Venetoclax Plus Obinutuzumab Demonstrates Durable Survival Benefit in Treatment-Naïve CLL

Chronic Lymphocytic Leukemia

| Image Credit: ©freshidea - stock.adobe.com

Fixed-duration therapy with venetoclax (Venclexta) plus obinutuzumab (Gazyva) led to 60% reduction in the risk of progression or death compared with chlorambucil plus obinutuzumab, with benefit seen regardless of TP53 or IGHV mutation status, in previously untreated patients with chronic lymphocytic leukemia (CLL), according to 6-year findings from the phase 3 CLL14 trial (NCT02242942).¹

The findings were presented by Othman Al-Sawaf, MD, of the Division of Hematology, Immunology, Infectiology, Intensive Care and Oncology at the University of Cologne in Germany, at the 17th Annual International Conference on Malignant Lymphoma.

Results showed that the 6-year progression-free survival (PFS) rate was 53.1% with venetoclax vs 21.7% with chlorambucil (HR, 0.40; 95% CI, 0.31-0.52; P < .0001). Median PFS was 76.2 months and 36.4 months with venetoclax and chlorambucil, respectively.

Results from the primary analysis earned the regimen an approval from the FDA in 2019 for the frontline treatment of patients with CLL/small lymphocytic lymphoma.² Five-year follow-up data were presented at the 2022 EHA Congress.³

The study enrolled patients with treatment-naïve CLL and coexisting medical conditions defined by the Cumulative Illness Rating Scale (CIRS) above 6 and/or creatinine clearance below 70 mL/min. Patients were randomly assigned 1:1 to 6 cycles of venetoclax and obinutuzumab followed by an additional 6 cycles of venetoclax, or 6 cycles of chlorambucil and obinutuzumab followed by another 6 cycles of chlorambucil, totaling 1 year of therapy.

PFS served as the primary end point of the trial. Secondary end points included response, minimal residual disease (MRD), and overall survival (OS).

In the venetoclax arm (n = 216), median age was 72 years, median CIRS score was 9 (range, 0-23), and median estimated creatinine clearance was 65.2 mL/min. All Binet stages were represented: A (21%), B (35%), and C (44%); as were tumor lysis syndrome (TLS) risk categories: low (13%), intermediate (64%), and high (22%). In the chlorambucil arm (n = 216), median age was 71 years, median CIRS score was 8 (range, 1-28), and median estimated creatinine clearance was 67.4 mL/min. The breakdown of Binet stage A (20%), B (37%), and C (43%) disease, and TLS low (12%), intermediate (68%), and high (20%) risk was similar to the investigational arm.

In the venetoclax arm, most patients had unmutated IGHV (61%); 12% had 17p deletion and/or TP53 mutation, and 34% of patients had only 13q deletion. In the chlorambucil arm, 59% of patients had unmutated IGHV; 12% had 17p deletion and/or TP53 mutation, and 36% had only 13q deletion. A total of 24% and 20% of patients in the investigational and control arms had no abnormalities, respectively.

Median observation time was 76.4 months.

Additional results indicated improved PFS regardless of intervention among patients without TP53 mutation/17p deletion. With venetoclax, median PFS was 76.6 months in patients without these markers vs 51.9 months in patients with them (HR, 2.29; 95% CI, 1.37-3.83; P = .001). With chlorambucil, median PFS was 38.9 months and 20.8 months in patients without and with the markers, respectively (HR, 1.66; 95% CI, 1.05-2.63; P = .03).

Median PFS was not reached (NR) with venetoclax in patients with mutated IGHV vs 64.8 months in those with unmutated IGHV (HR, 0.38; 95% CI, 0.23-0.61; P < .001). With chlorambucil, median PFS was 62.2 months and 26.9 months in patients with mutated and unmutated IGHV, respectively (HR, 0.33; 95% CI, 0.23-0.47; P < .001).

Notably, the presence of TP53 mutation/17p deletion did not seem to adversely affect PFS in patients with IGHV mutations who received venetoclax, whereas the 6-year PFS rates were 47.2% and 31.3% in patients with unmutated IGHV without and with TP53 deletion/mutation, respectively. “In the context of venetoclax/obinutuzumab, maximum lymph node size ≥5 cm, unmutated IGHV,and TP53 deletion/mutation are independent negative prognostic factors for PFS,” Al-Sawaf said.

Median time to next treatment was NR with venetoclax vs 52.9 months with chlorambucil, with 6-year rates of 65.2% and 37.1%, respectively (HR, 0.44; 95% CI, 0.33-0.58; P < .0001). “In both arms, most patients received targeted agents as second-line therapy, although 23% to 30% received second-line chemotherapy or chemoimmunotherapy,” Al-Sawaf said. BTK inhibitors represented the most common second-line therapy in both arms, followed by BCL-2 inhibitors.

Median OS was NR in both arms, with 6-year rates of 78.7% and 69.2% with venetoclax and chlorambucil, respectively (HR, 0.69; 95% CI, 0.48-1.01; P = .052).

MRD, which was evaluated in peripheral blood through next-generation sequencing, was sustained at 5 years at less than 10-4 in 1.9% of patients who received chlorambucil vs 7.9% of those who received venetoclax. MRD also correlated with long-term PFS, pointing to the prognostic value of end of treatment MRD status, Al-Sawaf explained. Similar results were seen with OS (HR, 3.42; 95% CI, 1.65-7.06; P < .001). “[These results] highlight the need for dedicated MRD-guided approaches,” Al-Sawaf said.

Regarding safety, post-treatment toxicity was rare in both arms. In the venetoclax arm, grade 3 or greater adverse effects included neutropenia (3.8%), thrombocytopenia (0.5%), anemia (1.9%), febrile neutropenia (0.9%), and pneumonia (3.3%). In the chlorambucil arm, these included neutropenia (1.9%), anemia (0.5%), febrile neutropenia (0.5%), pneumonia (1.4%), and infusion-related reaction (0.5%).

The rate of second primary malignancies was 14.2% with venetoclax vs 8.4% with chlorambucil, including melanoma (3.8% vs 1.9%), solid organ tumors (8.0% vs 5.1%), hematologic malignancies (1.4% vs 0.9%), and other malignancies (0.9% vs 0.5%). “No statistically significant difference in the cumulative incidence of second primary malignancies [occurred] between venetoclax/obinutuzumab and chlorambucil/obinutuzumab,” Al-Sawaf said, citing an incidence rate of 2.3% with venetoclax vs 1.4% with chlorambucil (P = .071).

“[The] secondary malignancy rate [will remain] under continued observation,” Al-Sawaf concluded.

Disclosures: Dr Al-Sawaf reported honoraria/personal fees from AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche; and research grants from AbbVie, BeiGene, Janssen, and Roche.

References

1. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized CLL14 study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 025.
2. AbbVie announces US FDA approval of Venclexta (venetoclax) as a chemotherapy-free combination regimen for previously untreated chronic lymphocytic leukemia patients. News release. AbbVie. May 15, 2019. Accessed June 22, 2023. https://news.abbvie.com/news/press-releases/abbvie-announces-us-fda-approval-venclexta-venetoclax-as-chemotherapy-free-combination-regimen-for-previously-untreated-chronic-lymphocytic-leukemia-patients.htm
3. 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.