Fixed-Duration Venetoclax Plus Ibrutinib Achieves Deep and Durable MRD Remissions in CLL
Two different trials presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition found that fixed-duration treatment with ibrutinib and venetoclax achieved deep and sustained undetectable measurable residual disease (MRD) status when used as first-line therapy for chronic lymphocytic leukemia (CLL).
A secondary analysis of the phase III GLOW trial showed that first-line treatment with fixed-duration ibrutinib/venetoclax elicited undetectable MRD responses that were deeper and longer-lasting compared with those achieved on treatment with chlorambucil/obinutuzumab; MRD status was better sustained during the first year posttreatment in the ibrutinib/venetoclax arm vs the control arm. GLOW included patients older than age 65 as well as younger patients between the ages of 18 and 64 with comorbidities.1
Updated results from the phase II CAPTIVATE trial, which also evaluated ibrutinib/venetoclax in two different cohorts, found that with an additional year of follow-up, there were no new disease progressions, deaths, or MRD recurrences in patients who had undetectable MRD and were randomly assigned to placebo after 12 months of the combination. CAPTIVATE enrolled patients younger than age 70, some with high-risk disease.2
MRD status is a known predictor of progression-free survival in CLL following chemoimmunotherapy and fixed-dose venetoclax plus an anti-CD20 antibody. The secondary analysis from GLOW sought to investigate MRD outcomes and correlations with progression-free survival in patients treated with fixed-dose ibrutinib/venetoclax compared with chlorambucil/obinutuzumab.
The study enrolled 211 patients with previously untreated CLL who were elderly (> age 65) or younger than age 65 with a cumulative illness rating score [CIRS] > 6 or a creatinine clearance < 70 mL/min. Patients were randomly assigned 1:1 to fixed-dose ibrutinib/venetoclax (3-cycle lead-in of ibrutinib followed by 12 cycles of ibrutinib/venetoclax) or chlorambucil plus obinutuzumab for 6 cycles. Patients who developed progressive disease were offered single-agent ibrutinib. In the previously reported primary progression-free survival analysis, treatment with ibrutinib/venetoclax was found to be superior to chlorambucil/obinutuzumab (hazard ratio [HR] = 0.216, P < .0001), as assessed by an independent review committee.3
Talha Munir, MBBS
At the ASH meeting, results of a separate MRD analysis of GLOW patients were reported by Talha Munir, MBBS, of St. James’s University, Leeds, United Kingdom.1 For this analysis, MRD was evaluated by next-generation sequencing with cutoffs of < 10–4 and < 10–5. Next-generation sequencing results are not yet available for the end of therapy plus the 18-month cutoff, Dr. Munir said. Undetectable MRD concordance was calculated in the peripheral blood and bone marrow 3 months after the end of therapy for patients who had paired blood and bone marrow samples.
An updated analysis with 34.1 months of follow-up showed that progression-free survival remained significantly greater with ibrutinib/venetoclax vs chlorambucil/obinutuzumab (P < .0001). The rate of progression-free survival at 30 months was 80.5% vs 35.8%, respectively. Overall survival was improved by 25% in the ibrutinib/venetoclax arm, with 11 deaths vs 16 in the control arm.
At 3 months after treatment, the undetectable MRD rate at < 10–4 was significantly higher with ibrutinib/venetoclax in the bone marrow (P < .0001) and in the peripheral blood (P = .0259). Undetectable MRD concordance in peripheral blood and bone marrow was 92.9% for ibrutinib/venetoclax vs 43.6% for chlorambucil/obinutuzumab. The undetectable MRD rate at < 10–5 was higher with ibrutinib/venetoclax vs chlorambucil/obinutuzumab in both the peripheral blood and bone marrow. In contrast with the control arm, most patients receiving ibrutinib/venetoclax who achieved undetectable MRD < 10–4 had deep responses of undetectable MRD < 10–5.
Undetectable MRD concordance at < 10–5 in peripheral blood and bone marrow was 90.9% for ibrutinib/venetoclax vs 36.8% for chlorambucil/obinutuzumab. A similar benefit for improved rate of undetectable MRD bone marrow with ibrutinib/venetoclax was evident across all prespecified subgroups.
Patients with IGHV-unmutated CLL had deep responses with ibrutinib/venetoclax, and the depth of response was similar in peripheral blood and bone marrow. Among patients with mutated TP53, five of seven achieved undetectable MRD < 10–5 in both the peripheral blood and bone marrow on ibrutinib/venetoclax.
With ibrutinib/venetoclax, undetectable MRD was sustained longer in peripheral blood from 3 months to 12 months after the end of treatment. The intention-to-treat rate of undetectable MRD < 10–4 decreased by 6% from end of therapy plus 3 months to end of therapy plus 12 months in the ibrutinib/venetoclax arm vs 27% in the control arm.
“More than 80% of patients sustained undetectable MRD during the first year off treatment with ibrutinib/venetoclax. Patients with detectable MRD > 10–4 in the ibrutinib/venetoclax arm were less likely to convert to progressive disease or have worsening of detectable MRD levels over the same period compared to controls,” Dr. Munir told listeners.
Further, patients on the ibrutinib/venetoclax arm who achieved a complete or partial response had a progression-free survival rate of 85% at 30 months, whereas most patients with a partial response experienced disease progression in the chlorambucil/obinutuzumab arm.
“As a result of this analysis, one cannot only say the proportion of patients achieving that undetectable MRD is superior with fixed-duration ibrutinib/venetoclax vs chlorambucil/obinutuzumab in older, unfit patients with CLL, but also that the level of undetectable MRD achieved is deeper with this fixed-duration combination,” stated senior author Arnon P. Kater, MD, PhD, of Amsterdam UMC, the Netherlands.
Arnon P. Kater, MD, PhD
“If undetectable MRD is observed at the end of fixed-duration first-line treatment with ibrutinib/venetoclax, it is a good surrogate marker for progression-free survival. We have learned this with other drug combinations in CLL—with chemoimmunotherapy and venetoclax/obinutuzumab as first-line therapy.
“On the other hand, patients who achieve MRD positivity at the end of treatment typically relapse following chemotherapy, as was seen for the control arm in GLOW. If patients had MRD-positive disease after ibrutinib/venetoclax, however, there were few clinical disease progressions during the first year after treatment, similar to patients who achieved undetectable MRD. The GLOW study shows that regardless of whether the patient achieves undetectable MRD or MRD positivity at the end of treatment with fixed-duration ibrutinib/venetoclax, molecular and clinical relapses were rare during the first year posttreatment. It will be important to reevaluate progression-free survival with longer study follow-up to see if this trend holds,” Dr. Kater continued.
“What is interesting and new is that patients treated with ibrutinib/venetoclax who had low detectable MRD largely remained at the same MRD level during the first year posttreatment instead of going on to a progressive state over time. MRD remissions are deeper with ibrutinib/venetoclax and more sustainable, regardless of the level of MRD at the end of treatment,” Dr. Kater said. “When we give ibrutinib now, we continue treatment until relapse, but patients continued on the drug can become refractory. The promise of GLOW is that you can stop treatment with ibrutinib/venetoclax, and the treatment will remain effective—and this was truly an unfit patient group.”
CAPTIVATE was a phase II study that evaluated ibrutinib/venetoclax in adults younger than age 70 with high-risk features in two cohorts: an MRD-guided cohort, where the treatment duration was according to the patient’s MRD status after 12 cycles of combination therapy; and a cohort of fixed-duration ibrutinib/venetoclax, where all patients stopped therapy after 12 cycles of the combination regardless of their MRD status at that time. At this year’s ASH meeting, lead author Paolo Ghia, MD, PhD, of Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy, reported updated results of the MRD cohort.
Paolo Ghia, MD, PhD
In the MRD-guided cohort (n = 164), patients who achieved confirmed undetectable MRD (defined as < 10–4 by eight-color flow cytometry) serially over at least three cycles and in both the peripheral blood and the bone marrow with combination therapy were randomly assigned to continue treatment on ibrutinib monotherapy or placebo until disease progression. Patients in the MRD-guided cohort who did not achieve confirmed undetectable MRD after 12 cycles of treatment on the combination were randomly assigned to continue ibrutinib monotherapy or the combination.
