Saroj Vadhan-Raj

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

PURPOSE This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma. PATIENTS AND METHODS Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading. CONCLUSION Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group.

PURPOSE To study the impact of Procrit (epoetin alfa; Amgen Inc, Thousand Oaks, CA) on quality of life, transfusion requirements, and hemoglobin in anemic cancer patients receiving chemotherapy. PATIENTS AND METHODS More than 500 community-based oncologists enrolled 2,342 patients with malignancies undergoing cytotoxic chemotherapy in an open-label study. Patients were treated with epoetin alfa 150 U/kg three times weekly, which could be doubled if the therapuetic response was judged inadequate. Total treatment was up to 4 months. RESULTS Of the 2,342 patients enrolled, data were available for 2,030 patients. Of the 2,030, 1,047 patients completed all 4 months of epoetin alfa therapy. Epoetin alfa was associated with significant increases in mean self-rated scores for energy level, activity level, and overall quality of life; these improvements correlated with the magnitude of the hemoglobin increase and were independent of tumor response. In addition, epoetin alfa was associated with a significant increase in mean hemoglobin and with a significant decrease in the proportion of patients requiring transfusions (baseline to final value, P < .001). Epoetin alfa was well tolerated. CONCLUSION Epoetin alfa is effective in improving the functional status and quality of life in anemic cancer patients receiving chemotherapy, as well as increasing hemoglobin level and decreasing transfusion requirements. Improvement in functional status can be attributed to an increase in hemoglobin level, demonstrating that quality of life in this group of patients can be improved by aggressively treating anemia. Further studies will be required to define the optimal doses and schedules for epoetin alfa.

Effects of Recombinant Human Granulocyte–Macrophage Colony-Stimulating Factor in Patients with Myelodysplastic Syndromes

The myelodysplastic syndromes are characterized by ineffective hematopoiesis and refractory cytopenias. In an attempt to improve hematopoiesis, we administered recombinant human granulocyte--macrophage colony-stimulating factor (GM-CSF) to eight patients with myelodysplastic syndrome, as part of a Phase I trial. The GM-CSF was given by continuous intravenous infusion daily for two weeks and then again after a two-week rest period. Over the entire dose range tested (30 to 500 micrograms per square meter of body-surface area), treatment was associated with marked increases in peripheral-blood leukocytes (5- to 70-fold), including granulocytes (5- to 373-fold), in all eight patients. The absolute number of monocytes, eosinophils, and lymphocytes increased in all patients. Three of eight patients also had 2- to 10-fold increases in platelet counts and improvement in erythropoiesis, with the result that two of three patients who had required red-cell and platelet transfusions no longer needed them (at 20 to 27 weeks of follow-up). Treatment was also associated with increased marrow cellularity and a decreased percentage of blasts in the bone marrow of patients with excess blasts, resulting in an increase in the ratio of differentiated myeloid cells to immature myeloid cells. We observed relatively few side effects, but bone pain was dose-limiting when it was associated with high white-cell counts. Our results showed that GM-CSF is a potent stimulator of hematopoiesis in vivo and may produce hematologic improvement in the short term (8 to 32 weeks of observation) in patients with myelodysplastic syndrome. More experience, with longer follow-up periods, will be necessary to assess the long-term safety and efficacy of this new treatment.

Stimulation of Megakaryocyte and Platelet Production by a Single Dose of Recombinant Human Thrombopoietin in Patients with Cancer

