Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model.

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. Although several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody-drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood and promotes killing by macrophages and natural killer cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.