The 2-year disease-free survival rate with time-limited treatment (randomly assigned to placebo) was maintained at 95% with an additional 1 year of follow-up. No new MRD relapses, disease progressions, or deaths were observed with one additional year of follow-up in patients with confirmed undetectable MRD treated with placebo or ibrutinib. The estimated 36-month progression-free survival rates were 95.3% with placebo and 100% with ibrutinib.
At a median follow-up of 38 months, no new safety concerns emerged with the combination of ibrutinib/venetoclax. The most common adverse events of any grade at 1 to 2 years after treatment were arthralgia (29% for the combination, 22% for ibrutinib monotherapy) and upper respiratory tract infection (20% and 15%, respectively). Grade 3 or higher adverse events were infrequent in both arms of the study, with the exception of neutropenia.
‘Promising Efficacy’ of Fixed-Duration Treatment
“Ultimately, these results in patients achieving confirmed undetectable MRD randomly assigned to placebo following an initial 12 cycles of the ibrutinib/venetoclax combination support the potential for treatment-free remission with an oral, once-daily regimen of first-line, fixed-dose ibrutinib/venetoclax. Among 12 patients who had disease progression following treatment, 9 had a partial response to single-agent ibrutinib and 3 have pending responses,” Dr. Ghia said.
“CAPTIVATE results show the promising efficacy of the combination of venetoclax/ibrutinib in patients with CLL who are treated for the first time. We gave 3 months of ibrutinib therapy to debulk disease, followed by 12 months of the combination. We have shown that patients who achieve undetectable MRD maintain their response, and 95% did not experience disease progression. This is not significantly different from patients who continue ibrutinib. Study results favor fixed-duration treatment with the combination of two potent drugs when achieving deep responses as undetectable MRD,” he said in a separate interview.
“What we don’t know at the moment is whether all patients can stop treatment at all MRD levels. That answer might be available in a separate cohort of patients not presented at the ASH meeting, where all patients stopped treatment after 12 months. So far, we have nice data that the 2-year progression-free survival rate is more than 95% regardless of the level of MRD. We need longer follow-up. The combination is not approved at the moment, and we have to wait for more data for approval,” he stated.
DISCLOSURE: Dr. Munir has served as a consultant or advisor for Janssen, AbbVie, AstraZeneca, MorphoSys, Alexion, Gilead, and Novartis; and has received honoraria from Janssen, AbbVie, AstraZeneca, Alexion, Apellis, Gilead, and Novartis. Dr. Kater has served on a steering committee for Genmab and LAVA; has received honoraria from AbbVie; and has received research funding from Bristol Myers Squibb, Roche/Genentech, Janssen, and AstraZeneca. Dr. Ghia has received honoraria and served as a consultant or advisor for AbbVie, AstraZeneca, ArQule/Merck Sharp & Dohme, Celgene/Juno/Bristol Myers Squibb, Janssen, Lilly/Loxo Oncology, MEI Pharma, Roche, and Sanofi; and has received research funding from AbbVie, AstraZeneca, Janssen, and Sunesis.
1. Munir T, et al: First prospective data on minimal residual disease (MRD) outcomes after fixed duration ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab for first-line treatment of CLL in elderly or unfit patients. 2021 ASH Annual Meeting & Exposition. Abstract 70. Presented December 14, 2021.
2. Ghia P, et al: First-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia. 2021 ASH Annual Meeting & Exposition. Abstract 68. Presented December 14, 2021.
3. Kater A, et al: Fixed duration ibrutinib and venetoclax versus chlorambucil plus obinutuzumab for first-line chronic lymphocytic leukemia. European Hematology Association 2021 Virtual Congress. Abstract LB1902. Presented June 12, 2021.
Joshua Brody, MD, Director of the CLL/Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai, New York, who was not involved in these trials, commented: “CLL is an extremely prevalent disease affecting nearly 200,000 patients in the United States. Most patient do not require...