Thrombocytopenia is an important clinical problem in the management of patients in hematology and oncology practices. In the United States, the use of platelet transfusions to manage severe thrombocytopenia has steadily increased: Approximately 4 million units were transfused in 1982, and more than 8 million units were transfused in 1992 [1, 2]. This marked increase in the need for platelets has paralleled advances in organ transplantation, bone marrow transplantation, cardiac surgery, and the use of dose-intensive therapy in the treatment of chemosensitive malignant conditions. Although platelet transfusions may decrease the risk for fatal bleeding complications, repeated transfusions increase the risk for transmission of bacterial and viral pathogens, transfusion reactions, and transfusion-associated graft-versus-host disease. These transfusions also contribute to increasing health care costs and inconvenience to patients [3]. Thus, an agent that can increase platelet production and prevent or attenuate thrombocytopenia would be an important advance. Thrombopoietin, the ligand for the c-Mpl receptor (found on platelets and megakaryocyte progenitors), was recently cloned by several investigators and was shown to be a primary regulator of platelet production in vivo [4-8]. Thrombopoietin promotes both the proliferation of megakaryocyte progenitors and their maturation into platelet-producing megakaryocytes. In preclinical studies done in normal mice and nonhuman primates, thrombopoietin increased platelet counts to a level higher than those previously achieved with other thrombopoietic cytokines [9, 10]. Moreover, in a murine model for myelosuppression, recombinant thrombopoietin given as a single dose decreased the nadir and accelerated platelet recovery in mice that had been rendered pancytopenic by sublethal radiation and chemotherapy [11]. In these studies, more prolonged treatment (for as long as 8 days) provided no additional benefit and was associated with marked thrombocytosis during the recovery phase. On the basis of these observations, we initiated a phase I and II clinical and laboratory investigation of recombinant human thrombopoietin in patients with cancer who were at high risk for severe chemotherapy-induced thrombocytopenia. This trial was divided into two parts: Part I studied thrombopoietin given before chemotherapy, and part II studied thrombopoietin given after chemotherapy. The objective of part I, the results of which are reported here, was to assess the hematopoietic effects, pharmacodynamics, and clinical tolerance of this novel agent in patients who had normal hematopoietic function before chemotherapy. Methods Patients Patients with sarcoma who had never had chemotherapy, were suitable candidates for subsequent chemotherapy, and did not have rapidly progressive disease were eligible for this trial. Patients were required to have a Karnofsky performance status score of 80 or more, adequate bone marrow (absolute neutrophil count 1.5 109/L; platelet count 150 109/L and 450 109/L), adequate renal function (serum creatinine level 120 mol/L), and adequate hepatic function (alanine aminotransferase level < 3 times normal; bilirubin level < 1.5 times normal). Patients with a history of thromboembolic or bleeding disorders, significant cardiac disease, or previous pelvic radiation were excluded. Written informed consent was obtained from all patients before study entry in accordance with institutional guidelines. Design During the phase I dose-ranging portion of this clinical cohort study, thrombopoietin was administered as a single intravenous dose 3 weeks before chemotherapy. At study entry, three patients were assigned to each of four dose levels (0.3, 0.6, 1.2, and 2.4 g/kg of body weight). Patients who had no dose-limiting toxicity and did not develop neutralizing antibodies to thrombopoietin were eligible to receive thrombopoietin at the same doses after chemotherapy. Recombinant Human Thrombopoietin The thrombopoietin used in this study was provided by Genentech, Inc. (South San Francisco, California). Thrombopoietin is a full-length glycosylated molecule produced in a genetically modified mammalian cell line and purified by standard techniques. It was mixed with preservative-free normal saline as a diluent for injections. Clinical and Laboratory Monitoring Before and during the clinical trial, patients were monitored by complete histories; physical examinations; and laboratory tests, including a complete blood cell count with differential counts, serum chemistry, coagulation profile, urinalysis, assessment of thrombopoietin antibody formation, chest radiography, and electrocardiography. Blood counts were obtained daily for the first 5 days and then at least three times per week. Peripheral smears were examined serially for platelet morphology. Platelet counts and the average size of platelets (mean platelet volume) were derived from 64-channel platelet histograms. Bone marrow