopenia associated with combination chemotherapy. We also wished to examine the possible mechanisms at a precursor level that might explain the nature of the response and the impact of optimal schedule. In addition, we evaluated the clinical safety and the potential for immunogenicity after multiple cycles of treatment with rhTPO in this study.
Patients In this phase I/II study, chemotherapy-naive patients with sarcoma who were suitable for treatment with chemotherapy were eligible if they were 15 to 65 years old and had an adequate Karnofsky performance status (  80%) and adequate renal, hepatic, and bone marrow functions. Patients with a history of prior pelvic radiation, surgery within 2 weeks, thromboembolic or bleeding disorders, or significant cardiac disease were excluded. Written informed consent was obtained from all patients before entry onto the study in accordance with the institutional guidelines.
Clinical and Laboratory Monitoring Bone marrow aspiration and biopsies were performed in consenting patients before and after rhTPO with or without chemotherapy. Bone marrow specimens were processed for morphologic analysis as described before16,20 and examined for overall cellularity, megakaryocyte counts, and morphology in a blinded manner.
rhTPO
Chemotherapy
Study Design
Schedule-finding phase.
Cycle 1 of chemotherapy (days 0 to 3) was given without rhTPO to serve as an internal control for each patient. Three weeks later, patients received a second course of chemotherapy at the same doses (cycle 2), with rhTPO administered by the schedules described below. Five cohorts of patients were treated in the initial schedule-finding phase (Fig 1A
Schedule-optimizing phase. Once the effective schedule was identified (ie, three predoses and one postdose), we wished to determine the importance of dose versus timing of the predose (Fig 1B  ). The next three cohorts were treated with two doses of rhTPO given as one predose (day -5) and one postdose (day 4). The dose of rhTPO for the predose was 1.2 µg/kg (cohort 6), 2.4 µg/kg (cohort 7), or 3.6 µg/kg (cohort 8). The postdose was kept constant (1.2 µg/kg) in all cohorts. Finally, to determine whether extending the postdose beyond day 4 would provide further benefit, two additional cohorts were treated (Fig 1B). RhTPO was given as one predose and one postdose (days -5 and 8) to cohort 9 and as three predoses and three postdoses (days -5, -3, -1, 4, 6, and 8) to cohort 10. A cohort of six patients was sequentially treated by each schedule. An additional six patients were treated by the schedule (ie, cohort 2) that was found most promising in the schedule-finding phase. Patients with stable or responsive disease after two cycles of treatment were eligible to receive four additional cycles, with rhTPO given using the same dose/schedule.
All patients received granulocyte colony-stimulating factor (G-CSF; 5 µg/kg/d), which was started on day 4 and continued until neutrophil recovery (
Statistical Methods
A total of 73 patients were enrolled onto the study. Two patients were considered ineligible for the study because the histology of their tumors was not confirmed to be sarcoma. Seventy-one patients (31 males and 40 females) with sarcoma of diverse histologic subtypes were treated. The median age was 47 years (range, 18 to 65 years), and the median Karnofsky performance status was 90 (range, 80 to 100). Five of the 71 patients were considered inassessable for hematopoietic response; two of these patients never received rhTPO because of congestive heart failure (one patient) and the disease-related death (one patient) in cycle 1. The other three patients were considered assessable for toxicity only because one patient required dose reduction of chemotherapy after one cycle because of poor tolerance and two patients required dose modification of rhTPO because of a marked thrombocytosis (one patient) or subclavian vein thrombosis (one patient).
Effects of rhTPO on Thrombocytopenia
The kinetics of platelet nadir and recovery in two cycles of chemotherapy are shown in Figure 3  . The nadir platelet count was lower in cycle 2 than in cycle 1 in the historical control group (Fig 3A) and all the cohorts that received rhTPO except for cohort 2 (Fig 3C and Table 1). In this group, treatment with rhTPO 5 days before cycle 2 resulted in an early thrombocytosis followed by higher nadir platelet count (nadir platelets mean ± SEM, 83 ± 14 x 103/µL v 123 ± 21 x 103/µL in cycles 1 and 2 respectively; P = .036) and an early platelet recovery (Fig 3 and Table 1). These findings indicate the importance of the predosing of rhTPO and the optimal timing of the predose of rhTPO (starting from day -5) in relation to chemotherapy to reduce the degree of thrombocytopenia. Cohort 5 (Fig 3F), who received all four predoses and no postdose, also had early thrombocytosis, but the depth of the nadir was not reduced, and the recovery was slower in cycle 2 (Fig 3). These findings indicate the importance of postdosing of rhTPO after completion of chemotherapy.
