Ibrutinib/Venetoclax vs Chlorambucil/Obinutuzumab in Previously Untreated Older Patients With CLL/SLL

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In a primary analysis of the phase III GLOW study, a once-daily, all-oral, fixed-duration dose of ibrutinib and venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) resulted in superior progression-free survival than treatment with chlorambucil and obinutuzumab. Arnon Kater, MD, PhD, and colleagues presented these findings at the European Hematology Association 2021 Virtual Congress (LBA1902).

The findings are reportedly the first data to show a positive clinical profile for a fixed-duration ibrutinib and venetoclax regimen as a first-line treatment for older patients.

Arnon Kater, MD, PhD

Arnon Kater, MD, PhD

Study Details

The phase III GLOW study recruited patients 65 years or older with previously untreated CLL or SLL. Patients aged 18 to 64 were also enrolled if they had a cumulative illness rating scale (CIRS) score greater than 6 or a creatinine clearance less than 70 mL/min. The study excluded patients with del(17p) or known TP53 mutations.

Patients were randomly assigned to receive 3 cycles of 420 mg/d of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax with venetoclax increased up to 400 mg/d (n = 106) or 6 cycles of a standard dose of chlorambucil and obinutuzumab (n = 105).

In the ibrutinib/venetoclax group, more patients had a CIRS score greater than six compared to patients in the chlorambucil/obinutuzumab group. In contrast, patients given chlorambucil and obinutuzumab had high lactate dehydrogenase levels.

The primary endpoint of progression-free survival was analyzed via an independent review committee. Secondary endpoints included undetectable residual disease in bone marrow and complete response rate.

Improved Outcomes With Ibrutinib/Venetoclax

After a median follow-up of 27.7 months, progression-free survival in the ibrutinib/venetoclax arm was not reached vs 21 months to the chlorambucil/obinutuzumab arm (hazard ratio [HR] = 0.216, P < .0001).

At 3 months after the end of treatment, undetectable measurable residual disease (MRD) in bone marrow was 51.9% in the ibrutinib/venetoclax arm vs 17.1% in the chlorambucil/obinutuzumab arm (P < .0001); in peripheral blood, the rate was 54.7% vs 39% (P = .0259). About 84.5% of patients maintained peripheral blood undetectable MRD from 3 months after treatment up until 12 months.

A significantly higher complete response was observed in the ibrutinib/venetoclax arm than the chlorambucil/obinutuzumab arm—38.7% vs 11.4 (P <  .0001). There was also a longer time to subsequent therapy (HR = 0.143) and median treatment duration (13.8 months vs 5.1 months).

Overall survival data were immature at the time of the analysis, with 11 deaths reported in the ibrutinib/venetoclax arm and 12 in the chlorambucil/obinutuzumab arm (HR = 1.048).

Safety Profile

A safety profile consistent with treatment of a population of older adults with comorbidities was observed in the ibrutinib/venetoclax group. The most common grade ≥ 3 treatment-emergent adverse events for patients administered ibrutinib plus venetoclax included neutropenia, diarrhea, and hypertension. The chlorambucil/obinutuzumab group reported experiencing neutropenia, thrombocytopenia, pneumonia, and tumor-lysis syndrome. Grade 5 treatment-related adverse events were observed in seven patients in the ibrutinib/venetoclax group and in two patients in the chlorambucil/obinutuzumab group.

The study authors concluded: “All-oral, once-daily, fixed-duration ibrutinib/venetoclax demonstrated superior progression-free survival vs chlorambucil/obinutuzumab as first-line treatment for CLL, independent of CIRS score and other covariates. Ibrutinib/venetoclax significantly improved depth and duration of remission, and thus extended time to next treatment. Undetectable MRD with ibrutinib/venetoclax was largely maintained 1 year after end of treatment. The safety profile for ibrutinib/venetoclax was consistent with treatment in an elderly comorbid population. These first randomized data demonstrate the positive clinical profile of fixed-duration ibrutinib/venetoclax in older patients.”

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