aspiration and biopsy were done before and 1 week after thrombopoietin treatment. The bone marrow specimens were initially fixed in 10% neutral formalin, embedded in paraffin, cut into sections 5 m thick, and stained with hematoxylin-eosin for morphologic analysis and with Masson trichrome for analysis of collagen fiber content. Fresh, air-dried smears of bone marrow were stained with Wright-Giemsa. Bone marrow samples were examined for overall cellularity and morphology in a blinded manner. Megakaryocyte counts were measured by choosing 10 high-power (40x) fields in areas without artifactual zones or trabecula. The relative size of the megakaryocyte was assessed by examining bone marrow aspirate smears using the Magiscan Image Analysis System (Compix, Cranberry, Pennsylvania). Bone marrow aspirates were also assayed for hematopoietic progenitor cell number and cycle status, for content of CD34+ and CD41+ cell subsets (by flow cytometry), and for megakaryocyte ploidy (by flow cytometry). Blood samples were assayed for hematopoietic progenitor cell number and for platelet function. Pharmacokinetics Profiles Serum samples were collected before and at 2, 5, 10, 60, and 90 minutes and 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours after thrombopoietin administration. Concentration-time profile at each dose level was evaluated by using standard pharmacokinetics methods. Serum thrombopoietin levels were quantitated by enzyme-linked immunosorbent assay for thrombopoietin [12]. Hematopoietic Progenitor Cell Assays Assays for colony-forming unit-granulocyte-macrophage (CFU-GM); burst-forming unit-erythroid (BFU-E); and colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM) using low-density bone marrow [13] and peripheral blood cells [14] were done with methyl cellulose assays. The percentage of bone marrow CFU-GM and BFU-E in DNA synthesis (S-phase of cell cycle) was measured by a high-specific-activity tritiated thymidine suicide technique [15]. Assays for colony-forming unit-megakaryocyte (CFU-MK) and burst-forming unit-megakaryocyte (BFU-MK) were done using a fibrin clot assay [16]. Ploidy Analysis Megakaryocyte-enriched cell fractions were prepared from bone marrow cell suspensions by using a Percoll gradient technique. Ploidy was determined by flow cytometric measurement of the relative DNA content after staining with propidium iodide in hypotonic citrate solution [17]. Cells were also stained with anti-CD41b (8D9)-FITC (SyStemix, Palo Alto, California) to allow gating on CD41b+ megakaryocytes. At least 3000 CD41+ events were collected for each sample. The percentage of CD41+ cells in ploidy class was determined from the fluorescence-activated cell-sorting dot plots. Platelet Function Platelet aggregation was measured in response to three agonists: adenosine diphosphate (final concentration, 20 g/mL), collagen (6 g/mL), and thrombin (5 g/mL). Standard methods were used [18]. The concentrations of agonists were chosen on the basis of previous in vitro studies done on blood from normal controls. The instruments used for the assays were the Bio/Data Pap 4A (Horsham, Pennsylvania) and the Crono-log 560CA (Havertown, Pennsylvania). Immunophenotypic Analysis Immunophenotypic analysis was done using anti-CD34 (Becton Dickinson, San Jose, California) and anti-CD41 monoclonal antibodies (Immunotech, Westbrook, Maine) by a standard dual-color flow cytometry technique [19]. Statistical Analysis Continuous variables were compared by using the Wilcoxon matched-pairs signed-rank test. Trends for possible dose-response relation were evaluated using the Spearman rank correlation coefficients (rS) between dose and outcome. Industry Role Thrombopoietin and partial funding for the study were provided by Genentech, Inc. The study was a collaborative effort between the principal investigator and the industrial sponsor. Data collection, data analysis, the writing of the manuscript, and the decision to publish the manuscript were under the control of the principal investigator. The manuscript was reviewed by the industrial sponsor before submission. Results Twelve chemotherapy-naive patients (7 men and 5 women) with sarcoma of diverse histologic sub-types were entered into the dose-ranging portion of this phase I trial, which studied thrombopoietin before chemotherapy. All patients were considered evaluable for clinical tolerance and response to thrombopoietin. The median age of these patients was 42 years (range, 16 to 63 years), and the median Karnofsky performance status score was 90 (range, 80 to 100). Four patients had previously received radiation therapy, and eight had previously had surgery. Peripheral Blood Counts Treatment with a single dose of thrombopoietin was associated with increases (1.3-fold to 3.6-fold) in platelet counts (baseline mean, 264 109/L; maximal mean, 592 109/L) (P = 0.002). The increase in platelet count was seen at all dose levels (Figure 1) in all patients. The peak response i

