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© 2000 American Society for Clinical Oncology Enhancement of Platelet Recovery After Myelosuppressive Chemotherapy by Recombinant Human Megakaryocyte Growth and Development Factor in Patients With Advanced CancerFrom the Centre for Developmental Cancer Therapeutics, Parkville; Amgen Australia, Kew, Victoria, Australia; and Amgen, Inc, Thousand Oaks, CA. See Appendix for a list of the affiliates of the Centre for Developmental Cancer Therapeutics. Address reprint requests to R. Basser, MD, CDCT, c/o Post Office, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; email russell.basser{at}nwhcn.org.au
PURPOSE: To explore the influence of dose and schedule on the ability of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) to abrogate thrombocytopenia after multiple cycles of chemotherapy and to mobilize peripheral-blood progenitor cells (PBPC). PATIENTS AND METHODS: In this open-label study, 68 patients with advanced cancer were randomized to receive PEG-rHuMGDF subcutaneously at different doses and durations before administration of carboplatin 600 mg/m2, cyclophosphamide 1,200 mg/m2, and filgrastim 5 µg/kg/d. PEG-rHuMGDF was not given after the first cycle of chemotherapy but was given after the second and subsequent cycles. Chemotherapy was given every 28 days for up to six cycles. RESULTS: In patients who received the same dose of chemotherapy for at least two cycles, the platelet nadir was significantly higher (47.5 x 109/L v 35.5 x 109/L; P = .003) and duration of grade 3 or 4 thrombocytopenia significantly shorter (0 v 3 days; P = .004) when PEG-rHuMGDF was administered after chemotherapy. There was no evidence of an effect of PEG-rHuMGDF when it was given before chemotherapy. Platelet recovery after the first cycle of chemotherapy was no different for different PEG-rHuMGDF regimens, and there was no difference between patients treated with PEG-rHuMGDF and historical controls treated with identical chemotherapy. There was a modest dose-related increase in progenitor cell levels after administration of PEG-rHuMGDF alone. Peak levels of PBPC occurred later in cycle 2 than in cycle 1 but were not different in magnitude. CONCLUSION: PEG-rHuMGDF abrogated severe thrombocytopenia after dose-intensive chemotherapy. However, it had only a modest effect on progenitor cell levels and did not enhance progenitor cell mobilization after chemotherapy and filgrastim.
THE DISCOVERY OF thrombopoietin (TPO),1-5 the central regulator of megakaryocytopoiesis and thrombopoiesis, gave rise to the hope of an effective method for prevention of thrombocytopenia without the use of blood products.6 Two recombinant thrombopoietic growth factors have been developed for clinical use: (1) pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF)3 and (2) full-length glycosylated recombinant human TPO (rHuTPO).1 In initial clinical trials, these cytokines were demonstrated to be potent stimulators of thrombopoiesis and were associated with few adverse effects.7-9 In addition, PEG-rHuMGDF10,11 and rHuTPO12 were also shown to enhance platelet recovery after a single cycle of chemotherapy. A number of observations of the biologic effects of PEG-rHuMGDF in humans were made during the early studies. For instance, the peak platelet count was not reached until approximately 2 weeks after commencement of PEG-rHuMGDF, and levels did not return to baseline for as long as 4 weeks.7 This was in contrast to the rapid effects of granulocyte colony-stimulating factor on absolute neutrophil counts (ANCs).13 Interestingly, treatment with PEG-rHuMGDF before chemotherapy seemed to enhance subsequent recovery of platelet counts.10 An additional observation was that administration of PEG-rHuMGDF increased the level of peripheral-blood progenitor cells (PBPC) when given alone14 or with filgrastim after chemotherapy.10 A limitation to these observations is that they were made during studies that were designed primarily to assess safety and to find clinically active doses of PEG-rHuMGDF. We performed the current study to explore the influence of dose and schedule on the ability of PEG-rHuMGDF to abrogate chemotherapy-induced thrombocytopenia and to mobilize PBPC.