Schedule-optimizing phase: Optimizing predose of rhTPO. Because the timing of the predose of rhTPO seemed important, it was felt that a single dose administered on day -5 might provide a similar benefit as three doses administered on days -5, -3, and -1. Therefore, three additional cohorts of patients were treated. rhTPO was administered as one predose (at 1.2, 2.4, or 3.6 µg/kg) on day -5 and one postdose (1.2 µg/kg) on day 4 (Fig 1B ). In these cohorts (cohorts 6, 7, and 8), the platelet nadir in cycle 2 was higher than in cycle 1 (mean ± SEM, 116 ± 15 x 103/µL v 78 ± 8 x 103/µL, respectively; P < 0.001) in 14 of 18 patients (Table 1). The kinetics of platelet response to rhTPO administered from day -5 as a single predose at 1.2 µg/kg (cohort 6) was similar (Fig 4B) to the response seen in cohort 2 (Fig 4A), who received rhTPO as three predoses (1.2 µg/kg for three doses). In this group, the platelet nadir was significantly higher in cycle 2 than in cycle 1 (mean ± SEM, 132 ± 23 x 103/µL v 77 ± 14x 103/µL, respectively; P = .005). The magnitude (Table 1) and the kinetics of response were similar at 2.4 and 3.6 µg/kg of predose rhTPO (Fig 4C and D). These findings further support the observation that the timing of predose is important, and indicate that a single predose of rhTPO (1.2 µg/kg) given at the optimal time provided a biologic effect similar to three doses of rhTPO (1.2 µg/kg x 3) and that higher doses (2.4 or 3.6 µg/kg) did not seem to provide additional benefit.
Optimizing the postdose of rhTPO. To determine whether delaying or extending the postdose of rhTPO to day 8 would provide any further improvement in platelet nadir and recovery, two additional cohorts were treated with rhTPO (1.2 µg/kg), one predose on day -5 and one postdose on day 8 (cohort 9) and three predoses on days -5, -3, and -1 and three postdoses on days 4, 6, and 8 (cohort 10). As shown in Figure 5 , delaying the administration of postdose of rhTPO to day 8 (cohort 9; Fig 5B) delayed the platelet recovery and increased the depth of the platelet nadir (Table 1). The platelet nadir was lower in cycle 2 than in cycle 1 in four of these six patients. This finding indicates the importance of the timing of the postdose to be given soon after completion of the chemotherapy. As shown in Figure 5, the kinetics of platelet nadir and recovery response to rhTPO administered as six doses (three predoses and three postdoses; Fig 5C) seemed similar to rhTPO administered as two doses (one predose and one postdose on days -5 and 4; Fig 5A). Although, the median nadir platelet count for the cohort was higher in cycle 2 than in cycle 1 (Table 1), in two of the six patients, the platelet nadir was lower. These findings indicate that more frequent dosing of rhTPO does not seem to provide any additional benefit in reducing the degree of thrombocytopenia.
Effect of rhTPO on Platelet Transfusions To evaluate the effect of rhTPO on cumulative thrombocytopenia, we analyzed the need for platelet transfusions based on the proportion of cycles transfused in four cycles (Table 1 ). Overall, 59 of 243 cycles required platelet transfusions; of these, 71% were required in cycles 3 and 4. Ninety-seven percent of these cycles (235 of 243 cycles) were administered at the full dose. Only 3% of the cycles required doxorubicin dose reduction to 75 mg/m2 in cycle 4 for severe mucositis. The need for platelet transfusion in four cycles was lower (17 [12%] of 138 cycles, P < .001) for the patient cohorts (cohorts 2, 5, 6, 7, and 8) who received rhTPO starting from day -5 (three predoses/one postdose or one predose/one postdose schedules) or day -7 (four predoses/no postdoses schedule) compared with the cohorts (cohorts 1, 3, and 4) who received rhTPO later, starting from day -3 or -1 or who received all doses after chemotherapy (28 [47%] of 60 cycles; Fig 6A). There was an increase in the trend for platelet transfusions in patients in whom postdosing of rhTPO was delayed (cohort 9) or continued up to day 8 (cohort 10, Table 1). The patient cohorts were somewhat heterogenous with regard to the degree of thrombocytopenia during cycle 1. Therefore, to determine whether differences in the need for platelet transfusions were related to the difference in inherent sensitivity of bone marrow of patient cohorts, only patients who had experienced grade 3 thrombocytopenia (nadir platelet count < 50,000/µL) in cycle 1 were analyzed (Fig 6). Similar trends were seen, with cohorts 2, 5, 6, 7, and 8 requiring lower transfusions (11 [23%] of 47 cycles, P = .009) than the other cohorts (26 [59%] of 44 cycles for cohorts 1, 3, and 4; three [43%] of seven cycles for cohort 9; and five [45%] of 11 cycles for cohort 10). A  2 test for equality of proportions in the proportion of cycles transfused in four cycles among 10 cohorts was performed and showed that cohort 7 had the lowest proportion requiring transfusion (P < .001). Also, using simple regression analysis, there was no significant effect of the platelet nadir in cycle 1 on the percentage change in cycle 2 (P = .208).
