H. E. Broxmeyer

Recombinant human thrombopoietin attenuates carboplatin-induced severe Thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer

Myelosuppression is a serious complication in patients who are receiving chemotherapy for cancer. The use of myeloid growth factors has reduced the incidence of febrile neutropenia (1, 2). However, thrombocytopenia has been managed predominantly by platelet transfusion and modification of the chemotherapy dose. Although platelet transfusion can reduce hemorrhagic complications, repeated transfusions increase the risk for transfusion reactions, alloimmunization, and transmission of infectious agents and increase health care costs (3). Recently, thrombopoietin was identified and cloned and became available for clinical investigations (4-7). In early clinical trials, therapy with thrombopoietin increased platelet counts before chemotherapy and enhanced platelet recovery after moderately myelosuppressive regimens (8-11). However, the value of this agent in preventing severe thrombocytopenia and averting the need for platelet transfusions has not been established. Carboplatin has a broad spectrum of antitumor activity and is highly effective in the treatment of gynecologic cancer; however, cumulative thrombocytopenia is frequently dose-limiting (12, 13). We therefore initiated a phase I/II trial of recombinant human thrombopoietin (rhTPO, a full-length glycosylated molecule) to evaluate the clinical safety and activity of this agent in patients with gynecologic cancer who are at high risk for chemotherapy-induced severe thrombocytopenia. Methods Patients Patients with platinum-sensitive, recurrent, or advanced gynecologic cancer were referred from multiple sources to our comprehensive cancer center. Patients were eligible if they had adequate Karnofsky performance status ( 80%); adequate bone marrow, renal, cardiac, and hepatic function; and life expectancy of at least 3 months. Patients with a history of rapidly progressive disease (marked increase in tumor size [>50%], ascites, or symptoms related to underlying cancer in the preceding 4-week period), pelvic irradiation, surgery within the previous 2 weeks, chemotherapy or radiotherapy within the previous 4 weeks, or thromboembolic or bleeding disorders were excluded. Design The study had two phases: a cohort dose-escalation (safety) phase and a dose-expansion (activity) phase. During the dose-escalation phase, a single dose of rhTPO was administered to assess clinical tolerance and hematopoietic effects. Three weeks later, patients entered cycle 1, in which they received carboplatin at a dose calculated to provide an area under the curve (AUC) of 11 by using the Calvert formula (carboplatin dose=target AUC [glomerular filtration rate + 25]). Three weeks later, upon recovery (absolute neutrophil count 1.5 109 cells/L and platelet count 100 109 cells/L), patients entered cycle 2, in which they received carboplatin (AUC, 11) followed by rhTPO every other day for four doses (on days 2, 4, 6, and 8). Cycle 1 served as an internal control for cycle 2. At least three patients were enrolled for each dose level of rhTPO (0.6, 1.2, 2.4, and 3.6 g/kg of body weight per day). The optimal biological dose was defined as the lowest active dose at which platelet count response reached a plateau. Once the optimal biological dose was established, prechemotherapy treatment with rhTPO was eliminated and 12 patients received carboplatin alone until thrombocytopenia (platelet count nadir<30 109 cells/L) was observed. In subsequent cycles, the optimal biological dose of rhTPO was given as secondary prophylaxis on the same schedule (days 2, 4, 6, and 8 [n=6]) or a modified schedule (days 1, 1, 3, and 5 [n=6]). Patients with stable or responsive disease who had not experienced prolonged thrombocytopenia (platelet count<20 109 cells/L for>7 days) in cycle 2 were eligible to receive four additional cycles. Patients received platelet transfusion (single donors when available or 4 units from random donors) for severe thrombocytopenia (platelet count<20 109 cells/L). Clinical and Laboratory Monitoring Patients were monitored by history taking; physical examinations; and laboratory tests, including complete blood counts (three times weekly and daily during the expected platelet count nadir), serum chemistry, urinalysis, chest radiography, and electrocardiography. Serum samples were screened for antibodies three times before the study and weekly during the study by using enzyme-linked immunosorbent assays based on full-length TPO, truncated TPO, and c-mpl receptor (14). Reactive sera were tested by using a bioassay based on inhibition of the TPO-dependent cell line. Neutralizing antibodies were defined as those that were inhibitory on bioassay and associated with clinically significant thrombocytopenia. Statistical Analysis Hematologic toxicity in cycle 1 (no rhTPO) was compared with that in cycle 2 (during which rhTPO was given) as the degree and duration of thrombocytopenia and time to platelet recovery (Wilcoxon signed-rank test) and the proportion of patients requiring platelet transfusions (McNemar test). The difference in the platelet count nadirs between two cycles (cycle 2 cycle 1) was analyzed for dose response by using one-factor (dose) analysis of variance with a linearity test and multiple comparisons test (SPSS, Inc., Chicago, Illinois). Role of the Funding Source Recombinant human thrombopoietin and partial funding for the study were provided by Genentech, Inc. (South San Francisco, California). The collection, analysis, and interpretation of data and the decision to submit the manuscript for publication were under the control of the principal investigator. Results Patients Twenty-nine patients were enrolled in the trial. All were evaluable except for one who declined treatment after one chemotherapy cycle. Twenty-five patients had previously received chemotherapy. Recombinant Human Thrombopoietin Treatment before Chemotherapy Treatment with a single dose of rhTPO before chemotherapy (n=16) resulted in a dose-dependent increase in platelet counts (mean count at baseline, 277 109 cells/L; maximum mean count, 462 109 cells/L [P<0.001]). After a peak response around day 15, platelet counts gradually decreased. No major changes were seen in leukocyte counts (mean count at baseline, 6.74 109 cells/L; mean count after treatment, 7.26 109 cells/L) or hemoglobin values (baseline value, 119.3 2.7 g/L; post-treatment value, 121.4 2.7 g/L). Recombinant Human Thrombopoietin Treatment after Chemotherapy Twenty-eight patients received rhTPO after carboplatin therapy (16 in the dose-escalation phase and 12 in the dose-expansion phase). Dose-Escalation Phase Therapy with rhTPO significantly reduced both the degree of thrombocytopenia (platelet count nadir, 53 109 cells/L and 35 109 cells/L [P=0.005]) and its duration (days on which platelet count was<50 109 cells/L, 3 and 6 [P=0.002]) in cycle 2 compared with cycle 1 (Table). At an rhTPO dose of 0.6 g/kg, the mean platelet count nadir did not differ between cycle 1 and cycle 2, but in cycle 2 it was twofold higher at 1.2 g/kg, 1.7-fold higher at 2.4 g/kg, and 1.2-fold higher at 3.6 g/kg. No linear dose response was seen (P=0.181). However, the difference in platelet count nadir was greater (P=0.027) for patients who received rhTPO at 1.2 and 2.4 g/kg than in those that received it at 0.6 and 3.6 g/kg. Because no greater benefit was seen at 2.4 g/kg, 1.2 g/kg was the lowest active dose and was considered the optimal biological dose for this regimen. Table. Effect of Recombinant Human Thrombopoietin Treatment on Carboplatin-Induced Thrombocytopenia and Platelet Recovery Dose-Expansion Phase To better assess the safety and activity of rhTPO at the optimal biological dose, six patients received cycles of carboplatin alone until they experienced thrombocytopenia (platelet count<30 109 cells/L). Recombinant human thrombopoietin was used in subsequent cycles as a secondary prophylaxis (1.2 g/kg), with the same schedule (days 2, 4, 6, and 8). As shown in the Figure, five of the six patients required platelet transfusion in cycle 1. Therapy with rhTPO decreased the severity of thrombocytopenia and eliminated the need for platelet transfusion in three patients and reduced the need for transfusion in one patient. Figure. Platelet counts after therapy with recombinant human thrombopoietin (1.2 g/kg administered on days 2, 4, 6, and 8) used as secondary prophylaxis after carboplatin treatment (cycle 2) ( solid line ) compared with those obtained by using carboplatin treatment alone (cycle 1) ( dotted line ). arrowheads stars Six additional patients received rhTPO (1.2 g/kg) 1 day before chemotherapy (day 1) and on days 1, 3, and 5 to determine whether the degree of protection could be further augmented. Five of the 6 patients experienced thrombocytopenia (platelet count<30 109 cells/L) in cycle 1 and received rhTPO in cycle 2. As with the original schedule, the need for platelet transfusion was eliminated in 3 of these 5 patients. The sixth patient experienced severe thrombocytopenia in cycle 2 and received rhTPO in cycle 3. After rhTPO therapy, this patients platelet count nadir increased and the need for platelet transfusion was eliminated. Thus, of 12 patients who received rhTPO as secondary prophylaxis, 11 initiated rhTPO therapy in cycle 2 and 1 initiated it in cycle 3. In this group, rhTPO increased the platelet count nadir by twofold and reduced the duration of severe thrombocytopenia by 4 days (Table). Platelet Transfusion and Recovery The need for platelet transfusion was markedly reduced with rhTPO (Table). Specifically, in the group that received rhTPO at the optimal biological dose (1.2 g/kg), 75% of patients required platelet transfusion in cycle 1 compared with 25% in cycle 2 (P=0.013). The number of transfusions required was reduced by 69% (16 compared with 5 transfusions). Therapy with rhTPO significantly enhanced platelet recovery (P<0.001) (Table). In cycle 2, 67% of patients recovered platelet counts of at least 100 109 cells/L by day 21,

