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Venetoclax Combined with Rituximab in Patients with Relapsed/Refractory CLL

December 30, 2021

An early-phase study of the combination of venetoclax, an investigational B-cell lymphoma 2 (BCL-2) selective inhibitor, with rituximab showed response rates of 80 percent in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), in a phase Ib study presented at the European Hematology Association Congress.

Venetoclax is a novel, once-daily oral treatment that works by preventing apoptosis of some cells – including lymphocytes – that can be expressed in certain types of cancer.

The cause of CLL is unknown, and there are few safe and effective treatments for it, the authors wrote, but the combination of venetoclax with rituximab is "encouraging." The study was presented by Andrew W. Roberts, MBBS, PhD, of the Royal Melbourne Hospital Department of Clinical Hematology and Bone Marrow Transplant Service in Australia, and head of Clinical Translation at the Walter and Eliza Hall Institute of Medical Research.

Eligible patients began treatment with 20 or 50 mg of venetoclax daily, which was increased weekly to final doses of 200 to 600 mg. After the weekly lead-in phase, monthly rituximab was added (at 375 mg/m2 and then 500 mg/m2) for a total of six doses. All patients had previously been treated with a median of two therapies. Response to treatment was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Minimal residual disease (MRD) was assessed in local laboratories using ≥4 color flow cytometry on cells in bone marrow (BM) and blood.

A total of 49 patients were enrolled in five dose-escalation cohorts (n=41) and a safety expansion cohort at 400 mg/day (n=8). Forty-five patients (92%) had prior rituximab therapy, and 14 (29%) were rituximab-refractory.

Dr. Roberts and colleagues reported that patients with CLL taking the venetoclax combination had an overall response rate (ORR) of 84 percent (n=41/49), with 41 percent of patients achieving either a complete response (CR) or CR with incomplete marrow recovery (CRi; TABLE). Response rates were similar in patients with the del(17p) karyotypic abnormality. Only 3 of 41 (7%) responders had progressive disease (at 5, 8, and 12 months). Eleven patients discontinued the study: six due to progressive disease, two due to adverse events (AEs), and three patients withdrew consent.

Additionally, six patients stopped venetoclax after achieving CR/CRi. Three patients maintained a response after a median of 12 months (0-21). "Potentially, the most interesting part of these initial results is the data regarding the patients who have been able to come off treatment and who continue to maintain their complete response," Dr. Roberts said

Minimal residual disease (MRD) was evaluable in 40 patients. MRD-negativity in BM was achieved in 13 out of 20 (65%) patients with CR/CRi and in 24 out of 49 (49%) patients overall.

In terms of safety, the most common overall treatment-emergent AEs seen in >25 percent of patients were neutropenia (53%), diarrhea and nausea (47%), upper respiratory tract infection (41%), pyrexia (37%), and fatigue, headache, and cough (each 33%). There was one treatment-emergent AE that led to death due to tumor lysis syndrome, and there were two treatment-emergent deaths that occurred in patients with progressive disease.

"The combination of venetoclax and rituximab has a tolerable safety profile and induces deep and durable responses," Dr. Roberts and colleagues concluded, adding that a randomized clinical trial is underway to further test for safety and efficacy of this combination.


Roberts A, Ma S, Brander D. Venetoclax (ABT-199/GDC-0199) combined with rituximab induces deep responses in patients with relapsed/refractory chronic lymphocytic leukemia. Abstract #S431. Presented at the 2015 European Hematology Association, Vienna, Austria, June 13, 2015.


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