Improved Efficacy with Response- and MRD-Guided Ibrutinib-Obinutuzumab (IO) Intensification after Ibrutinib-Venetoclax (IV) in First Line Chronic Lymphocytic Leukemia (CLL) Patients: Primary Analysis of the HOVON 158/Next STEP Phase 2 Trial
Authors: Levin Mark-David , Kersting Sabina , Dubois Julie , van der Holt Bronno , da Cunha-Bang Caspar , te Raa Doreen , Idink Cecile , De Boer Fransien , Droogendijk Jolanda , de Heer Koen , van der Burg Leonie , Nijziel Marten R. , Tick Lidwine , Levenga Henriettte , Silbermann Matthijs , Ludwig Inge , Beeker Aart , Bellido Mar , Van Der Kevie-Kersemaekers Anne-Marie , Mellink Clemens , Meulendijks Ine , Zoun-van den Dool Sjoerd , Abrahamse-Testroote Martine , Zwezerijnen Gerben , Niemann Carsten Utoft , Kater Arnon P. 
Published: December 2024

Introduction
Obinutuzumab-venetoclax (OV) and ibrutinib-venetoclax (IV) are effective time-limited first-line treatments for chronic lymphocytic leukemia (CLL). However, patients not achieving undetectable minimal residual disease (&lt;10-4, uMRD) or complete remission (CR/CRi) are prone to early relapse. While simultaneously combining O, I and V shows superior efficacy, it increases toxicity (Furstenau, JCO 2024).
A previous trial demonstrated that adding O to I improves uMRD rates, not at start of I but only after one year of I treatment, likely due to I-induced changes in CD20 expression (Rawstron, 2018, ASH Abstract 181).
Aiming to improve outcome while minimizing toxicity, the HOVON 158/NEXT STEP trial starts with IV treatment, followed by 6 cycles of IO treatment for patients with suboptimal response.
Methods
The HOVON 158/NEXT STEP trial is a non-randomized, phase 2, first-line study for all-comer CLL patients. Patients are treated with 3 cycles of I followed by 12 cycles of IV according to GLOW study (named cycles 1-15 IV). IWCLL response assessment and MRD evaluation in bone marrow (BM) are performed after cycle 15. Due to centralized review, IV continues through cycle 16. Patients achieving CR(i) with uMRD in BM enter observation. Others proceed to intensification with 6 cycles of IO. Primary endpoint was CR(i) with uMRD in BM 9 months after cycle 16 IV in the intensification group.
Results
Between December 2020 and August 2021, 84 eligible patients were included. Median age was 68 years (range 34-85), 67% were male, 18% had CIRS &gt; 6, median eGFR was 67 ml/min (range 39-132), 77% of patients would fulfill age/CIRS/eGFR criteria as used for inclusion in the GLOW trial, 44% had unmutated IGHV, 7% del 17p / TP53 mutation and 57% CLL-IPI (very) high risk. Median follow-up was 35 months (IQR 33-36) and 21 months (IQR 15-25) after cycle 16.
Of the 84 patients 73 (87%) completed IV, with 72 undergoing response assessment. Fifteen patients (21%) had CR with uMRD and were assigned to the observation group. During cycles 1-15 IV, AE's were reported per patient as maximum grade 2 (21%), grade 3 (51%), grade 4 (23%) and grade 5 (1%), predominantly hematological, infections or gastrointestinal. Temporary dose reduction of I or V for at least 14 days occurred in 40% of patients. Progression free survival (PFS) at 24 months was 94%, with 3 PD, of whom 1 during the intensification phase. Overall survival (OS) at 24 months was 98% with two treatment related deaths. Two patients received treatment in follow up.
Fifty-seven patients (79%) were assigned to IO intensification due to either MRD positivity (n=13), less than CR(i) (n=17) or both (n=27), of whom 2 patients did not have residual disease in hindsight and were analyzed in the observation group per protocol. In the intensification group 33 of 55 patients (60%, 90% CI: 48-71) reached CR(i) and uMRD in BM 9 months after cycle 16, meeting the primary endpoint. Therefore, the study successfully met the predefined success criteria, to reject the null hypothesis of a CR(i) and uMRD rate of 23% in the intensification group. At 24 months after start of intensification PFS was 92% (95% CI: 80-97) and OS 94% (95% CI: 82-98).
Of the 55 patients assigned to IO, no infusion related reactions (IRR) on O occurred. Five (9%) did not initiate intensification and 3 (6%) did not complete all 6 cycles due to AE (n=2) and death (n=1). During IO, AE's were reported as maximum grade 2 (46%), grade 3 (22%), grade 4 (4%) and grade 5 (2%), primarily due to infections. Four patients discontinued I and 1 O due to AE's.
Of the 17 patients in the observation group 2 patients (12%) had a grade 2 AE and 1 (6%) grade 3, and none had died, showed PD or received additional treatment during follow up, resulting in PFS and OS at 24 months of 100%.
Conclusion
MRD and response guided IO intensification leads to CR(i) with uMRD in 60% of patients without CR(i) and uMRD after IV in first-line CLL, with limited toxicity and no IRR. Overall, 60% of the full trial population achieved CR(i) with uMRD, with promising PFS and OS rates at median 35 months follow up. This response and MRD-guided intensification approach warrants randomized comparison to current standard of care.