OUTCOMES WITH BRUTON TYROSINE KINASE INHIBITION IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA AFTER PROGRESSION ON VENETOCLAX

Abstract

Introduction: The BCL2 inhibitor venetoclax entered clinical practice in the USA and Europe after the BTK inhibitor (BTKi) ibrutinib had become standard of care for relapsed CLL. Recent data indicate that venetoclax is efficacious after progression on ibrutinib (Jones et al., ASH, 2016), but efficacy of BTKi after progressive disease (PD) on venetoclax has not been explored. We report outcomes of CLL/SLL receiving BTKi treatment after PD on venetoclax. Methods: of 67 consecutive patients with BTKi naive relapsed/ refractory CLL/SLL treated on early phase venetoclax trials at two Australian centers (June 2011-March 2016), 10 received subsequent BTKi, either ibrutinib 420 mg daily or a novel BTKi on trial. Responses to BTKi were assessed according to iwCLL criteria with the 2012 Cheson addendum for novel therapies and analysed as of 1st October 2016. Results: of the 67 patients on venetoclax, eight developed progressive CLL/SLL. Six of these received ibrutinib as their next therapy, all commencing within 2 months of ceasing venetoclax (Table ). The two patients who did not receive ibrutinib progressed before this agent was available in Australia. Five of the six patients receiving ibrutinib achieved a PR at a median 6 (4-9) months. One patient had SD at 2 months. After a median follow up of 10 months (6-16), three remain alive with ongoing clinical response to BTKi at 6, 13 and 16 months. The other 3 died of PD. An additional four patients (Table Presented) received BTKi for progressive CLL after initially requiring salvage therapy for Richter transformation on venetoclax. All 4 had achieved a clinical response of their large cell lymphoma (3 CR, 1PR) with salvage chemotherapy, prior to BTKi (ibrutinib n = 3; novel BTKi n = 1) after subsequent CLL progression. All attained a PR and remain in ongoing response at 3, 19, 21, 20 months on BTKi (Figure 1). No unusual toxicities of BTKi were seen. Conclusions: Amongst this population with multiply relapsed CLL, confirmed responses were seen with BTKi therapy in 9/10 patients post PD on venetoclax. Together with the data for venetoclax after ibrutinib failure, these findings suggest that cross-resistance between BCL2 and BTK inhibitors is not manifest in most patients and justify the use of BTKi therapy after failure of venetoclax in BTKi-naïve patients.