PS1158 IBRUTINIB PLUS RITUXIMUB IN STEROID REFRACTORY AUTOIMMUNE HEMOLYTIC ANEMIA: ELABORATION OF TREATMENT APPROACH (ISRAEL): AN INTERIM ANALYSIS OF THE ROHS TRIAL

Background: Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are well recognized autoimmune complications (AIC) of chronic lymphocytic leukemia (CLL). Both AIHA and PRCA complicate patient management, have significant impact on quality of life and can be fatal. Ibrutinib is an irreversible inhibitor of BTK and ITK (interleukin‐2 inducible tyrosine kinase), mediating antibody dependent cellular cytotoxicity, which makes it attractive in treatment of AIC in the context of CLL. We present a pre‐planned interim analysis of a multicentre trial evaluating efficacy of ibrutinib in AIC. Aims: The primary objective of this study is to evaluate efficacy (response rate and its duration) of ibrutinib in combination with rituximab for steroid refractory AIHA and PRCA in patients with CLL. Methods: ISRAEL is an open‐label, multicentre, single arm, two staged study of combination of ibrutinib and rituximab in patients with AIHA/PRCA and underlying CLL. In stage I (induction) patients received ibrutinib 420 mg/day and rituximab (9 weekly with subsequent 3 monthly infusions); in stage II (maintenance) – ibrutinib was only given until relapse, progression or unacceptable toxicity. Inclusion criteria included proven diagnosis of CLL per iwCLL guidelines, the presence of clinically significant hemolysis with positive direct antiglobulin test (DAT) in case of AIHA, the presence of erythroblastopenia, confirmed by immunohistochemical staining with Glycophorin A and platelet level >100.000/mkl in case of PRCA, relapse of AIHA/PRCA after steroids, splenectomy or rituximab or refractoriness to glucocorticosteroid hormones. Results: Thirty three patients with CLL and AIC have been enrolled since February, 2017. The median age was 66 years (range 50 ‐ 82), 14 (42%) were female. 30 patients had AIHA and 3 PRCA. The median hemoglobin level at day of 1st infusion was 8,2 g/dL (range 6,5 – 11,3). Twenty two patients (66%) were transfusion‐dependent. Five patients (15%) had deletion 17p and 8 (24%) deletion 11q. Patients had received a median of 2 (range 1 – 6) lines of prior treatment for AIC, including steroids (n = 31), rituximab (n = 6), splenectomy (n = 3), RCD/R‐CVP (n = 13), alemtuzumab (n = 1), BR (n = 7) and other (n = 8). At time of reporting, 22 patients have completed induction. The median duration of ibrutinib treatment was 281 days (range 22 – 673). Adverse events were reported from 31 participants (94%). Of the 351 AEs, 321 (91,5%) were graded as CTCAE grade 1 – 2 and 30 (8,5%) as grade >3. The latter were represented by infections (n = 7), neutropenia (n = 7), arrhythmias (n = 4), arterial hypertension (n = 7), myalgias (n = 3). Two cases of sudden death were reported. Response of AIHA was evident in all patients. By day 141 4 (21%) patients achieved a DAT‐ve CR, 10 (53%) DAT+ve CR, 1 – DAT‐ve PR and 4 (21%) DAT+ve PR. All PR patients achieved transfusion independence. Two patients with PRCA achieved a CR by days 84 and 150, and 1 patient did not respond. Response of CLL, assessed at day 225 by IWCLL 2008 criteria was available in 19 patients. Seven patients (37%) achieved a CR, including one MRD‐negative case. Twelve patients (63%) were classified as PRs because of residual bone marrow infiltration (n = 12) along with persistent splenomegaly (n = 3) or persistent neutropenia (n = 2). No patients have relapsed so far. Summary/Conclusion: The combination of ibrutinib and rituximab demonstrated high activity in the treatment of patients with relapsed and steroid refractory AIHA with underlying CLL. The safety profile of IR combination corresponded to published data.