High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies--dose-response and schedule dependence.

PURPOSE To evaluate the efficacy and feasibility of high-dose ifosfamide (HDI) at a total dose of 14 g/m2 per cycle with mesna in combination with granulocyte colony-stimulating factor (G-CSF) in adult patients with sarcomas. PATIENTS AND METHODS Between July 1991 and February 1994, 74 patients with sarcomas (37 bone and 37 soft tissue) were treated on two simultaneous phase II studies that evaluated HDI given as a continuous infusion over 74 hours. G-CSF was started on day 5 at 5 microg/kg/d until recovery of granulocyte count. Additionally, between March 1993 and March 1994, 15 similar patients with previously treated bone or soft tissue sarcomas were treated on a pilot study in which the same total dose of ifosfamide was administered by a bolus schedule, along with mesna and G-CSF. Patients were treated until maximal response, and where possible, surgical resection of gross disease was performed. RESULTS Seventy-two patients from the phase II study using continuous infusion are assessable for response. Four complete responses (CRs) and 17 partial responses (PRs) were noted, for an overall response rate of 29% (95% confidence interval [CI], 19% to 39%). The response rate was 40% (95% CI, 24% to 56%) for bone sarcomas and 19% (95% CI, 6% to 32%) for soft tissue sarcomas. Fourteen patients from the pilot study that used a bolus schedule are assessable for response. One CR and seven PRs were noted, for an overall response rate of 57% (95% CI, 31% to 83%) and a response rate of 45% for soft tissue sarcomas. Two patients developed grade 3 to 4 renal toxicity, three developed grade 3 CNS toxicity, one had possible grade 3 cardiac toxicity, and two developed severe painful peripheral neuropathy. There were no treatment-related deaths. CONCLUSION HDI at 14 g/m2 with mesna and G-CSF is an active salvage regimen for patients with bone and soft tissue sarcomas. There is a definite positive dose-response curve, and bolus administration appears to be more active than continuous infusion.

Stimulation of Myelopoiesis in Patients with Aplastic Anemia by Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

Aplastic anemia is a syndrome in which pancytopenia occurs in the presence of hypocellularity of the bone marrow. To assess the biologic activities of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in aplastic anemia, we gave GM-CSF (60 to 500 micrograms per square meter of body-surface area) to 10 patients with moderate or severe disease, by continuous intravenous infusion daily for two weeks, and repeated the treatment after a two-week rest period. The treatment increased the white-cell count (1.6- to 10-fold) in all patients, primarily because of an increase in the numbers of neutrophils (1.5 to 20-fold), eosinophils (12- to greater than 70-fold), and monocytes (2- to 32-fold). Rates of hydrogen peroxide production in purified granulocyte fractions increased during GM-CSF treatment. Increases in bone marrow cellularity, myeloid precursor cells, and myeloid:erythroid cell ratios accompanied the white-cell response. Despite the in vivo response of the white-cells, the concentration of colony-forming cells remained the same. Measurable concentrations of interleukin-2 (2 to 15 units per milliliter) were found in the serum of 8 patients, and high levels of erythropoietin (81 to 1200 IU per liter) were found in 10 patients. The predominant side effects were constitutional symptoms. These results indicate that recombinant human GM-CSF is effective in stimulating myelopoiesis in patients with severe aplastic anemia and may benefit some patients in whom the disorder is refractory to standard forms of therapy.

Results of Two Consecutive Trials of Dose-intensive Chemotherapy With Doxorubicin and Ifosfamide in Patients With Sarcomas

The authors evaluate the efficacy and feasibility of dose-intensive doxorubicin and ifosfamide combination chemotherapy in patients with sarcomas. From January 1995 to April 1996, 33 evaluable patients with either metastatic sarcoma or primary sarcomas with a high-risk for metastases (all except one was previously untreated with chemotherapy) were treated on two consecutive protocols. The median age was 45 years (range, 15-68 years). The first protocol included doxorubicin at 75 mg/m2 given as a 72-hour infusion on days 1 to 3 along with ifosfamide at 2 g/m2/d over 2 hours x 5, days 1 to 5 (protocol AI 75/10). Granulocyte colony-stimulating factor (G-CSF) was used only if indicated according to American Society of Clinical Oncology guidelines. The second protocol included doxorubicin at 90 mg/m2 as a 72-hour continuous infusion and ifosfamide at 2.5 g/m2/d for 4 days (protocol AI 90/10) with prophylactic G-CSF. A median of four cycles were administered (range, 1-6). Three patients achieved a pathologic complete response (CR) and 18 patients achieved a partial response (PR) for a response rate (RR) of 64% (95% confidence interval (CI), 45-80%). Response rate for the subset of patients with soft-tissue sarcomas was 66% (95% CI, 46-82%). Only three patients progressed on therapy. Febrile neutropenia was noted in 31% of cycles at AI 75/10 and in 56% of cycles at AI 90/10. One patient developed reversible grade 3 central nervous system (CNS) toxicity. There was one treatment-related death on AI 90/10 secondary to doxorubicin cardiac toxicity at a cumulative dose of 435 mg/m2. Dose-intensive doxorubicin plus ifosfamide is feasible in appropriately selected patients and appears to be a very active regimen in patients with sarcomas. The authors are currently testing this regimen with G-CSF and thrombopoietin.