Importance of Predosing of Recombinant Human Thrombopoietin to Reduce Chemotherapy-Induced Early Thrombocytopenia

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 10(3)/microL v 80 +/- 7 x 10(3)/microL, respectively; P <.001) in 24 (80%) of the 30 patients (P <.001) in whom rhTPO (1.2 microg/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.

Once per cycle combination of long-acting hematopoietic growth factors (HGFs) pegfilgrastim and darbepoetin alfa (Peg-G + DPO) to reduce multi-lineage hematopoietic toxicity of chemotherapy with doxorubicin and ifosfamide (AI) in patients with sarcoma

8225 AI results in cumulative multi-lineage toxicity. In our previous study of filgrastim and epoetin alfa (G + EPO) with AI in chemo-naive pts, the incidence of neutropenic fever (NF) was 33% and red cell transfusions (PRBC Tx) 40% of cycles. The purpose of the present study was to evaluate safety, hematopoietic effects on progenitors, and efficacy of the new long-acting HGFs Peg-G + DPO in reducing the incidence of NF and PRBC Tx. AI (A 90 mg/m2; I 10 gm/m2) was administered on days 0–3. HGFs were administered SC once per cycle, with DPO (initial dose, 500 mcg) prior to (day 0) and Peg-G (6 mg) post (day 4) completion of AI. Cycles were repeated q 21 days (max 6 cycles). Bone marrow (BM) and peripheral blood progenitor cells were examined in cycle 1. The data for NF and PRBC Tx are shown below for both studies. The median duration of neutropenia during all 6 cycles remained ≤3 days with Peg-G as compared to a progressive increase in the duration with G (days ANC <500/mm3: 3, 3, 4, 5, 6, and 6 for C1–6, ...