Ibrutinib Combo Improves PFS Vs Chlorambucil Combo in CLL Genomic Subgroups

In the phase 3 GLOW study (NCT03462719), patients assigned to the experimental arm received 420 mg of ibrutinib orally once a day for up to 15 cycles plus venetoclax at a ramp up dose from 20 to 400 mg followed by ibrutinib as subsequent therapy in the case of progressive disease.

Treatment with ibrutinib (Imbruvica) plus venetoclax (Venclexta) yielded higher undetectable minimal residual disease (MRD) and progression-free survival (PFS) than chlorambucil (Leukeran) plus obinutuzumab (Gazyva) across most genomic subgroups in a population of patients with previously untreated chronic lymphocytic leukemia (CLL), according to findings from the phase 3 GLOW study (NCT03462719).

Investigators reported these findings as part of a poster presentation at the 2023 Annual Meeting of the Society of Hematologic Oncology (SOHO).

Across the intent-to-treat (ITT) population, the overall response rate (ORR) was 86.8% in the ibrutinib-based arm vs 84.8% in the chlorambucil-based arm, respectively, with corresponding complete response (CR) rates of 42.5% vs 12.4%, respectively. Additionally, those receiving ibrutinib plus venetoclax with a normal karyotype; 13q deletions; NOTCH1-ICD, SF3B1, ATM, and PCLO alterations; and mutated/unmutated IGHV had significantly improved CR rates (P <.001).

Investigators reported undetectable MRD in 54.7% of patients who received ibrutinib plus venetoclax vs 39.0% among those receiving chlorambucil plus obinutuzumab in the ITT population. Patients in the ibrutinib-based arm appeared to have higher undetectable MRD rates regardless of genomic alterations outside of trisomy-12 aberrations, IGLL5 mutations, and mutated IGHV.

In the ibrutinib arm, the undetectable MRD rate was 66.7% for those with present 13q deletions vs 49.3% in those without. Additionally, the undetectable MRD rate was 59.7% in those with unmutated IGHV vs 40.6% with mutated IGHV. Additionally, the undetectable MRD rates were 42.1% vs 57.5% in those with present and absent trisomy-12 aberrations, respectively, as well as 38.9% vs 58.0% in those with mutated and wild-type NOTCH1-ICD. Investigators noted that differences in these rates did not reach statistical significance.

Ibrutinib plus venetoclax significantly improved PFS compared with chlorambucil plus obinutuzumab after a median follow-up of 46 months (HR, 0.214; 95% CI, 0.138-0.334; P <.0001). A significant PFS improvement extended to all chromosomal and genomic subgroups with the ibrutinib-based regimen excluding non-significant improvements for those with trisomy-12 (HR, 0.58; 95% CI, 0.25-1.35; P = .202), NOTCH1-ICD mutations (HR, 0.42; 95% CI, 0.17-1.05; P = .055), and IGLL5 mutations (HR, 0.15; 95% CI, 0.02-1.37; P = .048).

Combining ibrutinib with venetoclax also led to an improvement in overall survival (OS) compared with chlorambucil plus obinutuzumab (HR, 0.487; 95% CI, 0.262-0.907).

In the phase 3 GLOW study, patients assigned to the experimental arm received 420 mg of ibrutinib orally once a day for up to 15 cycles plus venetoclax at a ramp up dose from 20 to 400 mg followed by ibrutinib as subsequent therapy in the case of progressive disease. In the comparator arm, patients received chlorambucil at 0.5 mg/kg on days 1 and 15 of cycles 1 to 6 plus 1000 mg of intravenous obinutuzumab on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 to 6.

The primary objective of this analysis of the GLOW study was assessing how baseline genomic alterations affected response, undetectable MRD rates, and PFS with the previously described treatments. Evaluating PFS and OS outcomes after 46 months of median follow-up was another objective.

Patients 65 years and older or 18 to 64 years old with adequate Cumulative Illness Rating scores or creatinine clearance and previously untreated CLL were eligible for enrollment on the study. Those with 17p deletions or known TP53 mutations were unable to enroll.

Investigators reported 11q deletions in 18.5% of the study population, trisomy-12 in 22.3%, and 13q deletions in 44.1%. Additionally, 58.8% and 31.8% of IGHV samples were unmutated and mutated, respectively. NOTCH1-ICD, SF3B1, ATM, XPO1, and RPS15 genetic mutations were the most common across the study population. It was highlighted that rates of genomic alterations were comparable between treatment arms.

Reference

Kater A, Hodkinson B, Moreno C, et al. Genomic alterations and outcomes with fixed-duration ibrutinib + venetoclax: results from the phase 3 GLOW study in patients with previously untreated chronic lymphocytic leukemia. Presented at the 2023 Society of Hematologic Oncology (SOHO) Annual Meeting; September 6–9, 2023; Houston, TX. Abstract CLL-584.