Venetoclax Plus Obinutuzumab Confers Long-Term Survival Benefits in Unfit Patients With CLL

Othman Al-Sawaf, MD

Venetoclax (Venclexta) plus obinutuzumab (Gazyva) remains an effective fixed-duration treatment option for patients with chronic lymphocytic leukemia (CLL) and coexisting conditions, according to updated efficacy and safety data from the ongoing phase 3 CLL14 trial (NCT02242942) presented during the 2022 EHA Congress.

At a median follow-up of 65.4 months, the median progression-free survival (PFS) for patients treated with venetoclax plus obinutuzumab was not reached (NR) compared with 36.4 months among patients treated with chlorambucil (Leukeran) plus obinutuzumab (HR, 0.35; 95% CI, 0.26-0.46; P < .0001). The 5-year PFS rates were 62.6% and 27.0%, respectively. Most patients treated with fixed-duration venetoclax plus obinutuzumab (63%) remain without a PFS event 4 years post treatment.

“What is important for us in these longer follow-ups is to really understand what happens with the disease dynamics and what happens with the patients when they get off treatment,” Othman Al-Sawaf, MD, a physician at the University Hospital of Cologne in Germany said in a presentation of the findings.

PFS benefits with venetoclax plus obinutuzumab were also observed across subgroups. The median PFS for patients without a TP53 deletion or mutation was NR in the investigational arm compared with 38.9 months in the control arm. Patients with a TP53 deletion or mutation experienced a median PFS of 49.0 months and 19.8 months, respectively.

Similarly, among patients with mutant IGHV status the median PFS was NR in the investigational arm compared with 59.9 months in the control arm. The median PFS for patients with unmutated IGHV was 64.2 months and 26.9 months, respectively.

The CLL14 study enrolled patients with previously untreated CLL and coexisting medical conditions deemed unfit, who were randomly assigned 1:1 to receive either venetoclax plus obinutuzumab (n = 216) or chlorambucil plus obinutuzumab (n = 216). To be eligible for the trial, patients needed to have a total cumulative illness rating scale (CIRS) score greater than 6 and/or a creatine clearance of less than 70 mL/min.

Patients in the venetoclax arm were treated with 12 cycles of venetoclax administered in a ramp-up dosing schedule with 6 cycles of obinutuzumab. In the control arm, patients received 12 cycles of chlorambucil with 6 cycles of obinutuzumab.

The primary end point was PFS. Key secondary end points included response, minimal residual disease (MRD), and overall survival (OS).

Baseline patient characteristics were well balanced between the 2 arms; the median age was 72 years and 71 years in the venetoclax plus obinutuzumab and chlorambucil plus obinutuzumab arms, respectively. The median total CIRS score were 9 (range, 0-23) and 8 (range, 1-28), respectively. The median estimated creatine clearance was 65.2 mL/min and 67.4 mL/min, respectively.

Patients in the investigational arm had low (14%), intermediate (64%), and high (22%) tumor lysis syndrome (TLS) risk. Patients also had Binet stage A (21%), B (35%), and C (44%) disease. Comparatively, patients in the control arm mostly had an intermediate TLS risk (68%) and Binet stage C disease (43%).

Most patients in both the investigational and control arms had unmutated IGHV (61% vs 59%). Twelve percent of patients in both arms had deleted and/or mutated TP53. Common cytogenic subgroups included deletion in 11q (17% vs 18%), trisomy in 12 (17% vs 19%), no abnormalities (24% vs 20%), and deletion in 13q alone (34% vs 36%).

Additional findings from the trial showed that the median time to next treatment (TTNT) was NR in the venetoclax arm compared with 52.9 months in the control arm. The 5-year TNNT rates were 72.09% and 42.84%, respectively (HR 0.42; 95% CI, 0.31-0.57; P < .0001).

Thirty-one patients in the venetoclax arm progressed to a second line of treatment compared with 94 patients in the chlorambucil plus obinutuzumab arm. Most of these patients in both arms subsequently received a Bruton tyrosine kinase (BTK) inhibitor as their second line therapy (58.1% vs 54.3%). PI3K inhibitors and CD20 antibodies were used in 1 patient each, both in the chlorambucil plus obinutuzumab arm. Chemotherapy or chemoimmunotherapy were used as a second line treatment in less than a third of patients in both arms (25.8% vs 30.9%).

Notably, the median OS was NR in either arm. The 5-year OS rates were 81.9% and 77.0% in the investigational and control arms, respectively (HR 0.72; 95% CI, 0.48-1.09; P = .12).

Additionally, a longitudinal MRD assessment found that 4 years after treatment with venetoclax plus obinutuzumab 18.1% of patients had sustained MRD of less than 10^-4. In the other arm, 1.9% of patients treated with chlorambucil plus obinutuzumab experienced sustained MRD of less than 10^-4 4 years after therapy.

The depth of remission beyond 10^-4 correlates with long-term PFS, which indicates the value of ultra-sensitive MRD assessments, Al-Sawaf noted. Patients treated with venetoclax plus obinutuzumab with MRD of at least 10^-4 experienced a shorter OS compared with those with MRD less than 10^-4.

In terms of safety, the most common adverse events (AEs) grade 3 or higher that occurred with venetoclax plus obinutuzumab included neutropenia (51.9%), thrombocytopenia (14.2%), anemia (7.5%), and febrile neutropenia (4.2%). After treatment, common grade 3 or greater AEs included neutropenia (4%), pneumonia (3.0%), and anemia (2%).

In the chlorambucil plus obinutuzumab arm, the most common grade 3 or higher AEs reported during treatment included neutropenia (47.2%), thrombocytopenia (15%), and infusion-related reactions (9.8%). After treatment, common grade 3 or higher AEs included neutropenia (1.9%), pneumonia (1.4%), and anemia (0.5%).

Secondary primary malignancy (SPM) events occurred in 55 patients and 44 patients in the investigational and control arms, respectively. Patients had at least 1 SPM at a rate of 20.8% and 15.0%, respectively. Common SPMs included non-melanoma skin cancer (9.0% vs 8.4%), solid organ tumors (7.1% vs 4.7%), and melanoma (3.8% vs 1.4%). Investigators noted that there was no statistical difference in the cumulative incidence of SPMs between the 2 arms.

“So far, there were no new safety signals [with venetoclax plus obinutuzumab],” Al-Sawaf concluded. “Secondary malignancies remain statistically not significant between the arms, but [we will] continue to follow-up on safety and survival in this study.”

Reference

Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 5- year results of the randomized CLL14 study. Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract S148