Autoimmune Hemolytic Anemia and Immune Mediated Thrombocytopenia in the Phase III RESONATE^TM Study of Ibrutinib Vs Ofatumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Including a Case Report

Introduction: Autoimmune hemolytic anemia (AIHA) and immune mediated thrombocytopenia (ITP) are frequent complications of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) that may evolve independently or occur at any stage of disease progression. Ibrutinib (Imbruvica^®), a first-in-class BTK inhibitor, is a once-daily single-agent approved by the US FDA for CLL patients (pts) who had received ≥1 prior therapy, and for CLL pts with deletion 17p. Comprehensive efficacy and safety results from the interim analysis of the phase III RESONATE (PCYC-1112) study have previously been reported, demonstrating that improved progression-free survival (PFS) and overall survival were seen with ibrutinib (ibr) as compared to ofatumumab (ofa) in pts with previously treated CLL/SLL. Interim analysis data from the Phase III RESONATE^TM study are presented for pts with autoimmune complications, including that of a case report in which recurrent AIHA/ITP episodes resolved following initiation of ibr.

Methods: History of AIHA and ITP along with status on study entry and resolution date when applicable were collected from 386 enrolled pts in both arms (ibr n=195; ofa n=191) who received study treatment. Ibr was administered at 420 mg once daily until PD or unacceptable toxicity. Ofa was administered at 300 mg followed by 2000 mg dose for up to 12 doses. Treatment emergent adverse events of ITP and AIHA are summarized for treated pts based on randomized arm as of the interim analysis. Pts with uncontrolled AIHA or ITP, defined as declining counts in the 4 weeks prior to randomization or requirement for steroids >20 mg/daily were excluded per study eligibility criteria. In addition, detailed medical history was reviewed for RESONATE patient MXC, as this patient was diagnosed with rapidly progressing CLL at its inception complicated by recurrent AIHA/ITP episodes over a 10-year course of CLL treatment.

Results: In the RESONATE trial, median age was 67 years with 40% ≥70 years, and median number of prior therapies was 3 (ibr) vs 2 (ofa). In all treated pts (ibr n=195; ofa n=191), 29 (15%) pts in ibr arm had a history of AIHA with 20 (10%) ongoing at study entry, compared to 30 (16%) pts in the ofa arm with only 9 (5%) ongoing at study entry. 18 (9%) pts in ibr arm had a history of ITP with 12 (6%) ongoing at study entry, compared to 20 (10%) pts in ofa arm with 10 (5%) ongoing at study entry. Nine ibr and 8 ofa pts reported both AIHA and ITP at baseline, including patient MXC. No pts on the ibr arm developed treatment-emergent AIHA or idiopathic thrombocytopenic purpura. Two pts on the ofa arm developed AIHA, 1 of which was Grade 3/4. Two pts on the ofa arm developed idiopathic thrombocytopenic purpura, both of which were Grade 3/4. Case history showed that patient MXC underwent first-line fludarabine followed by alemtuzumab as consolidation treatment for rapidly progressing CLL diagnosed in 2004. Patient had unmutated IGHV status and deletion 17p. In 2005, the patient underwent autologous peripheral blood stem cell transplant. First AIHA episode was noted in 2007, followed by ITP in 2008 despite prior steroid and IVIG treatment. Recurrent episodes of AIHA (n=6) and ITP (n=3) transpired over the course of CLL, not always related to simultaneous disease progression. After several treatment failures during the 3^rd AIHA episode and 2^nd ITP episode, splenectomy was performed to obtain temporary clinical control of autoimmune events, and low dose steroids were successfully administered. In March 2013, patient was randomized to ibr as part of the RESONATE trial, steroid use was discontinued, and no further episodes of AIHA/ITP have been observed since ibr initiation. The patient showed Coombs test negativity after only a few weeks following ibr treatment, and no CLL progression has been observed to date.

Conclusions: Efficacy and safety of ibrutinib has been evaluated in CLL/SLL pts including pts with ongoing AIHA/ ITP, both frequently noted complications of this disease. Data from the Phase III RESONATE study suggest that these CLL disease-related autoimmune complications did not limit ibrutinib treatment. This is supported by the lack of AIHA and ITP adverse events on the ibrutinib arm despite 19% having a history of these complications and further exemplified by a case report from the RESONATE study, where sequential episodes of severe AIHA/ITP ceased following ibrutinib initiation in the setting of disease control.