Patients Sixty-eight patients with advanced cancer were enrolled onto this study. Patients 18 years or older and with Karnofsky performance status of 60% or greater were eligible. At entry, an ANC of at least 1.5 x 109/L, platelet count of 120 to 500 x 109/L, and hemoglobin level of at least 90 g/L were required. Exclusion criteria included the following: history of vascular disease or thromboembolism within the previous 6 months; significant heart, lung, liver (serum bilirubin level > 20 µmol/L), or renal (creatinine clearance < 1.2 mL/sec) impairment; prior treatment with melphalan, carmustine, lomustine, or mitomycin; and radiotherapy to more than 30% of the red bone marrow. The study was approved by the institutional ethics committees of the participating hospitals. Each patient gave written informed consent before treatment.
Study Design
Part A. Thirty-seven patients were randomized to receive PEG-rHuMGDF (Amgen, Inc, Thousand Oaks, CA)7 1.0 µg/kg/d alone by subcutaneous injection for 1, 3, or 7 days (starting on day -14). Fifteen days after the first injection of PEG-rHuMGDF (day 0), patients were given carboplatin 600 mg/m2 followed by cyclophosphamide 1,200 mg/m2, both by intravenous infusion over 30 minutes. After all cycles of chemotherapy, patients received daily subcutaneous injections of filgrastim 5 µg/kg from the day after chemotherapy until an ANC of more than 10 x 109/L had been reached. After the first cycle of chemotherapy, PEG-rHuMGDF was not given. However, after the second and subsequent cycles of chemotherapy (up to four additional cycles), PEG-rHuMGDF 5µg/kg/d was administered for 1, 3, or 7 days (according to the previous randomization) from the day after chemotherapy. Part B. To investigate the potential of treatment with PEG-rHuMGDF before chemotherapy to enhance subsequent platelet recovery, 31 patients were randomized to receive PEG-rHuMGDF 3.0 µg/kg for one injection 11 days before chemotherapy, 3.0 µg/kg for one injection 7 days before chemotherapy, or 10 µg/kg for one injection 7 days before chemotherapy. Chemotherapy was identical to that of Part A. After all cycles of chemotherapy, patients received filgrastim (as above) until neutrophil recovery. After the first cycle of chemotherapy, PEG-rHuMGDF was not given. After the second and subsequent cycles of chemotherapy (up to five additional cycles), PEG-rHuMGDF 5µg/kg/d was administered for 3 days from the day after chemotherapy. Controls. This study used historical controls. Ten patients treated in a previous placebo-controlled phase I study of PEG-rHuMGDF were used as a control group for assessing the influence of pretreatment with PEG-rHuMGDF on platelet recovery after chemotherapy.7,14 This study had identical eligibility criteria, chemotherapy treatment, and supportive care criteria. The control patients were treated with placebo before and after the first cycle of chemotherapy and had similar characteristics to those treated in the current study.
Monitoring and Laboratory Studies Patients were monitored regularly for adverse effects. Clinical assessments were performed at least at the beginning of each cycle and as indicated. Platelet transfusions were given for a platelet count of 20 x 109/L or less and packed red cell transfusion for hemoglobin level less than 90 g/L. Patients were admitted to the hospital for febrile neutropenia (temperature > 38.2°C and ANC < 1 x 109/L) and were administered broad-spectrum intravenous antibiotics until neutrophil recovery (ANC > 0.5 x 109/L and afebrile). Chemotherapy doses for the second and subsequent cycles were reduced as clinically indicated. In Part A, reticulated platelets were assessed by staining with thiazole orange as previously described15 on every other day for 8 days, from the day of the first dose of PEG-rHuMGDF, and levels of PBPC14,16,17 were assessed daily for 14 days after the first dose of PEG-rHuMGDF. Samples were taken at regular intervals for PBPC levels after the first and second cycles of chemotherapy. Assays for PBPC were not performed in Part B. Plasma chemistry values and coagulation parameters were measured at baseline and before each cycle of chemotherapy. Serum was taken for assay of antibodies to MGDF at baseline, before each cycle of chemotherapy, at the end of the study, and as indicated thereafter.
