Frontline Venetoclax and Obinutuzumab Maintains Delay of Progression in CLL

Othman Al-Sawaf, MD

With further follow-up from the phase 3 CLL14 trial (NCT02242942), the median progression-free survival (PFS) was still reached with the fixed-dose regimen of venetoclax (Venclexta) and obinutuzumab (Gazyva) in patients with previously untreated chronic lymphocytic leukemia (CLL).¹

At a median follow-up of 52.4 months, the median PFS was not reached in the experimental arm vs 36.4 months in the chlorambucil/obinutuzumab control arm (HR, 0.33; 95% CI, 0.25-0.45; P <.0001). The 4-year PFS rate was 74.0% compared with 35.4% in favor of chlorambucil/obinutuzumab, according to findings presented during the European Hematology Association 2021 Virtual Congress.

“With longer follow-up, we see that PFS is still favored in the venetoclax arm,” said lead author Othman Al-Sawaf, MD, a physician with the University Hospital of Cologne in Germany, in a virtual presentation of the data. “The majority of patients remain without disease progression even 3 years after completing their treatment.”

He added that the combination of venetoclax/obinutuzumab conferred a PFS benefit over chlorambucil/obinutuzumab, irrespective of TP53 or IGHV mutation status. In the experimental arm, the median PFS was not reached vs 38.9 months for those on chlorambucil/obinutuzumab in patients without TP53 aberrations. For those who harbored TP53 aberrations, the median PFS was 49.0 months and 20.8 months, respectively.

However, in patients with mutated IGHV, the median PFS with the venetoclax arm was not reached vs 54.5 months for the control arm. In those with unmutated IGHV, the median PFS was 57.3 months and 26.9 months, respectively.

In the open-label, multicenter, CLL14 trial, investigators compared the combination of fixed-duration venetoclax and obinutuzumab vs obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were evenly randomized to receive either regimen for 12, 28-day cycles.

The primary end point was investigator-assessed PFS. Secondary end points included independent review committee–assessed PFS, minimal residual disease (MRD) status, overall response rate (ORR), complete response (CR) or CR with incomplete hematologic recovery rates (CRi), overall survival (OS), duration of response, event-free survival, median time to next treatment (TTNT), and safety.

Baseline characteristics were well balanced between the 2 treatment arms. Overall, the median age was 71.5 years (range, 41-89), 43.5% had Binet stage C disease, the median total Cumulative Illness Rating Scale score was 8.3, and the median estimated creatinine clearance was 66.2 ml/min. Most patients (66%) were in the intermediate tumor lysis syndrome (TLS) category. Sixty percent of patients had unmutated IGVH and 12% of patients had TP53 aberrations. Additionally, patients had 17p deletions (7.5%), 11q deletions (17.5%), 12 trisomy (18%), 13q deletion (35%), or no abnormalities (22%).

The median OS has not yet been reached in either arm (HR, 0.85; 95% CI, 0.54-1.35; P = .4929); the 4-year OS rates are 85.3% for the venetoclax arm vs 83.1% for the control arm.

The median TTNT was not reached in either treatment arm. The 4-year TTNT rate was 81.08% in the venetoclax/obinutuzumab arm compared with 59.9% for chlorambucil/obinutuzumab. Thirty-five patients in the experimental arm had progressive disease, 17 of whom required anti-leukemic treatment, compared with 122 and 70, respectively, in the control arm (HR, 0.46; 95% CI, 0.32-0.65; P <.0001).

Assessment of MRD in peripheral blood 30 months after the end of treatment showed that 26.9% of patients in the experimental arm still had undetectable MRD compared with 3.2% of patients in the chlorambucil/obinutuzumab arm.² Al-Sawaf added that patients in the control arm tended to lose MRD status after a median of 6 months vs 21 months with the venetoclax/obinutuzumab combination.

Regarding safety, there was no late onset or long-term toxicities with venetoclax/obinutuzumab in those evaluable for safety (n = 212 venetoclax/obinutuzumab; n = 214 chlorambucil/obinutuzumab). Posttreatment, most frequent adverse events that were grade 3 or higher with venetoclax/obinutuzumab and chlorambucil/obinutuzumab was neutropenia (4.0% vs 1.9%, respectively), thrombocytopenia (0.5% vs 0%), anemia (1.5% vs 0.5%), febrile neutropenia 1.0% vs 0.5%), pneumonia (3.0% vs 1.4%), and infusion-related reaction (0% vs 0.5%).

There were 34 deaths in the experimental arm, 7 (20.5%) of which were related to CLL. Forty-one deaths occurred in the control arm, 16 (39%) of which were related to CLL. Al-Sawaf said most deaths on study were related to comorbid conditions.

“We are really able to mitigate the risk features of CLL by effectively controlling the disease,” Al-Sawaf said. “Therefore, our patients do not die of their cancer anymore, which is quite a substantial improvement.”

Investigators recorded secondary primary malignancies in 42 in the chlorambucil/obinutuzumab group vs 47 in venetoclax/obinutuzumab group, which Al-Sawaf said was not statistically significant.

“One of the advantages of fixed-duration treatments is that there is virtually no toxicity when the patients get off treatment,” Al-Sawaf said. “Once they have completed those 12 cycles of treatment, we don’t see any long-term toxicity or late-onset toxicities, suggesting that fixed-duration treatments allow patients to really benefit from a lower risk of toxicity, a lower risk of drug-drug interactions—which is particularly relevant in these comorbid patients—and is therefore quite favorable for the majority of patients.”

The FDA approved the venetoclax/obinutuzumab combination as frontline treatment for patients with CLL or small lymphocytic lymphoma in May 2019. Previous data from the CLL14 trial showed that the combination reduced the risk for disease progression or death by 67% compared with chlorambucil/obinutuzumab (HR, 0.33; 95% CI, 0.22-0.51; P <.0001).³ In this earlier dataset, the ORR was 85% with venetoclax/obinutuzumab vs 71% in the control arm (P = .0007).

_References

_{1. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Abstract S146.}

_{2. New data shows AbbVie's Venclyxto/Venclexta fixed duration combination demonstrates sustained progression-free survival in chronic lymphocytic leukemia patients after three years off treatment. News release. Abbvie. June 11, 2021. Accessed June 11, 2021. https://bit.ly/3gtlG4Y}

_{3. FDA approves venetoclax for CLL and SLL. FDA. May 15, 2019. Accessed June 11, 2021. https://bit.ly/3iwXml9}