Continuous/Limited Venetoclax Plus Rituximab Yields Robust, Long-Lasting 5-Year Response in Relapsed CLL

Patients with relapsed chronic lymphocytic leukemia who were treated with either limited or continuous venetoclax and rituximab experienced improved responses during a 5-year follow-up.

Treatment with continuous or limited venetoclax (Venclexta) and rituximab (Rituxan) resulted in deep, long-lasting responses in patients with relapsed chronic lymphocytic leukemia (CLL), according to results of the phase 1b M13-365 study (NCT01682616) published in Blood; retreatment with the combination also appeared promising.

After a median follow-up of 5.3 years, the overall population was reported have a 5-year overall survival rate of of 86% (95% CI, 73%-94%), progression-free survival (PFS) rate of 56% (95% CI, 40%-70%), and a duration of response (DOR) rate of 58% (95% CI, 40%-73%). After a median of 1.4 years, 14 patients remained on continuous venetoclax monotherapy, and 19 discontinued limited treatment with venetoclax. The 5-year estimate of ongoing response remained similar among those who received continuous (71%; 95% CI, 39%-88%) vs limited-duration therapy (79%; 95% CI, 49%-93%). Of the 19 patients in the limited treatment group, 6 patients experienced subsequent disease progression after being off venetoclax for over 2 years.

A total of 49 patients enrolled on the open label multicenter dose escalation study. Patients had a median age of 68 years and had previously received a median of 2 prior therapies. Patients had a median time on venetoclax of 2.5 years, and as 24 patients had withdrawn from the study as of its publication. Patients received between 200 mg to 600 mg of venetoclax daily plus rituximab over a 6-month period followed by venetoclax monotherapy.

Additional findings from the study indicated that patients had an overall response rate of 86% (95% CI, 73%-94%),with 53% of patients achieving either a complete response (CR) or CR with incomplete marrow recovery (CRi; 95% CI, 38%-68%). In total, 29% of patients achieved a CR/CRi in 1 year, 16% in 1 to 2 years, and 8% had a CR/CRi after 2 years. After approximately 5.8 years, 1 patient achieved CR following additional infusions and dose escalations of rituximab and venetoclax.

For the 42 responders, the 5-year rate of ongoing response was 58% (95% CI, 40%-73%), with an estimated median duration of response of. A total of 61% of patients achieved bone marrow undetectable minimal residual disease (uMRD), with a median DOR of 6.2 years (95% CI, 5.4-6.3) compared with 2.2 years (95% CI, 0.8-2.8) for patients who did not achieve uMRD. Additionally, 33% of patients who did not achieve CR and/or uMRD withdrew from the study due to disease progression, adverse effects (AEs), and withdrawn consent. Patients who were deep responders were less likely to experience bulky adenopathy (39% vs 56%). The 5-year PFS rate for deep responders was 79% (95% CI, 59.1%-90.0%). The population also had an estimated median PFS of 6.5 years.

A total of 8 patients had continuous ongoing remission. The median time on venetoclax was 5.6 years, and the mean time of the study was 5.6 years. For these patients, the 5-year PFS rate was 79% (95% CI, 47-93) and they had an estimated median of 6.6 years (95% CI. 4.6-6.6). The 5-year estimated median DOR was 71% (95% CI, 39-88) and a median of 6.3 years (95% CI, 4.4-6.3).

Among the 19 patients who stopped treatment, 9 remained on the study with continued response and 4 withdrew with in ongoing response. A total of 15 patients achieved uMRD and CR, and 2 patients had uMRD and a partial response with residual adenopathy precluding assignment of CR. Patients who remained in remission had a 5-year PFS rate of 80% (95% CI, 49.4%-93.0%), and an estimated median PFS of 6.5 years (95% CI, 3.6-6.5).

Among the deep responders, 6 had stopped treatment and experienced disease progression after a median of 3.4 years. By the cutoff date, 2 patients did not require further therapy, and 4 were retreated with venetoclax and rituximab. One patient who was retreated achieved a PR and is still on therapy. A second patient achieved PR but discontinued following CLL progression and a third achieved uMRD and CR but developed asymptomatic progression; with additional retreatment, the third patient achieved a PR. Lastly, the fourth patient had an initial response of CR plus uMRD followed by disease progression; after data cutoff, they achieved PR.

All patients in the study experience treatment-emergent AEs (TEAEs), with 95% of patients experienced TEAEs beyond 2 years of treatment with venetoclax. A total of 82% patients had grade 3/4 TRAEs, with 52% experiencing toxicities beyond 2 years. The most common AE was neutropenia. Serious AEs (SAEs) occurred in 57% of patients and 43% experienced SAEs after 2 years of treatment. The most common SAE was pyrexia (10%) patients and pneumonia (10%) among those beyond 2 years of treatment.

Fatal myocardial ischemia occurred in 1 patient after 2 years of treatment. A total of 71% of patients experienced an infection of any grade after 2 years of treatment. Infection that was grade 3/4 or those considered to be SAEs were rare.


Ma S, Seymour JF, Brander DM, et al. Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy. Blood. 2021;138(10):836-846. doi:10.1182/blood.2020009578