Statistical Analysis
Patients and Chemotherapy The characteristics of patients at the time of enrollment are listed in Table 1 for each treatment regimen and for the total group. Patients had a variety of solid tumors, and there were no differences in the extent of prior treatment or baseline platelet counts between different cohorts. Sixty-two patients completed at least one cycle of chemotherapy. Six patients did not complete the first cycle of chemotherapy because of disease progression (n = 3), thromboembolism (n = 1), sudden death related to disease (n = 1), and acute renal failure unrelated to study medication or chemotherapy (n = 1). Forty patients received at least two cycles of the same dose of chemotherapy. The reason for reduction in the dose of the second cycle of chemotherapy was usually febrile neutropenia (n = 9), although two patients had dose-reduction because of prolonged grade 4 thrombocytopenia. The median number of cycles of chemotherapy received was four (range, one to six), and 11 patients completed six cycles of chemotherapy. The most common reason for ceasing treatment was disease progression.
Reticulated Platelets During Administration of PEG-rHuMGDF Alone In Part A, the increase in platelet counts after commencement of PEG-rHuMGDF was preceded by a rapid early increase in the proportion of young (reticulated) platelets (Fig 2). The proportion of reticulated platelets increased with duration of administration of PEG-rHuMGDF (P = .04): 4.5% (range, 1.7% to 21.7%) for 1 day, 5.8% (range, 2.9% to 16.9%) for 3 days, and 8.7% (range, 2.7% to 30.5%) for 7 days of PEG-rHuMGDF administration.
Blood Counts Before and After the First Cycle of Chemotherapy Before chemotherapy, the platelet counts rose from a baseline of 285 x 109/L (range, 148 to 601 x 109/L) to a peak of 637 x 109/L (range, 244 to 2,260 x 109/L) (Fig 3). The maximum count occurred on the 13th day (range, 8 to 17 days) after commencement of PEG-rHuMGDF. Patients who received PEG-rHuMGDF 1 µg/kg for 1 day had a significantly lower peak platelet count than those given PEG-rHuMGDF 1 µg/kg for 3 or 7 days or PEG-rHuMGDF 10 µg/kg for 1 day (P < .05 for multiple comparisons). However, it was interesting that the peak platelet count in the cohort given a single dose of 3 µg/kg was not superior to that of the group given PEG-rHuMGDF 1 µg/kg for 1 day. The fold increase in platelets from baseline for all patients was 2.1 (range, 1 to 5.1).
Despite the significant elevation of platelet counts at the commencement of chemotherapy, there was no difference in hematopoietic recovery after the first cycle of chemotherapy between any of the treatment cohorts (Fig 3) or compared with controls. For the whole group and placebo-treated controls, respectively, the platelet nadir was 27.5 x 109/L (range, 4 to 119 x 109/L) and 48.5 x 109/L (range, 13 to 186 x 109/L; P = .11), the duration of grade 3 or 4 thrombocytopenia was 4 days (range, 0 to 21 days) and 1 day (range, 0 to 11 days; P = .22), and time to a platelet count greater than 150 x 109/L after the nadir was 19 days (range, 16 to 24 days) and 19 days (range, 16 to 23 days; P = .86). Changes in and time to recovery of WBC counts and alterations in hemoglobin were similar in all groups before and after the first cycle of chemotherapy.
Blood Counts After the First and Second Cycles in Patients Who Received the Same Dose of Chemotherapy
There was no difference in the severity of leukopenia between cycles 1 and 2; however, there was an increased need for RBC transfusion in the second cycle (Table 2). The cumulative increase in red cell toxicity was also observed in control patients.
