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High rates of complete response and eradication of minimal residual disease with the combination of ibrutinib and venetoclax in previously treated chronic lymphocytic leukaemia

Eradication of minimal residual disease (MRD) is emerging as a new treatment goal in chronic lymphocytic leukaemia (CLL). By combining the Bcl-2 inhibitor venetoclax and the BTK-inhibitor ibrutinib, researchers were able to induce MRD negativity in one third of previously treated CLL patients. Importantly, this treatment was not associated with an increased incidence of tumour lysis syndrome (TLS), a serious side effect of venetoclax.

Ibrutinib is an oral BTK-inhibitor affecting antigen-induced proliferation & cell adhesion/migration. Venetoclax on the other hand is a potent, highly selective, orally bioavailable Bcl-2 inhibitor affecting CLL cell survival. Both ibrutinib and venetoclax are currently approved as single agents for CLL. Ibrutinib leads to a rapid nodal response with re-distribution of CLL cells into the peripheral blood, while venetoclax leads to depletion of CLL cells to levels where they cannot be detected in a proportion of patients. Combining the two mechanisms of action could potentially lead to a higher rate of deep responses and could increase the incidence of MRD negativity.

During ASH 2017, Hillmen et al. reported the results of the CLARITY trial, a feasibility study to investigate the safety and efficacy of ibrutinib combined with venetoclax in patients with relapsed/refractory CLL. The primary endpoint of CLARITY was MRD eradication (<0.01% CLL cells) in the bone marrow after 12 months of ibrutinib plus venetoclax, while key secondary objectives included MRD eradication (<0.01% CLL cells) in the marrow after 6 and 24 months, response rate, progression-free survival (PFS) and overall survival (OS).

The study at hand enrolled CLL patients who required therapy and either relapsed within 3 years of chemo-immunotherapy or had a 17p deletion and failed at least one line of therapy. After 8 weeks of ibrutinib monotherapy (420mg/day), venetoclax was added first at a dose of 10mg/day with weekly escalations to 20mg, 50mg, 100mg, 200mg to a final dose of 400mg/day. If MRD negativity was reached in the bone marrow at 8 months, the treatment was stopped after 14 months. In case of MRD eradication in the bone marrow at 14 months, the ibrutinib-venetoclax therapy was stopped after 26 months. In case of MRD positivity at 26 months, ibrutinib monotherapy was continued. Given the known risk for TLS in patients treated with venetoclax, all patients were given prophylactic uric acid reducing agents beginning at least 72 hours prior to starting venetoclax.

In total, 54 patients were recruited in the study. The median age of patients was 64 years and 69% of them were male. Ten of the enrolled patients harboured a del(17p), 13  had a del(11q) and 10 had mutated VH genes. Patients in the study received a median of 1 prior therapy (range 1-6). In 81% of patients, the prior therapy included chemo-immunotherapy with either FCR, or BR.

Overall, 63 adverse events were reported, including 25 events with grade 3/4 severity. The most common adverse events were bruising (N=33, 32 grade 1) and neutropenia (N=25, 16 grade 3). Only 1 case of TLS was reported (at 200mg dose), manifesting itself as an increased level of phosphate and creatinine. The TLS was managed by delaying venetoclax. No further TLS was seen after rapid re-escalation of venetoclax in this patient.

At the time of the analysis, 38 patients reached at least month 8, having received at least 6 months of ibrutinib plus venetoclax and having undergone a bone marrow and peripheral blood evaluation for MRD. In 38 efficacy-evaluable patients, all experienced at least a partial response to the combination of ibrutinib and venetoclax (objective response rate [ORR], 100%). Of these patients, 37% treated with the combination were negative for minimal residual disease (MRD) in the peripheral blood at 8 months. MRD was defined as fewer than 0.01% CLL cells in the BM. When testing the bone marrow (BM), the MRD-negative rate was 32%. Trephine was normal for 84% of patients (32/38). No difference was seen in the rate of MRD negativity in patients who failed prior FCR/BR, or idelalisib. A complete response (CR) was seen in 15 patients (39%). In 3 more patients (8%) a CR with incomplete blood recovery (CRi) was reported. The additional 20 patients (53%) achieved a partial response (PR) with the combination therapy, resulting in an objective response rate (ORR) of 100%.

In summary, the combination of ibrutinib with venetoclax was well tolerated in patients with relapsed/refractory CLL with one reported case of laboratory TLS. All patients in the trial had an objective response and in 18 patients a CR/CRi was obtained. With respect to the primary endpoint, 32% MRD negativity rate (no detectable disease) in the bone marrow was seen after 6 months of ibrutinib-venetoclax. These early results suggest a potent synergy between ibrutinib & venetoclax. Results for the trial’s secondary endpoints of safety and absence of detectable disease in the bone marrow after 6 and 24 months of combination therapy will be reported at a later time.


Hillmen P, Munir T, Andy Rawstron A, et al. Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy. Presented at ASH 2017; Abstract #428.


Speaker Peter Hillmen


Professor Peter Hillmen, MD, PhD, Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom


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