In this issue of Blood, Flinn et al report the results of a phase 1b study combining venetoclax and obinutuzumab (VO) to treat both relapsed/refractory and previously untreated chronic lymphocytic leukemia (CLL).1
Targeted therapy has come of age in the treatment of CLL, first with the addition of anti-CD20 monoclonal antibodies including rituximab and obinutuzumab to chemotherapy, followed by small molecule inhibitors blocking critical signaling pathways or overexpressed antiapoptotic proteins. Ibrutinib has been shown to irreversibly inhibit Bruton tyrosine kinase in the B-cell receptor signaling pathway. Continuous treatment with ibrutinib monotherapy has shown dramatic efficacy in both untreated and previously treated CLL patients.2 Venetoclax, a potent inhibitor of B-cell lymphoma 2 (BCL-2), restores normal apoptosis in CLL cells and was initially approved for previously treated CLL patients.
The need for continuous therapy with ibrutinib monotherapy is highlighted by the low rate of complete responses (CRs), largely due to persistent disease in the bone marrow (BM). Very little is known about the durability of response after stopping ibrutinib in patients who stop for reasons other than disease progression. The addition of rituximab to ibrutinib did not prolong response despite higher CR rates and more frequent undetectable minimal residual disease (uMRD).3
In the phase 3 iLLUMINATE trial for previously untreated patients, the combination of ibrutinib and obinutuzumab demonstrated superior progression-free survival compared with chlorambucil and obinutuzumab (ChlO). But only ∼20% of subjects achieved uMRD responses in the BM, and there was no significant difference between the 2 groups.4 Given these results, it is doubtful that the addition of obinutuzumab could facilitate time-limited therapy when combined with ibrutinib.
Venetoclax has also been used as continuous monotherapy in trials of high-risk patients with relapsed or refractory CLL, and there are reports of even high-risk patients maintaining their response after stopping treatment. The largest reported experience is the MURANO trial, which randomized previously treated patients to bendamustine and rituximab vs venetoclax and rituximab.5 Rituximab was given during the first 6 months of therapy while venetoclax was administered for a maximum of 2 years. With a median follow-up of 36 months, 71.4% of venetoclax/rituximab-treated patients were still free of progression with only 14% of patients receiving subsequent therapy. This combination also achieved deep responses, with uMRD in 64% of patients who completed 2 years of treatment without progression. This depth of response was clinically meaningful, with 97.6% of patients with uMRD remaining free of progression with median follow-up of 10 months after stopping therapy, compared with only 62% with detectable MRD.
At present, the role of combination therapy remains unclear, especially in previously untreated patients. A phase 1b study involving only 12 patients showed that ibrutinib, obinutuzumab, and venetoclax could be given in patients with relapsed CLL, with 6 patients achieving uMRD responses after 12 months of therapy.6 The same group reported their preliminary results of this same combination in an expanded cohort of relapsed patients as well as in a treatment-naive cohort.7 Two-thirds of the 25 treatment-naive patients and one-half of the 25 relapsed patients achieved uMRD at the end of therapy.
The combination of venetoclax and ibrutinib has been studied in 2 phase 2 trials involving treatment-naive patients with equally impressive results.8,9 In the first trial, treatment duration in 80 patients was 12 months with no patient progressing from CLL. After completion of treatment, 61% had no detectable CLL in their BM. In the second trial, 163 patients were treated, with 9 of the first 11 achieving BM uMRD. A third study using this combination in 49 relapsed patients demonstrated a 39% BM uMRD response after 12 months of treatment.10
The study by Flinn et al in this issue describes the use of obinutuzumab with venetoclax to treat CLL. In the treatment-naive group of 32 patients, 78% achieved a CR or CR with incomplete count recovery and 78% achieved uMRD in the BM after 6 months of obinutuzumab and 12 months of venetoclax. In the relapsed group of 46 patients, 62% achieved uMRD in the BM, although these patients were eligible to continue venetoclax monotherapy indefinitely. These are the highest rates of uMRD reported with combination therapy.
A subsequent phase 3 randomized trial of VO vs ChlO in treatment-naive CLL patients demonstrated superior progression-free survival in favor of VO with 57% of 216 patients achieving uMRD in the bone marrow with sustained uMRD responses 12 months after treatment completion.11 As a result, venteoclax is now approved in the US for all patients with CLL.
Like a prize fighter in the early rounds of a championship bout, an early knockdown can be game-changing. Combinations of novel, targeted drugs with differing mechanisms of action are entering the ring as formidable challengers to monotherapies. Will a winner emerge? And can we rely on time-limited therapy? Venetoclax with obinutuzumab provides a knockout (KO) punch to CLL. Can it arise again to fight another day?
Conflict-of-interest disclosure: S.C. received honoraria from Janssen and Pharmacyclics (nonpromotional education programs); had a consulting or advisory role for AbbVie, Celgene, Janssen, Novartis, Pharmacyclics, Astellas, and Astra Zeneca; received research funding (institutional and salary support) from AbbVie, Acerta, Celgene, Gilead, Janssen, Pharmacyclics, and Takeda; received travel, accommodations, and expenses from AbbVie, BeiGene, Celgene, Genentech, Janssen, and Pharmacyclics; is on the data safety monitoring committee for BeiGene; and provided expert advice for patent litigation in Canada and South Korea for Genentech.
