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1013 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Frontline Targeted Therapy Combinations
Hematology Disease Topics & Pathways:
Combination therapy, Treatment Considerations, Measurable Residual Disease
Monday, December 9, 2024: 5:30 PM

Mark-David Levin1, Sabina Kersting, MD, PhD2*, Julie Dubois, MD, PhD3*, Bronno van der Holt, PhD4,5*, Caspar da Cunha-Bang, MD, PhD6*, Doreen te Raa, MD, PhD7*, Cecile Idink, MB, PhD8*, Fransien De Boer, MD, PhD9*, Jolanda Droogendijk, MD10*, Koen de Heer, MD, PhD11*, Leonie van der Burg, MD12*, Marten R. Nijziel, MD, PhD13, Lidwine Tick, MD, PhD14*, Henriettte Levenga, MD15*, Matthijs Silbermann, MD16*, Inge Ludwig, MD, MSc17*, Aart Beeker, MD18, Mar Bellido, MD, PhD19*, Anne-Marie Van Der Kevie-Kersemaekers, PhD20*, Clemens Mellink20*, Ine Meulendijks4*, Sjoerd Zoun-van den Dool4*, Martine Abrahamse-Testroote21*, Gerben Zwezerijnen22*, Carsten Utoft Niemann, MD, PhD23* and Arnon P. Kater, MD, PhD24

1Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands
2Department of Hematology, Haga Ziekenhuis, Den Haag, Netherlands
3Department of Hematology, University of Amsterdam, Amsterdam, Netherlands
4ErasmusMC, Rotterdam, Netherlands
5Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
6Department of Hematology, Rigshospitalet, Copenhagen, Denmark
7Ziekenhuis Gelderse Vallei, Ede, Netherlands
8Zorgsaam, Terneuzen, NLD
9Ikazia Hospital, Rotterdam, Netherlands
10Elisabeth Tweesteden ziekenhuis, Tilburg, NLD
11Department of Internal Medicine, Flevoziekenhuis, Almere, Netherlands
12Antonius ziekenhuis, Sneek, Netherlands
13Maxima Medical Center Eindhoven/Veldhoven, Eindhoven, Noord-Brabant, NLD
14Maxima Medisch Centrum, Eindhoven, Netherlands
15Groene Hart ziekenhuis, Gouda, Netherlands
16Ter Gooi ziekenhuis, XZ HILVERSUM, NLD
17Department of Hematology, Bernhoven Hospital, Uden, Netherlands
18Spaarne Ziekenhuis, Hoofddorp, Netherlands
19University Medical Center Groningen and University of Groningen, Groningen, Netherlands
20AmsterdamUMC, Amsterdam, NLD
21ErasmusMC, Rotterdam, NLD
22Cancer Center Amsterdam, Amsterdam UMC Radiology and Nuclear Medicine, Amsterdam, Netherlands
23Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
24Amsterdam University Medical Center, Amsterdam, on behalf of HOVON, Netherlands

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 (<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 > 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.

Disclosures: Levin: Janssen, AbbVie: Other: Travel. Dubois: Roche Genentech: Research Funding. van der Holt: Intergroupe Francophone du Myelome (IFM): Other: Honoraria for data safety monitoring board membership. Bellido: Amgen: Other: Financial Contribution to Attend Workshop; Janssen: Other: Financial Departmental Contribution for Educational Purposes. Niemann: CSL Behring, Genmab, Takeda, Beigene, MSD, Lilly: Consultancy; AbbVie, Janssen, AstraZeneca, Novo Nordisk Foundation, Octapharma: Consultancy, Research Funding; Novo Nordisk: Research Funding. Kater: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; LAVA: Membership on an entity's Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee, Research Funding.

*signifies non-member of ASH