Ibrutinib in previously treated chronic lymphocytic leukemia patients with autoimmune cytopenias in the RESONATE study

Autoimmune cytopenias occur in up to 10% of patients during the course of chronic lymphocytic leukemia (CLL), with autoimmune hemolytic anemia (AIHA) the most common, followed by immune-mediated thrombocytopenia (ITP). These disorders may occur at any time during disease course and depend on complex interactions between the malignant clone, impaired T-cell function, microenvironment and the immune system. Prevalence of AIHA ranges from 2.9 to 10.5%, and is generally associated with advanced disease. Clinically significant ITP occurs in ~ 2% of patients. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase (BTK), is indicated by the US FDA for the treatment of patients with CLL/small lymphocytic lymphoma (SLL), including patients with 17p deletion, and allows for treatment without chemotherapy. In addition to BTK, ibrutinib targets members of the Tec kinase family, ITK and TEC, and TXK which may impact immune function. To address the impact of ibrutinib on CLL-associated AIHA/ITP, we retrospectively analyzed data from patients in the phase 3 RESONATE study comparing ibrutinib versus ofatumumab in previously treated CLL, including patients with history of ongoing complications of AIHA and/or ITP. History of AIHA and/or ITP was collected as complications of CLL, including status at study entry (ongoing/resolved), from 386 patients who received study treatment for this analysis (n= 195 ibrutinib; n= 191 ofatumumab). Per the study protocol, AIHA was defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytes (above ULN) or bone marrow erythropoiesis in the absence of bleeding) and at least one marker of autoimmune mechanism (positive direct antiglobulin for IgG or C3d, cold agglutinins). ITP was defined by platelets ⩽ 100 000 per μl and increased megakaryocytes on bone marrow exam. Patients with uncontrolled AIHA or ITP (defined as declining counts within the screening period or requirement for steroids 420 mg daily) were excluded from the RESONATE study. Other patients with AIHA/ITP including those meeting IWCLL 2008 criteria for treatment were eligible. Standard supportive care medications were permitted per protocol. Protocol-defined AIHA and ITP were reported at the discretion of the investigator at study entry based on assessments made during the screening period. Baseline hemoglobin and platelet counts for the present analysis were based on measurements from the first day of study treatment. Hemoglobin and platelet counts over time were assessed in patients with ongoing AIHA (n= 21 ibrutinib; n= 9 ofatumumab) and ongoing ITP (n= 12 ibrutinib; n= 10 ofatumumab) at study entry, respectively. Corticosteroid use for autoimmune complications and treatment-emergent adverse events (AEs) of AIHA and ITP were collected for all treated patients. Ofatumumab data were censored at initiation of crossover to ibrutinib. Ofatumumab regimen was limited to 6 months; AE reporting period for this arm was complete at publication of interim analysis. Status of AIHA and ITP associated with CLL at study entry is shown in Table 1. At baseline, patients on ibrutinib with ongoing AIHA had median hemoglobin of 10.4 g/dl (range: 8.1–13.7), which increased to 12.4 g/dl (range: 10.3–14.6) at 24 weeks (Figure 1a). Patients on ibrutinib with ongoing ITP had median platelet count of 49 × 10 per liter (range: 20–138× 10) at baseline compared with 94× 10 per liter (range: 64–248×10) at 24 weeks (Figure 1b). In patients on ofatumumab, median hemoglobin for patients with AIHA and platelet counts for patients with ITP were 10.2 g/dl (range: 7.3–12.9) and 66 × 10 per liter (range: 23–126× 10),