PBPC Levels
There was no difference in PBPC mobilization after the first and second cycles between the groups of patients who received different schedules of PEG-rHuMGDF. Administration of PEG-rHuMGDF after the second cycle of chemotherapy resulted in an earlier peak in PBPC mobilization compared with cycle 1 (Table 4, Fig 6). Thus, 12 days after chemotherapy, there was a 10-fold increase in the levels of PBPC observed with PEG-rHuMGDF (cycle 2) compared with filgrastim alone (cycle 1). However, peak levels of all subsets of progenitor cells were not different, including megakaryocyte colony-forming cells (data not shown). These results indicate that PEG-rHuMGDF did not enhance the ability of chemotherapy and filgrastim to mobilize PBPC but that it acted to alter the kinetics of mobilization.
Toxicity One hundred seventy-nine cycles of chemotherapy were administered. The median number of cycles given per patient before dose reduction was required was two (range, one to six). For patients who received at least two cycles of chemotherapy without dose reduction, three cycles were given before dose reduction. The most common severe toxicities (grade 3 or 4) were thrombocytopenia and febrile neutropenia, which occurred in 25 (15%) of 179 and 23 (13%) of 179 cycles, respectively, and which constituted the reason for reduction in chemotherapy dose. Other severe toxicities were uncommon and generally related to chemotherapy or disease progression. Two patients experienced a deep venous thrombosis, and one had a peripheral arterial embolism, all of which occurred in the setting of a normal platelet count. Treatment was otherwise well tolerated, and there were no acute toxicities related to PEG-rHuMGDF. One patient developed persistent severe pancytopenia and hypoplasia on bone marrow biopsy after six cycles of chemotherapy, in association with the appearance in the serum of antibodies to MGDF that were able to neutralize rHuTPO in a bioassay. Antibodies remained detectable, and she continued to be dependent on platelet and RBC transfusions for more than 12 months after the completion of treatment. Further details of this case are given elsewhere (Basser et al, manuscript submitted for publication).
In the current study, we addressed several hypotheses raised by observations made in our initial phase I trials with PEG-rHuMGDF.7,10,14,18 We sought to further define the kinetics of the release of immature (reticulated) platelets into the circulation, the effects of dose and schedule of PEG-rHuMGDF on platelet recovery after dose-intensive chemotherapy, the safety of the cytokine after multiple cycles of chemotherapy, and the ability of PEG-rHuMGDF to mobilize PBPC. The dose-related increase in the proportion of immature platelets released into the circulation confirms that this is an early identifiable biologic effect of administration of PEG-rHuMGDF. The increase from baseline in the 7-day cohort was approximately 2.5-fold, whereas the total platelet count did not increase to this degree until at least 14 days after starting PEG-rHuMGDF. The increase in reticulated platelets at early time points suggests an early action of PEG-rHuMGDF on existing megakaryocytes within the bone marrow. This is in contrast to data that suggest that TPO does not stimulate platelet shedding from megakaryocytes.19 In our previous study, platelet recovery seemed to be enhanced in those patients who received PEG-rHuMGDF before chemotherapy.10 We designed the current study to investigate this observation further. After the first cycle of chemotherapy, before which patients received one of six different schedules of PEG-rHuMGDF, we found no difference in the platelet nadir, duration of thrombocytopenia, or time to platelet recovery. This was despite the fact that patients commenced chemotherapy with an elevated platelet count. A number of explanations might account for this inconsistency. It may be that the dose, duration of administration, and timing of administration of PEG-rHuMGDF before chemotherapy were not optimal and that further exploration of these factors might reveal a clinically important effect. It is of interest to note that patients given PEG-rHuMGDF 3 µg/kg over 3 days had higher peak platelet counts than those given a single dose, which indicates that the thrombopoietic effects