Ibrutinib Plus Venetoclax Improves Undetectable MRD Responses in Elderly, Unfit CLL

Fixed-duration treatment with ibrutinib (Imbruvica) and venetoclax (Venclexta) led to deeper and prolonged undetectable minimal residual disease (uMRD) responses vs chlorambucil and obinutuzumab (Gazyva) in the frontline treatment of elderly or unfit patients with chronic lymphocytic leukemia (CLL), translating to fewer relapses in the first year following treatment cessation, according to data from the phase 3 GLOW trial (NCT03462719).

With 34.1 months of follow-up after treatment completion, the rate of uMRD below 10-4 and 10-5 was significantly higher with ibrutinib/venetoclax (n = 106) compared with chlorambucil/obinutuzumab (n = 105) in the bone marrow and peripheral blood

In the bone marrow, the rate of uMRD was 51.9% (10-4, 11.3%; 10-5, 40.6%) with ibrutinib/venetoclax vs 17.1% (10-4, 9.5%; 10-5, 7.6%) with chlorambucil/obinutuzumab. In the peripheral blood, these rates were 54.7% (10-4, 11.3%; 10-5, 43.4%) and 39.0% (10-4, 21.0%; 10-5, 18.1%), respectively.

“All-oral, once-daily, fixed-duration ibrutinib plus venetoclax achieved deeper and better sustained uMRD responses vs chlorambucil/obinutuzumab as assessed by next-generation sequencing [NGS],” lead study author Talha Munir, MBBS, a consultant hematologist at St James’s Hospital in Leeds, United Kingdom, and coauthors, wrote in the poster presented at the 2022 SOHO Annual Meeting.

In the primary analysis of the GLOW trial, ibrutinib plus venetoclax led to an improvement in independent review committee (IRC)–assessed PFS compared with chlorambucil and obinutuzumab (HR, 0.216; P < .0001). MRD status has been associated with PFS following chemoimmunotherapy and fixed-duration therapy with venetoclax and an anti-CD20 antibody. However, the effect of MRD on the activity of ibrutinib and venetoclax is not known.

To that end, investigators evaluated MRD outcomes and association with PFS from the GLOW trial.

The study had enrolled patients with previously untreated CLL who were at least 65 years of age or who were under the age of 65 and had a cumulative illness rating score (CIRS) above 6 or creatinine clearance below 70 mL/min.

A total of 211 patients were randomly assigned to receive 420 mg of ibrutinib daily for 3 cycles prior to receiving ibrutinib plus venetoclax for 12 cycles, or 0.5 mg/kg of chlorambucil on days 1 and 15 for 6 cycles plus 1000 mg of obinutuzumab on days 1, 2, 8, and 15 of cycle 1, and day 1 of cycles 2 through 6.

The primary end point of the trial was IRC-assessed PFS. In the current analysis, MRD was evaluated via NGS with a sensitivity of either 10-4 or 10-5 until 12 months after the end of treatment. Peripheral blood and bone marrow concordance was calculated for patients with uMRD in the peripheral blood 3 months after the end of treatment who had a paired bone marrow sample.

Additional results showed that the uMRD concordance in the bone marrow and peripheral blood below 10-4was 92.9% for ibrutinib/venetoclax vs 43.6% for chlorambucil/obinutuzumab. At a sensitivity of 10-5, the uMRD concordance was 90.9% and 36.8%, respectively.

In a subgroup analysis, uMRD below 10-4 in the bone marrow favored the use of ibrutinib/venetoclax regardless of age, baseline ECOG performance status, CIRS total score, Rai stage, bulky disease, elevate lactate dehydrogenase, IGHV status, and deletion 11q status.

Moreover, uMRD in the peripheral blood was better sustained with ibrutinib/venetoclax vs chlorambucil/obinutuzumab from 3 cycles after the end of treatment to 12 cycles after the end of treatment. Specifically, 84.5% (n = 49/58) of patients had uMRD below 10-4 and 80.4% (n = 37/46) had sustained uMRD below 10-5 with ibrutinib/venetoclax vs 29.3% (n = 12/41) and 26.3% (n = 5/19) with chlorambucil/obinutuzumab, respectively.

Only 6% of patients in the ibrutinib/venetoclax arm lost uMRD below 10-4 compared with 27% of those in the chlorambucil/obinutuzumab arm. 

“Patients with detectable MRD ≥10-4 in the ibrutinib/venetoclax arm were less likely to convert to progressive disease vs those in the chlorambucil/obinutuzumab arm and have worsening of detectable MRD levels,” the study authors wrote.

Further results showed that the PFS rate was better sustained following treatment with ibrutinib/venetoclax vs chlorambucil/obinutuzumab in patients with uMRD below 10-4 in the bone marrow. However, even in patients with detectable MRD of at least 10-4 in the bone marrow or peripheral blood, the PFS rate above 90% was sustained during the first year after treatment completion with ibrutinib/venetoclax, whereas early relapse was common with chlorambucil/obinutuzumab.

Lymph node responses were also generally maintained in patients with uMRD below 10-4 in the bone marrow 3 months after the end of treatment. Additionally, lymph node responses were better maintained over time with ibrutinib/venetoclax compared with chlorambucil/obinutuzumab in patients with detectable MRD of at least 10-4in bone marrow 3 months after the end of treatment.

“A unique relationship between MRD status and PFS may be explained by broader clearance of multiple disease compartments resulting from complementary mechanisms of ibrutinib and venetoclax,” the study authors concluded. “Additional follow-up is warranted to confirm the longer-term impact of MRD status on PFS.”

Reference

1. Munir T, Moreno C, Owen C, et al. First prospective data on minimal residual disease (MRD) outcomes after fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of CLL in elderly or unfit patients: the GLOW study. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-106