Adding Umbralisib and Ublituximab (U2) to Ibrutinib in Patients with CLL: A Phase 2 Study of an MRD-driven Approach

Abstract Purpose: Ibrutinib has transformed the management of CLL, though its use is limited by toxicity and resistance. In this study, we utilized an “add on” approach for patients treated with ibrutinib in the front-line or R/R settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment free observation (TFO). Experimental Design: Patients were eligible if they received ibrutinib in any line of therapy for ≥6 months and had detectable MRD (flow cytometry, 10-4 sensitivity). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. Results: 28 patients were enrolled of which 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7 - 67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol while 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. PFS at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, increased ALT/AST 4%. Conclusions: This triplet approach utilizes addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable.