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Time-Limited Venetoclax Combinations Superior to Chemoimmunotherapy in Fit Patients with CLL

JHOP - February 2022 Vol 12, No 1 - ASH Highlights
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Use of time-limited venetoclax-based combination therapy was superior to chemoimmunotherapy in achieving undetectable minimal residual disease (MRD) in the peripheral blood by month 15 in fit patients with chronic lymphocytic leukemia (CLL), according to results of a study presented at the 2021 American Society of Hematology annual meeting.1

Moreover, undetectable MRD rates in the bone marrow and complete response rates were significantly higher with 2 time-limited venetoclax-based regimens versus chemoimmunotherapy—the combination of venetoclax plus obinutuzumab and the triplet regimen of venetoclax, obinutuzumab, and ibrutinib, but not with the combination of venetoclax plus rituximab. Undetectable MRD is strongly associated with extended progression-free survival.

“All treatments given in the study showed a good safety profile in this fit patient population,” stated Barbara Eichhorst, MD, Center of Integrated Oncology Cologne Bonn, University Hospital, Germany, who presented the results.

For fit patients with CLL, continuous treatment with a Bruton tyrosine kinase inhibitor, such as ibrutinib or acalabrutinib, is replacing chemoimmunotherapy as standard of care in the first-line setting, particularly in patients with unfavorable prognostic factors. The time-limited combination of venetoclax plus obinutuzumab, and the triplet regimen of venetoclax, obinutuzumab, plus ibrutinib have produced high rates of undetectable MRD.

For frontline therapy, the combination of venetoclax plus obinutuzumab is FDA-approved in this setting based on data from a study in unfit patients with CLL. However, data from a fit cohort have not been previously available.

The GAIA-CLL13 clinical trial evaluated the efficacy and safety of 3 venetoclax plus CD20 antibody-based regimens versus chemoimmunotherapy as first-line treatment for fit patients with CLL who do not have TP53 mutations or deletions.

The study enrolled treatment-naïve fit patients with CLL requiring therapy. “Fit” was defined as cumulative illness rating scale score ≤6 and normal creatinine clearance with ≥70 mL/min. Patients with TP53 mutations or deletions were excluded, because they have a poor response to chemoimmunotherapy, which would have biased the study in favor of the experimental arms.

Patients were randomized in a 1:1:1:1 ratio to:

  • Chemoimmunotherapy for 6 cycles: fludarabine, cyclophosphamide, rituximab (FCR) for patients aged ≤65 years and bendamustine plus rituximab for patients aged >65 years
  • Venetoclax (standard ramp-up from cycle 1, day 22, 400 mg daily, to cycle 2-12) and rituximab (375/500 mg/m22 day 1, cycle 1-6)
  • Venetoclax plus obinutuzumab (1000 mg on days 1, 8, 15, of cycle 1, and day 1 of cycles 2-6)
  • Venetoclax plus obinutuzumab and ibrutinib (420 mg daily, cycle 1-12; if MRD is detectable, continued to cycle 36).

From February 2016 to September 2019, a total of 926 patients (median age, 61 years) were randomized to chemoimmunotherapy with FCR (N = 150) or to bendamustine plus rituximab (N = 79); venetoclax plus rituximab (N = 237); venetoclax plus obinutuzumab (N = 229); or venetoclax, obinutuzumab, plus ibrutinib (N = 231). The majority of the patients had advanced Binet stage (stage B, 37.8%; stage C, 35.6%), and 56% of the patients had no IGHV mutation. In all, 14 did not receive a study treatment and were not included in the safety analysis.

The data cutoff for the first co-primary end point analysis was February 28, 2021. The median observation time was 27.9 months.

The study’s co-primary end point of undetectable MRD in peripheral blood at month 15 was met: the rate of undetectable MRD in the intent-to-treat population was significantly higher with venetoclax plus obinutuzumab (86.5%) than with chemoimmunotherapy (52.0%; P <.0001). The triplet of venetoclax, obinutuzumab, plus ibrutinib also showed a superior undetectable MRD rate of 92.2% compared with chemoimmunotherapy (P <.0001), whereas the rate for venetoclax plus rituximab was 57%.

Corresponding bone marrow undetectable MRD rates in the intent-to-treat analysis were 37.1%, 43.0%, 72.5%, and 77.9%, respectively. The overall response rates and complete response rates for the 4 regimens at month 15 mirrored the pattern for undetectable MRD rates.

The most common grade 3 to 5 treatment-emergent adverse events were neutropenia (50.5% for all patients), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%), and pneumonia (5.3%). Atrial fibrillation and bleeding events occurred more frequently in patients who recieved the triplet regimen, whereas infusion-related reactions were most common in the combination of venetoclax plus obinutuzumab.

Reference

  1. Eichhorst B, Niemann C, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments (RVe, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia (CLL) of fit patients: first co-primary endpoint analysis of the international intergroup GAIA (CLL13) trial. Blood. 2021;138(suppl 1):Abstract 71.
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