First-Line Ibrutinib Plus Venetoclax Vs Chlorambucil Plus Obinutuzumab in Elderly or Comorbid Patients (Pts) with Chronic Lymphocytic Leukemia (CLL): Glow Study 64-Month Follow-up (FU) and Adverse Event (AE)-Free Progression-Free Survival (PFS) Analysis
Authors: Niemann Carsten Utoft , Munir Talha , Owen Carolyn , Follows George , Hernandez Rivas Jose-Angel , Benjamini Ohad , Janssens Ann , Levin Mark-David , Robak Tadeusz , Simkovic Martin , Voloshin Sergey , Vorobyev Vladimir I. , Ysebaert Loic , Schuier Natasha , Baeten Kurt , Xu Ping , Tran Nguyet , Levitan Bennett S. , Kavanagh Claire , Kater Arnon P. 
Published: December 2024

Introduction: Time-limited ibrutinib plus venetoclax (Ibr+Ven) demonstrated superior PFS, overall survival (OS), and time to next treatment (TTNT) vs chlorambucil plus obinutuzumab (Clb+O) in elderly or comorbid pts with untreated CLL in the GLOW study (Niemann et al. Lancet Oncol 2023). Longer FU provides insight into the sustained benefit of Ibr+Ven and the predictive clinical impact of IGHV status and minimal residual disease (MRD) at end of treatment (EOT). With various effective treatment (tx) options available in CLL, balancing overall benefit with AEs is important. As such, a tx-emergent AE (TEAE)-free PFS analysis provides a clinically meaningful assessment of tx benefit by capturing the time pts spend without significant toxicity or disease progression, offering a more comprehensive view of tx impact. Here we report clinical outcomes from the 64-mo FU of the GLOW study, including subgroup analysis by IGHV and MRD status, and an evaluation of grade 3/4 (G3/4) TEAE-free PFS benefit.

Methods: Elderly or comorbid pts with untreated CLL/small lymphocytic leukemia were randomized 1:1 to Ibr+Ven (3 cycles Ibr lead-in then 12 cycles Ibr+Ven, n = 106) or 6 cycles Clb+O (n = 105). MRD in peripheral blood was measured by next-generation sequencing 3 months post-EOT (EOT+3), with undetectable MRD (uMRD) defined as &lt; 10-4. TEAEs were collected until 30 days after EOT; therefore, AE collection was longer for Ibr+Ven vs Clb+O (median exposure: Ibr+Ven, 13.8 mo vs Clb+O, 5.1 mo). AEs after this were not considered tx emergent unless specifically considered tx related by investigator. Outcomes reported include investigator-assessed PFS, TTNT, and OS. Additionally, TEAE-free PFS was assessed (using restricted mean survival time, based on G3/4 TEAEs only), including quantification of time spent in different health states (time with G3/4 TEAEs and G3/4 TEAE-free PFS).

Results: At a median FU of 64 mo, Ibr+Ven prolonged PFS, reducing the risk of progression or death by 73% vs Clb+O (HR 0.27 [95% CI, 0.18-0.39]; p &lt; 0.0001); 60-mo PFS rates were 59.9% and 17.8% for Ibr+Ven and Clb+O, respectively. Ibr+Ven prolonged PFS independent of IGHV status (unmutated IGHV [uIGHV], HR 0.26 [95% CI, 0.17-0.42]; p &lt; 0.0001; mutated IGHV [mIGHV], HR 0.24 [95% CI, 0.10-0.62]; p = 0.0014). Estimated 60-mo PFS rates in the Ibr+Ven arm were 52.2% and 82.5% for pts with uIGHV (n = 67) and mIGHV (n = 32), respectively. In the Ibr+Ven arm, PFS rates at 48 mo post tx were 69% in pts who achieved uMRD at EOT+3 (n = 58) and 61% in pts with detectable MRD (dMRD; n = 31). Among Ibr+Ven-treated pts with uIGHV, PFS rates at 48 mo post tx were 67% for those achieving uMRD at EOT+3 (n = 40) and 40% for those with dMRD (n = 16). For Ibr+Ven-treated pts with mIGHV, PFS rates at 48 mo post-tx were ≥ 84% regardless of MRD status (uMRD, n = 13; dMRD, n = 14).

Ibr+Ven prolonged TTNT and reduced risk of need for second-line (2L) therapy vs Clb+O in pts with uIGHV (HR 0.18 [95% CI, 0.09-0.36]; p &lt; 0.0001); there was no difference in TTNT in pts with mIGHV (HR 1.20 [95% CI, 0.31-4.60], p = 0.7878). Ibr+Ven prolonged OS vs Clb+O, reducing relative risk of death by 54% (HR 0.46 [95% CI, 0.27-0.79]; p = 0.004); 60-mo OS rates were 81.6% and 60.8% for Ibr+Ven and Clb+O, respectively. OS rates were prolonged in pts with mIGHV (HR 0.22 [95% CI, 0.06-0.77]; p = 0.010), while a trend was seen in pts with uIGHV (HR 0.51 [95% CI, 0.26-1.02]; p = 0.052).

At 64-mo FU, the time pts spent without significant toxicity or progression (TEAE-free PFS) was significantly longer for Ibr+Ven vs Clb+O (52 vs 31 mo, respectively). TEAE-free PFS analysis showed that while pts receiving 15 mo of Ibr+Ven spent slightly more time in the G3/4 toxicity state vs pts receiving 6 mo of Clb+O (2 vs 1 mo), pts in the Ibr+Ven arm spent substantially more time in TEAE-free PFS (50 vs 30 mo). These results show a 20-mo improvement in TEAE-free PFS with Ibr+Ven vs Clb+Ob, indicating longer disease control without significant toxicity.

Conclusion: With 64-mo FU, Ibr+Ven continues to show superior PFS, reduced risk of requiring 2L tx, and sustained OS advantage vs Clb+O. Moreover, analysis integrating clinical benefits and risks shows improved survival time free from G3/4 toxicity or relapse for Ibr+Ven. This long-term FU of time-limited Ibr+Ven provides valuable insights into the combination's durable efficacy and tolerability profile, offering a robust foundation for informed clinical decision-making in pts with previously untreated CLL.