Ibrutinib, a Bruton’s tyrosine kinase inhibitor, and venetoclax, a B-cell lymphoma 2 inhibitor, are both approved for the treatment of chronic lymphocytic leukemia (CLL) in the frontline and relapsed/refractory settings. Studies have been initiated to evaluate the synergistic potential of combined use of these agents. At the 2019 ASH Annual Meeting, updated results from an investigator-initiated phase 2 trial focusing on minimal residual disease (MRD) were reported.
The study enrolled treatment-naïve patients with CLL who met 2008 International Workshop on Chronic Lymphocytic Leukemia treatment criteria. Eligible patients had ≥1 of the following high-risk characteristics: del(17p) or mutated TP53, del(11q), unmutated IGHV, or were aged ≥65 years. Patients received ibrutinib 420 mg daily for 3 cycles, followed by escalating doses of venetoclax to a 400-mg daily target dose. At 24 cycles, patients were assessed for bone marrow (BM) undetectable MRD (uMRD); at this juncture, only MRD-positive patients were permitted to continue ibrutinib. In addition to MRD status, other end points included progression-free survival (PFS) and overall survival (OS).
A total of 80 patients were enrolled; baseline characteristics were representative of the previously untreated CLL population. The median follow-up was 27 months. Of the 75 patients initiating venetoclax after 3 cycles of ibrutinib monotherapy, 12/74 (16%) achieved BM uMRD remission after 3 cycles of combination treatment. The proportion increased to 30/72 (42%) after 6 cycles, 45/69 (65%) after 12 cycles, and 37/49 (75%) after 24 cycles.
Neither median PFS nor median OS were reached during the evaluation period; in fact, no patients had CLL progression. Three patients died, one from disseminated central nervous system cryptococcal infection (unrelated to ibrutinib), another from infectious complications of fungal pneumonia, and the third from bilateral pneumonia. Two patients developed Richter transformation. In total, 14 of 80 patients withdrew from the trial. Five patients discontinued treatment during ibrutinib monotherapy, and 9 during combination therapy.
The most common any-grade treatment-emergent adverse events included easy bruising, arthralgia, diarrhea, nausea/vomiting, myalgia, skin rash, nail changes, hypertension, fatigue, and oral mucositis. Atrial fibrillation (any grade) occurred in 12 patients (15%); of these, 8 (10%) were of grade ≥3 severity. Grade ≥3 infections were reported in 15 patients (19%), with neutropenic fever occurring in 4 patients.
Based on the sustained responses and impressive MRD remission rates, the investigators concluded that combined ibrutinib and venetoclax is an effective, safe, chemotherapy-free oral regimen for patients with high-risk, previously untreated CLL.
Jain N, et al. ASH Abstract 34. Session 642.