Neutropenia in Myelosuppressed Cancer Patients Treated with Recombinant Human Erythropoietin (EPO)

Abstract

Recombinant human erythropoietin (EPO) has been used extensively for 3 decades to treat various forms of anemia, including anemia associated with cancer treatment. Multiple randomized, placebo controlled clinical trials conducted since the late 1980's found that EPO treatment ameliorated anemia, reduced transfusion requirements, and improved quality of life measures in cancer patients receiving myelosuppressive chemotherapy. However, results of several of these trials suggested that EPO treatment might also exacerbate neutropenia in these patients. This possible side effect had been anticipated by a pre-clinical observation that neutrophil production in long-term marrow cultures was suppressed by EPO. However, chemotherapy-induced neutropenia was expected in these clinical trials and not studied, nor reported, in detail. Recently, primary data from 5 prospective randomized, placebo controlled clinical trials of EPO treatment in cancer patients undergoing myelosuppressive chemotherapy, sponsored by Johnson & Johnson, became available through the Yale Open Data Access (YODA) project*. These data allowed us to compare serial neutrophil counts (ANCs) from 1650 study subjects with various forms of cancer who participated in these 5 clinical trials and were randomly assigned to either EPO or placebo treatment. Individual clinical trial sample sizes varied from 71 to 922 (Table below). ANC values were recorded weekly in 2 trials but less frequently in the other 3. In our analysis we determined the percent of study subjects with recorded ANC values <1500/mm3, <500/mm3, and <200/mm3 during the initial 12 weeks of each trial for individuals assigned either to placebo or to EPO treatment. Mantel-Haenszel odds ratios were used as measures of differences between treatment groups. In addition, Poisson regression was used to assess differences in the total numbers of ANC measurements <500/mm3 per study subject per 12 weeks on study that had been recorded in each treatment group. In each trial more study subjects assigned to EPO than to placebo treatment were found to have had at least one ANC <500/mm3 reflecting severe neutropenia (Table). Study-specific odds ratios for this difference ranged from 1.24 to 2.08 and the Mantel-Haenszel odds ratio for the combined studies was 1.48 with a 95% Confidence Interval (CI) of 1.08 - 2.03, p =0.014. A statistically significant odds ratio was also found for ANC values of <200/mm3 (1.73, 1.10-2.70, p=0.016), but not for neutropenic ANC values overall, i.e. <1500/mm3 (1.18, 0.93-1.50, p=0.17). Total numbers of recorded ANC values <500/mm3 per study subject per 12 weeks on study were also significantly different - 0.66 (95% CI, 0.57-0.76) in the EPO treatment group vs. 0.49 (0.42-0.60) in the placebo group, p=0.0075. This analysis of 5 randomized placebo controlled clinical trials carried out from 1988 to 2002 finds that EPO treatment of individuals undergoing myelosuppressive chemotherapy was associated with statistically significant increases in the incidence of severe neutropenia and suggests that competition between the erythroid and myeloid lineages may occur in the setting of suppressed hematopoietic reserves when the erythroid lineage is pharmacologically amplified. *This study, carried out under YODA Project 2017-2486, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C.. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C.. Table Disclosures No relevant conflicts of interest to declare.