Favorable Outcomes for Patients Treated with U2 with Co-Morbidities or Concomitant Medications: A Retrospective Analysis of Unity-CLL Phase 3 Trial

Background: The median age at diagnosis of patients with Chronic Lymphocytic Leukemia (CLL) is 70 years, which presents unique challenges for disease management, as these patients have more comorbidities and often require multiple concomitant medications. While some baseline characteristics (e.g., history of cardiovascular or bleeding issues) may create potential risk for significant medical events, others (e.g., hypertension, joint pain) threaten the ability of patients to stay on long-term continuous BTKi, compromising optimal therapeutic benefit. The tolerability of Bruton's tyrosine kinase inhibitors (BTKi) can be suboptimal in these patients, emphasizing the need for novel non-chemotherapy regimens with a differentiated risk profile. The combination of umbralisib and ublituximab (U2) demonstrated superior progression-free survival (PFS) and overall response rates (ORR) compared to chemoimmunotherapy in the primary analysis of the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311) (Gribben et al. 2020). Herein, an analysis was conducted of patients treated with U2 on UNITY-CLL who had a pre-existing comorbidity or concomitant medication that could potentially preclude the use of BTKi. Methods: Patients ≥18 years of age with CLL who were treatment-naïve (TN) or previously treated (PT) requiring treatment per iwCLL criteria with adequate organ function and ECOG PS ≤2 were eligible. Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy. Stratification factors included treatment status (TN vs. PT) and deletion 17p (del17p) status. Umbralisib was given orally at 800 mg once daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and on Day 1 every 3 cycles after Cycle 6. The primary endpoint was independent review committee (IRC)-assessed PFS of U2 compared to O+Chl. Key secondary endpoints included IRC-assessed ORR, complete response, undetectable minimal residual disease (uMRD), duration of response, and safety, assessed from the first dose until 30 days after the last dose of study medication. BTKi risk factors were defined by the comorbidities and concomitant medication categories listed in Table 1 and include pre-existing arrythmias, cardiovascular dysfunction, history of major bleeding, hypertension, and joint pa