BTK Inhibitor Ibrutinib Plus Venetoclax Improved PFS vs Chlorambucil and Obinutuzumab Regimen Among Older Patients With Previously Untreated CLL

Results from the Phase 3 GLOW Trial

According to the phase 3 GLOW trial published in the Journal of Clinical Oncology, treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, plus venetoclax, a BCL-2 inhibitor,  yielded less frequent relapses during the first year after treatment, vs a chemoimmunotherapy regimen of chlorambucil and obinutuzumab for patients with previously untreated chronic lymphocytic leukemia (CLL) who were older or had comorbidities, regardless of unmutated immunoglobulin heavy-chain variable region (IGHV) status and minimal residual disease (MRD) status at 3 months after end of treatment (EOT).

Additionally, progression-free survival (PFS) rates remained higher with treatment with ibrutinib plus venetoclax vs chlorambucil and obinituzumab, including among patients who did not achieve undetectable MRD. 

Although chlorambucil plus obinutuzumab is a standard first-line treatment among older patients with CLL, it “requires frequent infusions that carry the risk of infusion-related reactions,” Talha Munir, MBBS, St James's Hospital, Leeds, United Kingdom, and coauthors stated. 
“Ibrutinib and venetoclax, each approved for treating CLL alone or in combination with CD20 antibodies, have complementary mechanisms of action that work synergistically,” they added. The study authors aimed to analyze this treatment combination and its potential effect on MRD, as well as the possible association between MRD and PFS among older patients with previously untreated CLL. 

A total of 211 older patients with previously untreated CLL were randomly assigned to receive either ibrutinib plus venetoclax (n = 106) or chlorambucil plus obinutuzumab (n = 105). The GLOW trial used next-generation sequencing to assess undetectable MRD at <1 CLL cell per 10,000 (<10−4) and <1 CLL cell per 100,000 (<10−5) leukocytes. PFS analysis was centered on MRD status at 3 months post-treatment. 

At 3 months post-treatment, ibrutinib plus venetoclax demonstrated significantly higher rates of deeper undetectable MRD status (<10−5)  in both the bone marrow and peripheral blood in 40.6% and 43.4% of patients, respectively, versus 7.6% and 18.1% of patients receiving chlorambucil plus obinutuzumab. Among the patients achieving undetectable MRD in peripheral blood, these levels were sustained through the initial post-treatment year in 80.4% of the ibrutinib plus venetoclax group, versus 26.3% of the chlorambucil plus obinutuzumab group. Additionally, patients with detectable MRD (≥10−4) in peripheral blood at 3 months post-treatment demonstrated a higher chance of sustaining MRD levels through 1 year post-treatment when treated with ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab. 

At a year post-treatment, PFS rates were significantly higher among patients treated with ibrutinib plus venetoclax, regardless of their MRD status at 3 months post-treatment. PFS rates were 96.3% among patients with undetectable MRD and 93.3% among patients with detectable MRD in this group, compared to 83.3% and 58.7% among patients who received chlorambucil plus obinutuzumab. These rates remained high among patients with unmutated IGHV treated with ibrutinib plus venetoclax., regardless of MRD status in the bone marrow. 

Dr Munir et al concluded, “Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib [plus] venetoclax versus chlorambucil [plus] obinutuzumab regardless of MRD status at [3 months post-treatment] and IGHV status.” 
“Even for patients not achieving [undetectable] MRD (<10−4), PFS rates remained high with ibrutinib [plus] venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time,” they added. 

As for the impact of this research, “Older and frail CLL patients treated with ibrutinib [plus] venetoclax have a better PFS regardless of the MRD status than patients receiving chlorambucil [plus] obinutuzumab,” wrote Journal of Clinical Oncology associate editor Suzanne Lentzsch, MD, PhD. “Ibrutinib [plus] venetoclax should be the preferred regimen for this patient population. Longer follow-up from the GLOW study will be essential to determine if the current trend with ibrutinib [plus] venetoclax persists.”

Source: 

Munir T, Moreno C, Owen C, et al. Impact of minimal residual disease on progression-free survival outcomes after fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in the GLOW study. J Clin Oncol. 2023;41(21):3689-3699. doi:10.1200/jco.22.02283