Effects on Other Cell Lineages Neutropenia. All patients received G-CSF from cycle 1 in this study. All patients experienced grade 4 neutropenia (nadir neutrophils, < 500/µL). The duration of severe neutropenia was slightly lower in cycle 2 than in cycle 1 (mean ± SEM, 2.8 ± 0.2 days v 3.5 ± 0.2 days; P = .015). However, the incidence of neutropenic fever requiring antibiotics was not significantly different between the two cycles (41% in cycle 1 v 47% in cycle 2). Thus, rhTPO did not diminish the biologic effect of G-CSF on the neutrophil lineage.
Anemia.
Anemia was cumulative in nature. The proportion of patient requiring RBC transfusions was not significantly different among the different cohorts (P = .255, Fig 6
Effects on Bone Marrow
The bone marrow cellularity and number of megakaryocytes decreased after chemotherapy and rhTPO in all patients (Table 2 ). However, in the patients that received predosing with rhTPO from day -5, the number of megakaryocytes was still two-fold higher than their baseline value and was four-fold higher than the patient cohorts that received rhTPO starting from later time points (Table 2). Despite marked decrease in overall cellularity, many mature-appearing megakaryocytes were easily visible on bone marrow smears (Fig 7).
Clinical Tolerance The side effects were similar for both cycles of chemotherapy with or without rhTPO (Table 3 ). Treatment with rhTPO was well tolerated without any symptoms that can be attributed to rhTPO, except for the incidence of deep vein thrombosis of the right subclavian vein and axillary vein in one patient (cohort 10) that developed when the platelet count was 875,000/µL. rhTPO treatment was discontinued, and thrombosis was resolved with anticoagulation. Another patient (cohort 6), who developed central venous catheter site infection, was found to have an old obstruction of the subclavian vein on venous flow study. Subsequent venography revealed no evidence of thrombosis. In addition, one patient (cohort 10) developed a marked thrombocytosis (2 x 106/µL platelet count) in cycle 2 and required a dose reduction of rhTPO (from 1.2 µg/kg to 0.3 µg/kg) in subsequent cycles. Eight patients had minor episodes of bleeding (epistaxis, cutaneous, vaginal or hemorrhoidal bleeding, and hematuria). Two patients had grade 3 episodes of bleeding (rectal and nasal) that required transfusions at platelet counts greater than 15,000/µL. A total of 293 samples were available for analysis of antibodies to thrombopoietin. Sera from six patients reacted positive in the c-mpl receptor assay on one or more occasions. All of these samples were negative for neutralizing antibodies in the HU-3 bioassay. Furthermore, all patients (n = 66) in this study experienced recovery of platelet counts to more than 100,000/µL on median day 21 (range, day 13 to 36) after the last cycle of chemotherapy with rhTPO.
Myelosuppression is a common complication in patients who are receiving cytotoxic treatment. The Food and Drug Administration–approved myeloid growth factors have been used effectively after chemotherapy to reduce neutropenia and the incidence of neutropenic fever.24,25 However, rhTPO, when used in a manner similar to myeloid growth factors after chemotherapy for multiple doses, has not shown consistent clinical benefit.15–20 The complexity of the clinical development of rhTPO may in part be related to the time period required for the platelet production after stimulation of progenitors/precursors by rhTPO. The purpose of our study was to identify a schedule of rhTPO in relation to chemotherapy that would take into account the kinetics of chemotherapy-induced platelet nadir and the kinetics of platelet response to rhTPO to reduce the severity of early thrombocytopenia and the need for platelet transfusions. The results of this study demonstrate the importance of the timing of rhTPO administration for it to have an impact on platelet nadir and recovery after intensive chemotherapy. The AI regimen uniformly causes cumulative thrombocytopenia. In our previous trial without rhTPO, all historical control patients experienced more severe thrombocytopenia in cycle 2 compared with cycle 1. In the trial reported here, 80% of the patients that received an rhTPO dose 5 days before and a dose after chemotherapy (three predoses/one postdose or one predose/one postdose schedules) had a platelet nadir higher in cycle 2 than in cycle 1 compared with only 17% of the patients in whom rhTPO was administered at later time points, indicating the importance of predosing. However, patients who received all four doses before chemotherapy and no postdose (cohort 5) or who received rhTPO 5 days before chemotherapy but had a postdose delayed by 4 days (cohort 9), despite having early thrombocytosis, had a lower platelet nadir and slower platelet recovery. Thus, these findings demonstrate the importance of optimal timing of both predosing and postdosing to have maximal impact on the platelet nadir. This schedule-dependent platelet-sparing effect of rhTPO can be explained by