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,

Phase I trial of recombinant interferon gamma in cancer patients.

Interferon gamma (IFN-gamma) is a lymphokine with potent in vitro effects on cell growth and immune function. We have investigated the effects of rIFN-gamma (sp act approximately 2 X 10(7) U/mg, purity greater than 99%) in 16 evaluable patients with advanced malignancy in a phase 1 trial. Patients were treated with six-hour intravenous (IV) infusions daily, five days a week for 2 weeks. After a 2-week rest period, the IV treatment cycle was repeated. Responders were maintained on repeated IV treatment cycles or daily intramuscular (IM) injections. Patients were entered at fixed dose levels of 0.1, 0.5, or 1.0 mg/m2/d. The maximum safely tolerated dose was 0.5 mg/m2. The most common side effects were constitutional symptoms, including fever, chills, fatigue, and myalgias. Reversible and transient increases in hepatic transaminase and decrease in granulocyte counts were seen. Treatment was associated with a dose-dependent increase in serum levels of beta 2 microglobulin. Partial responses (PRs) were observed in one patient with Hodgkins disease and one patient with chronic lymphocytic leukemia. Fairly constant levels of serum IFN were found at four and six hours during infusion, followed by a rapid decline within one to two hours. We conclude that rIFN-gamma can be safely administered by a six-hour IV infusion and that it can induce in vivo some of the biologic effects reported in in vitro studies.

Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level.

PURPOSE The purpose of this study was to optimize the dose, schedule, and timing of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administration that would best abrogate myelosuppression in patients with sarcoma. PATIENTS AND METHODS Sarcoma patients who had experienced severe myelosuppression after chemotherapy with Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dacarbazine ([CyADIC], cycle 1) were eligible. GM-CSF was administered during a 14-day period until 1 week before cycle 2 of CyADIC and was resumed 2 days after cycle 2 completion. The schedule subsequently was modified to allow the earlier administration of GM-CSF in which CyADIC was compressed from 5 days to 3 days, and GM-CSF was administered immediately after the discontinuation of CyADIC in cycle 2. To understand better the impact of GM-CSF on bone marrow stem cells, the proliferative status of bone marrow progenitors was examined during treatment. To evaluate the effects of GM-CSF on effector cells, select functions of mature myeloid cells were also examined. RESULTS In the seven patients who were treated on the initial schedule, GM-CSF enhanced the rate of neutrophil recovery; however, severe neutropenia was not abrogated, By using the modified schedule in 17 patients, GM-CSF significantly reduced both the degree and the duration of neutropenia and myeloid (neutrophils, eosinophils, and monocytes) leukopenia. The mean neutrophil and mature myeloid nadir counts were 100/mm3 and 280/mm3 in cycle 1 and 290/mm3 and 1,540/mm3 in cycle 2 (P less than .01 and P less than .001). The duration of severe neutropenia (neutrophil count less than 500/mm3) and myeloid leukopenia (myeloid leukocyte count less than 1,000/mm3) were reduced from 6.2 and 6.8 days in cycle 1 to 2.8 and 1.4 days in cycle 2 (P less than .001). While 16 of 17 patients experienced severe myeloid leukopenia (less than 500/mm3) in cycle 1, only two of 17 experienced severe myeloid leukopenia in cycle 2 (P less than .001). Overall, severe neutropenia was abrogated in seven patients, which made them eligible for dose-escalation of Adriamycin. The fraction of cycling progenitors increased threefold on GM-CSF and decreased dramatically below the baseline within 1 day of GM-CSF discontinuation. CONCLUSIONS The modified schedule improved the beneficial effects of GM-CSF by enhancing myeloprotection and permitting dose-intensification of chemotherapy. The increased myeloid mass and quiescent progenitors at the initiation of chemotherapy suggest that GM-CSF might allow further chemotherapy dose-rate intensification by shortening the interval between courses.