Minimal Residual Disease (MRD)-Adapted Duration of Front-Line Venetoclax and Obinutuzumab Treatment for Fit Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Roeker Lindsey , Mato Anthony R. , Zelenetz Andrew D. , Park Jae H. , Geyer Mark Blaine , Derkach Andriy , Nemirovsky David , Islam Prioty , Falchi Lorenzo , Palomba Maria Lia , Kumar Anita , Salles Gilles , Lue Jennifer Kimberly , Goldberg Aaron D. , Stephens Deborah M. , Duffy Victoria , Panton Gail , Tyznar Dianna , Dorsey Colleen , Soni Dhara , Hutzler Claire , Nogan Lauren , Allen Alexandra , Nyima Tenzin , Nguyen Thu Quynh , Shah Monica , Cook Tamotha R , Abillar-Wright Jennifer , Brutus Jamila , Laudati Carissa , Kikani Bejal , Coombs Catherine C , Silvestrone Michael R. , Jensen Christopher E. , Fakhri Bita , Thompson Meghan C. 
Published: December 2024

Introduction: Venetoclax and obinutuzumab (Ven/Obin) is approved as a 1 year fixed-duration treatment regimen in the front-line (1L) setting for patients (pts) with CLL. Extended follow up from the CLL14 study has demonstrated that undetectable measurable residual disease (uMRD) at the end of treatment (EOT) predicts longer progression free survival (PFS). However, whether Ven/Obin treatment duration can be tailored based on an individual pt's depth of response to optimize outcomes has not been well studied.
Methods: In this phase 2 investigator-initiated study (NCT04447768), pts who required 1L therapy (tx) per iwCLL criteria were treated with Ven/Obin, and tx duration was directed by MRD status. Key inclusion criteria: age ≥ 18 years, CIRS comorbidity score ≤ 6, ECOG ≤ 1, adequate marrow and organ function.
Obin 1000mg was given on Cycle 1 Day 1 (C1D1)/2, 8, 15, and D1 of C2-6. Ven was dose escalated over 5 weeks starting on C1D22 to 400mg daily. Each cycle was 28D. All pts had peripheral blood (PB) MRD testing by next generation sequencing (ClonoSEQ) at C7. For pts who achieved uMRD (defined as &lt;10-6; uMRD6), PB MRD testing was repeated at C9. Pts with uMRD6 in PB at C9 completed 9C of tx and entered treatment free observation (TFO). Pts with detectable MRD (dMRD) at C7 were tested again at C12. Those with uMRD5 (defined as &lt;10-5) in PB at C12 completed 12C of tx and entered TFO. Pts who had dMRD at C12 completed 24C of tx and entered TFO regardless of MRD status. Bone marrow (BM) biopsy was performed at EOT; BM MRD status did not dictate treatment duration. Pts were followed for clinical progression, and next CLL-directed tx was delivered and recorded if iwCLL criteria for therapy were met. Primary endpoint is 36-month (mo) PFS.
Results: As of 7/1/2024, this study has fully accrued 100 pts. Median age at enrollment was 58 years (range 34-81), 71% male, 90% white. Median CIRS score was 3 (range 0-6), 89% had ECOG 0. Rai stage 1/2 for 73%, 3/4 for 27%. Baseline cytogenetics: 7.3% del17p, 19% del11q, 20% trisomy 12, 59% del13q, 12% complex karyotype (CK; ≥3 abnormalities by stimulated karyotype or SNP-ARRAY). 50% unmutated IGHV. 16% TP53 mutated.
With median follow-up (f/u) of 24 mos, 24-mo PFS is 92% and overall survival (OS) is 95% for the entire cohort. Of the 81 pts who have reached C9, 41 pts were uMRD6 at both C7 and C9 and discontinued therapy. Twenty-nine pts were uMRD5 at C12 and discontinued therapy. Three pts remained dMRD (10-5 sensitivity) at C12 and completed 24 cycles of therapy (1 uMRD5, 2 dMRD at C24). Three pts discontinued tx before C9 MRD testing (reasons for discontinuation: 1 intolerance, 1 withdrawal of consent, 1 death unrelated to tx or disease), 16 have not yet reached C9. 8 discontinued tx outside of meeting protocol requirements (6 at C9, 2 at C12) and are included in the intention-to-treat survival analysis. For those who were uMRD in PB at each time point, BM was uMRD6 for 68% at C9 and 67% uMRD5 at C12.
PFS at 12 mos following completion of tx was 91% for those who discontinued tx after 9C (median f/u 27 mos from C1D1) vs. 95% for those who discontinued tx after 12C (median f/u 27 mos from C1D1). PFS at 24 mos following tx completion is identical to 12 mos, though only 33 pts have reached this landmark. There is no significant difference in PFS between those who completed 9 and 12 C of therapy (p=0.7). Two pts treated with 9C of tx required subsequent treatment; one pt required CLL-directed treatment after 10 mos of TFO (later diagnosed with Richter's transformation and died) and one pt experienced Richter's transformation and was treated after 5 mos of TFO. No pt receiving 12C or more of tx have progressed.
Pts who had early uMRD6 at C7 vs. those who did not were more likely to have tri12 (31% vs. 8%, p=0.012) and less likely to have del13q (50% vs. 73%, p=0.035). There was no significant difference in rates of TP53 aberrations, CK, or IGHV mutational status.
Conclusion: This study supports the use of MRD testing to guide duration of Ven / Obin therapy in the 1L setting. Early discontinuation of Ven/Obin for pts who are uMRD6 at C9 achieves similar PFS to pts who completed 12C of Ven/Obin and have uMRD5 status before entering TFO. In this study, concordance rate between PB and BM was relatively low (approximately two-thirds concordance) at 10-6 (C9) and 10-5 (C12) sensitivities. Longer follow-up from this study will inform the impact of PB and BM MRD status on PFS and if additional Ven/Obin beyond 12C improves outcomes for those who remain dMRD.