Thrombocytopenia Induced by CMC-544 and Its Amelioration Using Oprelvekin (Neumega®/Recombinant Human Interleukin-11)

CMC-544 is CD22-specific cytotoxic immunoconjugate of calicheamicin that has demonstrated significant anti-tumor activity in phase I clinical trial in B-NHL patients (Blood2005;106:230). In this trial, thrombocytopenia was reported as the most common dose-limiting adverse event. The present non-clinical study attempted to provide insights into the observed thrombocytopenia associated with CMC-544 treatment in B-NHL patients. In vitro, CMC-544 neither bound to nor caused aggregation of platelets in platelet-rich plasma of human or murine origin. When administered to mice, a single dose of CMC-544 resulted in a 50% to 75% reduction in the number of circulating platelets with a nadir on day 3 or 4. The platelet levels returned to normal at the latest by day 12. Similar effects were also observed in cynomolgus macaques with nadirs on day 4 or 5. CMC-544 dose not cross-react with either murine or cynomolgus macaque CD22. Unconjugated anti-CD22 antibody, G5/44 (humanized IgG4 antibody) had no effect on circulating platelets. CMC-544-induced thrombocytopenia in mice was associated with a concomitant reduction in circulating levels of thrombopoietin (TPO) with a nadir on day 4. In contrast, treatment with carboplatin, a cytotoxic chemotherapeutic agent known to cause thrombocytopenia, caused thrombocytopenia in mice but with a nadir on day 11. Unlike that with CMC-544, carboplatin-induced thrombocytopenia was associated with an increase in the levels of circulating TPO. Thus, CMC-544-induced thrombocytopenia appears to be mechanistically and kinetically distinct from that associated with conventional cytotoxic chemotherapeutic agents. In this murine model, pretreatment with human IGIV (Carimune) failed to prevent CMC-544-associated thrombocytopenia. However, subcutaneous pretreatment of mice with oprelvekin (Neumega/rhIL-11; 250 ug/kg) significantly reduced the magnitude of the CMC-544-associated thrombocytopenia. When evaluated in cynomolgus macaques, daily subcutaneous pretreatment with oprelvekin (125 ug/kg) for 5 days completely prevented CMC-544-associated thrombocytopenia and also suppressed elevations in serum hepatic aminotransferases associated with the CMC-544 treatment. Concurrent administration of oprelvekin with CMC-544 failed to prevent the initial thrombocytopenia but did accelerate complete recovery of platelets counts to the pretreatment levels and also suppressed elevations in serum hepatic aminotransferases. These results suggest that thrombocytopenia associated with CMC-544-treatment may in part be due to CMC-544-induced hepatic changes, including decreased TPO production. This study further provides evidence that oprelvekin not only stimulates megakaryocytes to produce platelets but is also hepatoprotective, reducing the degree of CMC-544-mediated hepatotoxicity. We have presented preclinical evidence that the prophylactic use of oprelvekin can ameliorate CMC-544-induced thrombocytopenia and thus, supports the clinical evaluation of oprelvekin administered with CMC-544 to augment its therapeutic benefit in patients with B-non-Hodgkin’s lymphoma.