of PEG-rHuMGDF are related to duration of administration, as well as total dose. It may be that a high dose of PEG-rHuMGDF given over a longer period might be more effective than any of the regimens tested. However, the increase in platelet count to a peak at the time that chemotherapy was commenced suggests that starting PEG-rHuMGDF 10 to 14 days before chemotherapy did achieve the desired clinical effect. Despite this up to five-fold elevation in platelet counts, there was no suggestion of a schedule-related effect on any measure of platelet toxicity after chemotherapy, and none of the cohorts was superior to historical controls. The most likely explanation for the discrepancy between this and our previous study is the analysis of a larger number of patients in the former (n = 67 and n = 14, respectively) that has counterbalanced the wide variation in response observed with different individuals. Thus, we conclude that treatment with PEG-rHuMGDF before chemotherapy does not abrogate subsequent thrombocytopenia. This is supported by a report of patients with acute leukemia who received induction chemotherapy, in which pretreatment with PEG-rHuMGDF also failed to reduce the severity of thrombocytopenia.20 Platelet recovery was compared in cycles 1 and 2 in patients who received both cycles of chemotherapy without a reduction in dose. Administration of PEG-rHuMGDF after the second cycle resulted in significant reduction in the severity of thrombocytopenia relevant to the first cycle, when no PEG-rHuMGDF was given. In contrast, historical controls had an increase in severity of thrombocytopenia with successive cycles. However, PEG-rHuMGDF was not able to eliminate the risk of severe thrombocytopenia with treatment. Twenty-five of the 40 patients who were able to receive two or more cycles of chemotherapy without a reduction in dose experienced grade 4 thrombocytopenia, whereas severe neutropenia occurred in only three of these patients. Maintenance of dose-intensity of this chemotherapy with PEG-rHuMGDF and filgrastim is, therefore, only possible for a limited number of cycles. Whether this applies to other regimens is yet to be determined. Others have reported abrogation of severe thrombocytopenia after dose-intensive chemotherapy with PEG-rHuMGDF in patients with lung cancer21 and with rHuTPO in women with gynecologic malignancies.12 Encouragingly, PEG-rHuMGDF was shown to reduce platelet toxicity and transfusion requirements in patients who received intensive chemotherapy for non-Hodgkin’s lymphoma.22 These are early results and only report on the initial cycles of chemotherapy and, therefore, must be interpreted with caution. The ability of these agents to maintain dose-intensity of these regimens over multiple cycles will remain undefined until complete descriptions are published. However, such a role for PEG-rHuMGDF is consistent with the situation in which interleukin-11 has been demonstrated to be of clinical benefit.23 Perhaps a more important issue is whether the maintenance of chemotherapy dose-intensity by PEG-rHuMGDF or rHuTPO is desirable. It is noteworthy that there are few completed randomized trials of increased chemotherapy dose-intensity with growth factor alone, and the available data have generally not shown this to be superior to standard doses.24-26 This latter point is important because outside of clinical trials of dose-intensive chemotherapy, severe thrombocytopenia is infrequent in adult patients with solid tumors. Unfortunately, PEG-rHuMGDF has not reduced platelet transfusion requirements in the clinical situations in which severe chemotherapy-induced thrombocytopenia is most likely to occur, namely treatment of acute leukemia27 and high-dose chemotherapy with stem-cell support.28,29 Furthermore, these studies used a platelet count of 20 x 109/L as the threshold for transfusion, and it has recently been shown that lowering the threshold for platelet transfusion to 10 x 109/L is safe.30,31 The likely impact of these findings is a reduction in the clinical need for a thrombopoietic growth factor. The amino-terminal residues of TPO share almost 50% sequence similarity with human erythropoietin,19 and preclinical data suggest that TPO might be able to increase RBC production and enhance erythroid recovery after chemotherapy.32 