A Phase II Study of Time-Limited Treatment with Acalabrutinib Plus Obinutuzumab in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia

Background: Patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) often receive treatment with BTK inhibitors (BTKi) with or without anti-CD20 monoclonal antibody. At the present time, it is recommended that therapy with BTKi is continued long-term, however prolonged treatment with BTKi can be complicated by side effects and/or development of resistance. As an alternative, we developed a time-limited combination therapy of acalabrutinib and obinutuzumab that incorporates treatment discontinuation after 24 cycles of therapy. We report results from the first 37 patients with TN CLL enrolled in this trial (NCT04505254).

Methods: Patients with TN CLL and indication for therapy per iwCLL criteria receive acalabrutinib, 100 mg BID for 24 cycles (each cycle is 28 days), combined with monthly obinutuzumab infusions for 6 months, starting in cycle 3. Patients who achieve complete remission (CR) after 6 cycles of combination therapy continue with acalabrutinib as monotherapy. Patients with a PR or SD receive 6 additional cycles of the combination therapy (cycles 9 – 14) before transitioning to acalabrutinib as monotherapy. Treatment is discontinued after 24 cycles in all patients. After treatment discontinuation, patients transition to observation and can resume therapy if they relapse and meet iwCLL criteria for starting salvage therapy. The primary objective is to determine the durability of treatment-free remissions after 24 cycles of therapy. Secondary objectives include assessing the efficacy of re-treatment, and determining factors associated with prolonged remission. Correlative studies of T-cell compartment during treatment are ongoing.

Results: 37 patients with the median age of 68 years (range, 40 – 83 years) have been enrolled and 23 are evaluable for a response. About 5% have del(17p) or TP53 mutation, 38% have unmutated IgHV and 51% have advance stage disease (Rai stage III/IV). After a median follow-up of 14 months, 36 patients are alive (97%), one patient died due to complications from bacterial pneumonia during cycle 3; 33 patients remain on study (89%). Two patients were taken off study due to recurrent infections (cholecystitis, cellulitis), and one due to loss of health insurance. The estimated two-year PFS and OS are 96.7%. In this ongoing study, the overall response rate is 100% in evaluable patients, with CR observed in 12 patients (52%) and PR in 11 patients (48%) as best response. CR rate after 24 cycles of therapy is 62%. The median levels of measurable residual disease (MRD) in the bone marrow (BM) evaluated by flow cytometry decreased from 84.30% at baseline (median, range, 36.10 – 94.70%) to 0.12% (range, 0 – 3.60%) after 24 cycles with 4 patients (31%) achieving undetectable MRD in the BM. At this time, 13 patients have already completed 24 cycles of therapy and discontinued treatment. With a median follow-up of 9 months after treatment discontinuation, 10 patients remain in remission and 3 patients experienced disease relapse, two of them requiring retreatment.

Conclusions: Time-limited therapy with acalabrutinib and obinutuzumab induces remissions in patients with TN CLL with 62% of patients achieving a CR. After a median follow-up of 9 months after therapy discontinuation, 10/13 (77%) of patients remain in remission. Ongoing correlative studies and longer follow-up will define the patient characteristics that are associated with long remissions after time-limited therapy with acalabrutinib and obinutuzumab. This may help to identify patients for whom this approach could become an alternative to continuous BTK inhibitor therapy.