Updated GLOW Study Results of First-Line Fixed-Duration Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab

The GLOW trial (NCT03462719) demonstrated the superiority of fixed-duration ibrutinib + venetoclax treatment compared with chlorambucil + obinutuzumab in terms of progression-free survival (PFS), sustained undetectable minimal residual disease (uMRD) responses, and overall survival (OS) in patients with previously untreated chronic lymphocytic leukemia (CLL) who are older and/or have comorbidities.¹ Updated results of the phase 3 GLOW trial (57-month follow-up) for the ibrutinib + venetoclax combination were presented at the 2023 American Society of Hematology annual meeting and summarized here.

The GLOW trial enrolled patients aged ≥65 years or aged 18 to 64 years with a Cumulative Illness Rating Scale score >6 or creatinine clearance <70 mL/min; patients with del17p or known TP53 mutations at screening were excluded.² Eligible patients were randomized 1:1 to receive ibrutinib + venetoclax (3 cycles of ibrutinib lead-in, followed by 12 cycles of ibrutinib + venetoclax) or 6 cycles of chlorambucil + obinutuzumab.² Primary end point was investigator-assessed PFS; secondary endpoints included uMRD rates, time to next treatment (TTNT), and OS.² In patients with ≥partial response (PR), MRD was assessed sequentially over time in peripheral blood (PM); uMRD was defined as <1 CLL cell per 10,000 leukocytes (< 10^-4) and detectable MRD (dMRD) as ≥1 CLL cell per 10,000 leukocytes (≥10^-4).²

A total of 211 patients were enrolled; of these, 106 received ibrutinib + venetoclax and 105 received chlorambucil + obinutuzumab therapy.² Baseline characteristics were reflective of an elderly and/or comorbid population; 63.2% of patients in the ibrutinib + venetoclax arm and 54.3% of patients in the chlorambucil + obinutuzumab arm had unmutated immunoglobulin heavy chain variable region genes (uIGHV).² With a median follow-up of 57.3 months, ibrutinib + venetoclax therapy continued to significantly prolong PFS compared to chlorambucil + obinutuzumab (hazard ratio [HR], 0.256; P<.0001), with higher 54-month PFS rates (66.5 % vs 19.5%).² In the ibrutinib + venetoclax arm, 54-month PFS rates were 59% for patients with unmutated IGHV and 90% in those with mutated IGHV.² In the ibrutinib + venetoclax arm, PFS rates at 42 months post-treatment were higher in patients who achieved uMRD at 3 years after end of treatment (EOT+3) than those with MRD ≥10^-4 (78% vs 70%).² A similar trend was observed in the uIGHV cohort, with higher PFS rates at 42 months post-treatment in those achieving uMRD at EOT+3 than in those with MRD ≥10^-4 (78% vs 50%), which was in contrast to the mIGHV cohort, where PFS rates at EOT+3 were ≥91% regardless of MRD status at EOT+3.²

At EOT+3, 54.7% of patients had uMRD in the ibrutinib + venetoclax arm; at 38 months after end of treatment (EOT+38), 32.1% of patients had uMRD. In addition, TTNT was prolonged for patients receiving ibrutinib + venetoclax versus chlorambucil + obinutuzumab. Compared to chlorambucil + obinutuzumab, first-line ibrutinib + venetoclax therapy was associated with a 87.9% risk reduction in requiring second-line therapy (HR, 0.185; P<.0001) among all patients.²

In the OS analysis, ibrutinib + venetoclax continued to demonstrate improved OS versus chlorambucil + obinutuzumab (HR, 0.453; P=.0038), with higher estimated 54-month OS rates (84.5% vs 63.7%).²

There were 19 total deaths in the ibrutinib + venetoclax arm and 39 in the chlorambucil + obinutuzumab arm; 3 deaths in the ibrutinib + venetoclax arm and 13 in the chlorambucil + obinutuzumab arm were due to post-treatment infections and 2 deaths and 7 deaths, respectively, were due to secondary primary malignancies.²

Longer follow-up data of the GLOW study indicate that fixed-duration ibrutinib + venetoclax shows sustained PFS superiority versus chemoimmunotherapy in patients with previously untreated CLL, with particular benefit in patients with uIGHV (if uMRD achieved) and mIGHV (regardless of MRD status) at EOT+3.

Source:

1. Niemann C, Munir T, Moreno, C et al. Residual disease kinetics among patients with high-risk factors treated with first-line fixed-duration ibrutinib plus venetoclax (ibr+ven) versus chlorambucil plus obinutuzumab (clb+o): the Glow study. Blood. 2022;140(suppl_1):228-230.
2. Moreno C, Munir T, Owen C, et al. First-line fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (chlorambucil + obinutuzumab): 55-month follow-up from the GLOW Study. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Abstract 634.