However, PEG-rHuMGDF had no effect on hemoglobin or WBC count, either when given alone or after chemotherapy. In fact, RBC transfusion requirements were greater in cycle 2 compared with cycle 1, which is consistent with the expected cumulative increase in bone marrow damage. None of the clinical reports of PEG-rHuMGDF and rHuTPO has shown an influence on RBC production.7-12,21,22,27-29 When PEG-rHuMGDF was given alone, multilineage mobilization of progenitor cells was observed, which is consistent with our previous findings.14 The peak levels occurred on the 11th day after commencement of growth factor, irrespective of its duration of administration, and remained elevated until at least the 14th day. In contrast, filgrastim results in almost immediate release of PBPC, the levels of which peak by approximately the fifth day of treatment and decrease as soon as the drug is ceased.33-35 This difference in the kinetics of mobilization was also observed after chemotherapy. Levels of all subsets of progenitor cells increased at a later time in the second cycle, when PEG-rHuMGDF was given in addition to filgrastim, than in the first cycle, when filgrastim was given alone. Perhaps surprisingly, the peak level of progenitor cells was similar in both cycles, which suggests that the primary effect of PEG-rHuMGDF in combination with filgrastim was on the kinetics of progenitor cell release. Similar results were reported in studies with rHuTPO and filgrastim,36,37 in which the combination produced an approximately two-fold increase in CD34+ cell yields compared with that produced by filgrastim alone.37 This resulted in a reduced number of apheresis procedures to collect a target number of PBPC. Whether such an effect is clinically meaningful is debatable. Other potent, early acting growth factors, including stem-cell factor17,35,38,39 and interleukin-3,40-42 have shown a similar magnitude of effect, but their role in routine clinical practice is still to be determined. In conclusion, we have shown that PEG-rHuMGDF can significantly reduce the severity of thrombocytopenia in patients who undergo multiple cycles of dose-intensive chemotherapy. PEG-rHuMGDF only modestly increases the number of circulating progenitor cells, and rather than enhancing mobilization of PBPC by chemotherapy and filgrastim, it acts primarily to alter the kinetics of progenitor cell release.
Affiliates of the Centre for Developmental Cancer Therapeutics: Ludwig Institute Oncology Unit, Austin Repatriation Medical Centre; Ludwig Institute for Cancer Research; Department of Medical Oncology, Peter MacCallum Cancer Institute; Department of Haematology and Medical Oncology, Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital; Walter and Eliza Hall Institute for Medical Research; and Department of Haematology and Medical Oncology, Western Hospital, Parkville, Victoria, Australia.
Supported in part by grants from the following institutions: Anti-Cancer Council of Victoria, Carlton; the National Health and Medical Research Council, Canberra; the Cooperative Research Centre for Cellular Growth Factors, Parkville, Victoria, Australia; and Amgen, Inc, Thousand Oaks, CA. We thank the following for their support of the study: C. Alt, Dr P. Bardy, J. Bartlett, J. Boyd, Prof A. Burgess, Dr R. DeBoer, Dr M. Chipman, Dr J.C. Ding, M. Dodds, G. Duggan, Dr S. Fan, J. Hay, W. Hopkins, Dr P. Mitchell, R. Mansfield, Dr S. Ng, L. Phelan, H. Ranouw, A. Ransom, Dr M. Rosenthal, W. Saunders, Dr J. Seymour, Dr J. Szer, and the ward staff and staff of the Diagnostic Hematology Departments, Austin-Repatriation Medical Centre, Royal Melbourne and Western Hospitals, Parkville; R. Mrongovius, J. Renwick, and B. Thomson, Amgen Australia, Kew, Victoria, Australia; and Dr J. Nichol, D. Barron, T. Paine, Dr W.P. Sheridan, and Dr D. Tomita, Amgen, Inc, Thousand Oaks, CA.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
100 x 109/L after the nadir. 
) and proportion of immature (reticulated) platelets (
) before the first cycle of chemotherapy in Part A for patients given PEG-rHuMGDF 1 µg/kg for 1, 3, or 7 days.
, n = 11), 3 (
, n = 10), or 7 days (
, n = 12) commencing 14 days before chemotherapy; 3 µg/kg commencing 11 (
, n = 9) or 7 days (•, n = 10) before chemotherapy; or 10 µg/kg commencing 7 days before chemotherapy (
, n = 12).
