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Older patients with newly diagnosed chronic lymphocytic leukemia (CLL) had an almost 80% reduction in the risk of disease progression or death with a fixed-duration, all-oral regimen, according to a randomized study.

Patients assigned to the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) had yet to reach median progression-free survival (PFS) after a median follow-up of 27 months, whereas the control regimen of obinutuzumab (Gazyva) and chlorambucil led to a median PFS of 21.0 months. The estimated difference between the two treatment arms translated into a 78.4% reduction in the risk of progression or death in favor of ibrutinib-venetoclax.

Additionally, more than three times as many patients obtained complete responses with the ibrutinib-venetoclax regimen. Significantly more patients in this group achieved undetectable minimal residual disease (MRD) in bone marrow and peripheral blood, reported Arnon P. Kater, MD, of Amsterdam University Medical Centers, during the European Hematology Association virtual congress.

"The GLOW trial is the first phase III study of an all-oral, once-daily, fixed-duration regimen," said Kater. "Ibrutinib and venetoclax showed a significant improvement in progression-free survival compared to standard-of-care chemoimmunotherapy in first-line CLL. [Ibrutinib-venetoclax] provided greater depth of responses, as demonstrated by higher rates of complete remission and undetectable MRD status. Responses and undetectable MRD are highly durable 1 year after completing treatments."

The results are consistent with those of the phase II CAPTIVATE trial, which involved a younger, fitter patient population, he added. "We now have experience across a broad spectrum of more than 400 CLL patients treated with [ibrutinib-venetoclax] in the first-line setting."

During a discussion that followed the presentation, Kater demurred when asked whether the results make ibrutinib-venetoclax the new standard of care for newly diagnosed CLL. Instead, he cited the potential for more choices for first-line therapy.

"You can now choose an all-oral fixed-duration regimen. You can choose venetoclax with obinutuzumab, which is also fixed duration. You have targeted treatments and also ibrutinib maintenance. But, indeed, you have a very good choice option for both fit and unfit patients," he emphasized.

Both ibrutinib and venetoclax have demonstrated efficacy as initial treatment for CLL, including a with ibrutinib and a with venetoclax in combination with an anti-CD20 antibody. Currently, ibrutinib is taken daily until disease progression and venetoclax is also dosed once daily as part of a 12-cycle combination therapy.

"While continuous single-agent ibrutinib is an established standard of care in first-line CLL, the hope is that combining with venetoclax will lead to deeper responses and enable an alternative treatment approach that could offer patients time off treatment," said Kater.

GLOW included 211 patients with untreated CLL. Eligibility criteria included age ≥65 or age <65 and a cumulative illness rating scale (CIRS) score >6 or creatinine clearance <70 mL/min. Patients with 17p deletion or TP53 mutations were excluded. Patients randomized to ibrutinib-venetoclax began treatment with 3 cycles of ibrutinib, followed by 12 cycles of ibrutinib-venetoclax. Patients in the control arm received 6 cycles of chlorambucil and obinutuzumab.

The primary endpoint was PFS by independent review, and secondary endpoints included undetectable MRD in bone marrow, complete response rate by independent review, objective response rate by independent review, and overall survival (OS).

The patient population had a median age of 71 and a median CIRS score of 8 to 9. The primary analysis showed a significant reduction in the PFS hazard (95% CI 0.131-0.357, P<0.0001), which remained consistently in favor of the ibrutinib-venetoclax arm across subgroups. Investigator-assessed PFS yielded results similar to those of the independent review committee.

Three months after end of treatment, undetectable MRD rates in bone marrow were 51.9% with ibrutinib-venetoclax and 17.1% for obinutuzumab-chlorambucil (P<0.0001). These rates in peripheral blood were 54.7% versus 39.0% (P=0.0259). Kater said that 84.5% of patients with undetectable MRD in bone marrow with ibrutinib-venetoclax maintained the status to an assessment at 12 months post-treatment.

More patients had complete responses with ibrutinib-venetoclax, whether assessed by independent review (38.7% vs 11.4%, P<0.0001) or investigators (45.3% vs 13.3%, P<0.0001). Median time to subsequent therapy and time on randomized therapy were significantly prolonged with the all-oral regimen.

"The safety profiles for both arms were as expected given the known safety profiles of ibrutinib, venetoclax, and chlorambucil-obinutuzumab in an older, comorbid CLL population," noted Kater. "The ibrutinib lead-in effectively debulked the tumor, as only 2% of patients remained at risk for tumor lysis syndrome at the start of venetoclax dosing."

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