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CLL-106 First Prospective Data on Minimal Residual Disease Outcomes After Fixed-Duration Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for First-Line Treatment of CLL in Older Adult or Unfit Patients: The GLOW Study

T. Munir, C. Moreno, C. Owen, G. Follows, O. Benjamini, A. Janssens, MD. Levin, A. Osterborg, T. Robak, M. Simkovic, D. Stevens, S. Voloshin, V. Vorobyev, M. Yagci, L. Ysebaert, Q. Qi, A. Steele, N. Schuier, K. Baeten, DB. Caces, C. Niemann, A. Kater

. 2022 ; 22 Suppl 2 (-) : S264-S265. [pub] -

Language English Country United States

Document type Journal Article, Randomized Controlled Trial

Persistent link   https://www.medvik.cz/link/bmc22024258

CONTEXT: Minimal residual disease (MRD) is a predictive marker for progression-free survival (PFS) in chronic leukocytic leukemia (CLL) following chemoimmunotherapy and fixed-duration treatment with venetoclax and anti-CD20 antibodies. This has not been explored for ibrutinib+venetoclax (Ibr+Ven), a fixed-duration treatment with mechanisms of action that synergistically eliminate CLL subpopulations in distinct tumor compartments. OBJECTIVE: Investigate MRD outcomes at primary analysis of phase 3 GLOW study (NCT03462719). DESIGN: Randomized, open-label, active-control study. PATIENTS: Patients aged ≥65 years or 18-64 years with a CIRS score >6 or creatinine clearance <70 mL/min were randomized 1:1, stratified by IGHV mutational and del11q status, to Ibr+Ven (n=106) or chlorambucil+obinutuzumab (Clb+O) (n=105). Excluded: patients with del17p or known TP53 mutations. INTERVENTIONS: Ibr+Ven (3 cycles of ibrutinib lead-in, then 12 cycles of Ibr+Ven) or 6 cycles of Clb+O. MAIN OUTCOME MEASURES: Primary endpoint: independent review committee-assessed PFS; secondary endpoint: rate of undetectable MRD (uMRD; <10-4); exploratory endpoints: MRD analyses. MRD results are by next-generation sequencing, reported 3 months after end of treatment (EOT+3) unless otherwise noted. RESULTS: Rates of uMRD<10-4 were higher for Ibr+Ven versus Clb+O in bone marrow (BM) (51.9% vs. 17.1%; P<0.0001) and peripheral blood (PB) (54.7% vs. 39.0%; P=0.0259). For Ibr+Ven, BM uMRD was higher for uIGHV (58.2%) versus mutated IGHV (44.4%). With Ibr+Ven, 84.5% (49/58) of patients maintained PB uMRD from EOT+3 to EOT+12 versus 29.3% (12/41) with Clb+O. Rates of uMRD<10-5 were higher for Ibr+Ven versus Clb+O in BM (40.6% vs. 7.6%), including patients with uIGHV (45.5% vs. 5.6%). uMRD<10-5 in PB was largely sustained from EOT+3 to EOT+12 with Ibr+Ven (80.4% [37/46]) but not Clb+O (26.3% [5/19]). PFS rates for Ibr+Ven during the 12 months after EOT were >90% for patients with uMRD<10-4 and patients with detectable MRD; however, Clb+O arm patients with detectable PB MRD relapsed more quickly than those with uMRD<10-4. CONCLUSIONS: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment versus Clb+O in older adult or unfit patients with previously untreated CLL.

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$a CONTEXT: Minimal residual disease (MRD) is a predictive marker for progression-free survival (PFS) in chronic leukocytic leukemia (CLL) following chemoimmunotherapy and fixed-duration treatment with venetoclax and anti-CD20 antibodies. This has not been explored for ibrutinib+venetoclax (Ibr+Ven), a fixed-duration treatment with mechanisms of action that synergistically eliminate CLL subpopulations in distinct tumor compartments. OBJECTIVE: Investigate MRD outcomes at primary analysis of phase 3 GLOW study (NCT03462719). DESIGN: Randomized, open-label, active-control study. PATIENTS: Patients aged ≥65 years or 18-64 years with a CIRS score >6 or creatinine clearance <70 mL/min were randomized 1:1, stratified by IGHV mutational and del11q status, to Ibr+Ven (n=106) or chlorambucil+obinutuzumab (Clb+O) (n=105). Excluded: patients with del17p or known TP53 mutations. INTERVENTIONS: Ibr+Ven (3 cycles of ibrutinib lead-in, then 12 cycles of Ibr+Ven) or 6 cycles of Clb+O. MAIN OUTCOME MEASURES: Primary endpoint: independent review committee-assessed PFS; secondary endpoint: rate of undetectable MRD (uMRD; <10-4); exploratory endpoints: MRD analyses. MRD results are by next-generation sequencing, reported 3 months after end of treatment (EOT+3) unless otherwise noted. RESULTS: Rates of uMRD<10-4 were higher for Ibr+Ven versus Clb+O in bone marrow (BM) (51.9% vs. 17.1%; P<0.0001) and peripheral blood (PB) (54.7% vs. 39.0%; P=0.0259). For Ibr+Ven, BM uMRD was higher for uIGHV (58.2%) versus mutated IGHV (44.4%). With Ibr+Ven, 84.5% (49/58) of patients maintained PB uMRD from EOT+3 to EOT+12 versus 29.3% (12/41) with Clb+O. Rates of uMRD<10-5 were higher for Ibr+Ven versus Clb+O in BM (40.6% vs. 7.6%), including patients with uIGHV (45.5% vs. 5.6%). uMRD<10-5 in PB was largely sustained from EOT+3 to EOT+12 with Ibr+Ven (80.4% [37/46]) but not Clb+O (26.3% [5/19]). PFS rates for Ibr+Ven during the 12 months after EOT were >90% for patients with uMRD<10-4 and patients with detectable MRD; however, Clb+O arm patients with detectable PB MRD relapsed more quickly than those with uMRD<10-4. CONCLUSIONS: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment versus Clb+O in older adult or unfit patients with previously untreated CLL.
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$a Moreno, Carol $u Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
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$a Owen, Carolyn $u Tom Baker Cancer Centre, Calgary, Canada
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$a Follows, George $u Addenbrookes Hospital, Cambridge, United Kingdom
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$a Benjamini, Ohad $u Sheba Medical Center, Ramat Gan, Israel
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$a Janssens, Ann $u UZ Leuven Gasthuisberg, Leuven, Belgium
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$a Levin, Mark-David $u Albert Schweitzer Hospital, Dordrecht, Netherlands
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$a Osterborg, Anders $u Karolinska University Hospital, Stockholm, Sweden
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$a Robak, Tadeusz $u Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland
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$a Simkovic, Martin $u University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
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$a Stevens, Don $u Norton Cancer Institute, Louisville, USA
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$a Voloshin, Sergey $u Russian Scientific and Research Institute of Hematology and Transfusiology, St. Petersburg, Russian Federation
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$a Yagci, Munci $u Gazi Universitesi Tip Fakultesi, Ankara, Turkey
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$a Ysebaert, Loic $u Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
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$a Qi, Qianya $u Janssen Research & Development, Raritan, USA
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$a Steele, Andrew $u Janssen Research & Development, Spring House, USA
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