several possible mechanisms. First, predosing with rhTPO (day -5) resulted in a marked increase in the number of bone marrow megakaryocytes before chemotherapy. Thus, predosing with rhTPO increased the reservoir of platelet precursors, which led to an increase in platelet counts before decline induced by chemotherapy. Second, because platelets have a life span of 9 to 10 days, the response in platelets would be expected to last for several days.16 Third, despite a marked decrease in overall cellularity after chemotherapy, the number of megakaryocytes was still significantly higher than baseline, and they were largely mature polyploid cells, indicating that rhTPO protected megakaryocytes from chemotherapy-induced apoptosis. This notion is supported by prior observations that rhTPO is a survival factor and prevents programmed cell death in megakaryocytes and progenitors in vitro.26–28. Thus, the increased number of mature megakaryocytes after chemotherapy can induce further increase in platelet production, thereby reducing nadir and enhancing recovery. The decrease in severity of thrombocytopenia was also associated with a significantly lower platelet transfusion requirement in four cycles for patients that received rhTPO from day -5 (as three predoses/one postdose or one predose/one postdose) or day -7 (four predoses/no postdoses) compared with patients that received rhTPO at later time points. The lower need for platelet transfusion in cohort 5, who received all four predoses and no postdose, is of interest because this group did not show a reduced platelet nadir in cycle 2, however, they experienced less cumulative thrombocytopenia in subsequent cycles as assessed by the need for the platelet transfusions. Although the basis for this finding is not well understood, it may be related to protective effects of rhTPO predosing on progenitors/precursors against repetitive chemotherapy cycles by promoting expansion of progenitor pool, by decreasing the proliferative rate through a negative feedback process mediated by increased platelets, or by acting as a cell-survival factor.26–28 One of the most intriguing findings of this study was that only two doses of rhTPO at a low dose (1.2 µg/kg), administered as one dose 5 days before and another dose the day after chemotherapy, were sufficient in achieving a platelet-protective effect. Our findings did not show an additional benefit of higher doses or more frequent administration in this setting. In fact, despite the increase in platelet nadir in cycle 2, there was a trend to an increase in the need for platelet transfusions in patients who received multiple rhTPO doses (three predoses and three postdoses). A plausible explanation for this finding may be that prolonged stimulation with rhTPO after chemotherapy may delay maturation of megakaryocytes or release of the platelets or both.29,30 However, given our small sample size, future larger trials will be required to determine whether additional doses will provide further benefit. Treatment with rhTPO was well tolerated, and no adverse events were attributed to its use other than one documented incident of deep vein thrombosis. No patient in this study developed neutralizing antibodies to rhTPO, the full-length, glycosylated molecule. In summary, our findings indicate the critical importance of timing of rhTPO administration in relation to chemotherapy to obtain optimal benefit. Although rhTPO administered only after chemotherapy may be sufficient to achieve reduction in thrombocytopenia after short regimens or regimes that cause a late nadir, such as carboplatin, as shown before.20 However, with the longer and more intensive regimens, especially those that cause early and deep nadir, administration of rhTPO both before and after chemotherapy may be necessary to achieve maximal benefit. Randomized clinical trials are now ongoing to further determine the importance of the schedule and timing of rhTPO after multiple chemotherapy regimens.
We thank Walter N. Hittelman, PhD, for critical review of the manuscript, Carolyn Hays, RN, for collecting and assembling the data, Sean D. Raj for assistance with analysis, and Margylynn White for assistance with manuscript preparation.
Supported in part by Public Health Service grant Nos. RO1 HL56416 and DK53674 from the National Institutes of Health, Bethesda, MD, various donors funds, and a research grant from Pharmacia Oncology, Peapack, NJ.
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28. Wlodarski P, Wasik M, Ratajczak MZ, et al: Role of p53 in hematopoietic recovery after cytotoxic treatment. Blood 91:2998–3006, 1998 29. Nagasawa T, Osada M, Komero T, et al: In vitro and in vivo deprivation of thrombopoietin induces megakaryocytic apoptosis and regulates platelet production. Exp Hematol 25:897, 1997 (abstr 591)
30. Zauli G, Vitale M, Falcieri E, et al: In vitro senescence and apoptotic cell death of human megakaryocytes. Blood 90:2234–2243, 1997 Submitted August 1, 2002; accepted May 23, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
