Deep Response With Venetoclax Plus Rituximab in Relapsed/Refractory CLL

Combining the selective BCL2 inhibitor venetoclax with rituximab may increase the depth and durability of response in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a report from the phase Ib M13-365 study published in the Lancet Oncology.

John F. Seymour, MBBS, from the Department of Hematology at the Peter MacCallum Cancer Centre in Melbourne, Australia, and co-authors found that patients who received the combination treatment had a response rate of 86 percent, including a complete response (CR) rate of 51 percent.

“In the setting of relapsed/refractory CLL, both venetoclax and rituximab can be given safely at their recommended single-agent doses (400 mg daily for venetoclax and 500 mg/m2 for rituximab),” Dr. Seymour told ASH Clinical News. “We do not need to compromise optimal dosing to deliver these agents in combination.”

The M13-365 study included adult patients with relapsed/refractory CLL or small lymphocytic lymphoma who had disease that required therapy (per standard International Workshop on CLL criteria); an Eastern Cooperative Oncology Group performance status score of ≤1; and adequate marrow, renal, and hepatic function. Patients were excluded if they had previously undergone hematopoietic cell transplantation, had uncontrolled autoimmune cytopenias, or had any other active malignancy within 3 years. Patients received no more than three previous myelosuppressive regimens and had not received a monoclonal antibody for CLL within 8 weeks prior to venetoclax dosing, an anticancer therapy within 14 days, or an antileukemic steroid therapy within 7 days.

Venetoclax was administered daily with a stepwise escalation from 200-600 mg. One week after the target dose of venetoclax was achieved, rituximab 375 mg/m2 was administered during the first month and titrated to 500 mg/m2 for months 2-6. Per study protocol, patients continued venetoclax monotherapy until unacceptable toxicity, disease progression, or drug cessation. The maximum tolerated dose of venetoclax was not identified, and a 400 mg dose was recommended for phase II of the study.

Between August 6, 2012, and May 28, 2014, 49 patients were enrolled (41 in the dose-escalation cohort and 8 in the safety expansion cohort). As of data cutoff (March 4, 2016), 31 patients (63%) remained on the study. The median follow-up was 28 months (range = <1-42 months) for all patients and 29 months (range = 21-42 months) for patients still on the study. Eighteen patients discontinued treatment for the following reasons: disease progression (n=11), toxicity (n=3), withdrawal of consent (n=3), and loss to follow-up (n=1).

The most common adverse events (AEs) were grade 1/2 self-limited gastrointestinal (GI) events (including diarrhea [n=27; 55%] and nausea [n=25; 51%]) and upper respiratory tract infections (n=28; 55%).

Seventy-six percent of patients (n=37) experienced grade 3/4 AEs, the most common of which were peripheral blood cytopenias, including neutropenia (n=26; 53%), thrombocytopenia (n=8; 16%), anemia (n=7; 14%), febrile neutropenia (n=6; 12%), and leukopenia (n=6; 12%). The most common serious AEs were pyrexia (n=6; 12%), febrile neutropenia (n=5; 10%), lower respiratory tract infection (n=3; 6%), and pneumonia (n=3; 6%).

Five patients experienced tumor lysis syndrome (TLS), which resulted in one death. Following those events, the study protocol was amended to include a lower starting dose of venetoclax (20 mg) and modified TLS prophylaxis. Among the 32 patients in whom venetoclax was resumed, no clinical TLS was observed.

Twenty patients (41%) had dose reductions, most commonly because of cytopenias (n=9; 18%) and GI events (n=4; 6%). Three deaths were reported, from metabolism and nutrition disorders (n=1) and neoplasms (n=2).

Time to first response was 2.9 months (range = 0.7-15.7 months), and CRs were attained for a median of 9.2 months (range = 6.4-28.6 months). (TABLE)  By the end of therapy, 25 patients (51%) achieved CR or CR with incomplete marrow recovery (CRi) as best response. The best responses according to venetoclax dose level were as follows:

  • 200 mg: 33% CR/CRi, 67% nodular PR/PR
  • 300 mg: 50% CR/CRi, 30% nodular PR/PR, 10% stable disease
  • 400 mg: 75% CR/CRi, 13% stable disease (not assessed in 1 patient)
  • 500 mg: 57% CR/CRi, 29% nodular PR/PR, 14% stable disease
  • 600 mg: 50% CR/CRi, 40% nodular PR/PR, 10% stable disease
  • safety expansion: 38% CR/CRi, 50% nodular PR/PR, 13% progressive disease

Of the 42 patients who were evaluable for bone marrow minimal residual disease (MRD), 28 (67%) became MRD negative, including 20 patients who achieved CR (80%). MRD negativity was achieved within 7 months of therapy initiation in 79 percent of patients (n=22/28). Eleven of the MRD-negative patients who achieved CR ceased all therapy after a median of 10 months (range = 4-37 months) and remained progression-free off therapy.

“The data indicate that MRD-negative CRs are now readily achievable in patients with relapsed CLL and that patients achieving such deep responses need not continue therapy indefinitely,” the authors noted.

Disease progression occurred in 11 patients in the overall study population; the median time to progression had not been reached at the time of data cutoff, with 82 percent of patients (95% CI 66-91) estimated to be progression-free at 2 years. The 2-year estimate for ongoing response was 89 percent (95% CI 72-96).

The study is limited by its small patient population and limited follow-up. “The size of the study was modest, and it is not a randomized comparison against venetoclax alone,” Dr. Seymour said. “While the responses are extremely encouraging, current follow-up (28 months) is insufficient to accurately define the duration of responses and allow meaningful comparison of progression-free survival relative to venetoclax alone.”


Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230-40.

TABLE. Response by Venetoclax Dose Level
  200 mg


300 mg


400 mg


500 mg


600 mg


Safety Expansion,
400 mg


Overall response 100% (n=6) 80% (n=8) 75% (n=6) 86% (n=6) 90% (n=9) 88% (n=7) 86% (n=42)
(95% CI 73-94)
CR or CRi 33% (n=2) 50% (n=5) 75% (n=6) 57% (n=4) 50% (n=5) 38% (n=3) 51% (n=25)
(95% CI 36-66)
Nodular PR or PR 67% (n=4) 30% (n=3) 0 29% (n=2) 40% (n=4) 50% (n=4) 35% (n=17)
(95% CI 22-50)
SD 0 10% (n=1) 13% (n=1) 14%


10% (n=1) 0 8% (n=4)
PD 0 10% (n=1) 0 0 0 13% (n=1) 4% (n=2)
Not assessed 0 0 13% (n=1) 0 0 0 2% (n=1)
Negative marrow MRD response 50% (n=3) 30% (n=3) 75% (n=6) 57% (n=4) 70% (n=7) 62% (n=5) 57% (n=28)
CR = complete response; CRi = complete response with incomplete marrow recovery; PR = partial response; SD = stable disease; PD = progressive disease; MRD = minimal residual disease