Background:

MCL is a B-cell non-Hodgkin lymphoma for which auto-HCT is often employed in first CR, based on non-randomized phase 2 trials, and a randomized trial (Dreyling et al, Blood 2005) conducted before the advent of more effective induction and maintenance regimens. The TRIANGLE trial (Dreyling et al, Lancet 2024) suggested that auto-HCT may not add benefit to more effective induction and maintenance regimens containing high-dose cytarabine, rituximab and BTK inhibitors. E4151 explored whether auto-HCT benefits pts achieving deep first remission, as measured by a highly sensitive immunoglobulin high throughput sequencing minimal residual disease (MRD) assay.

Methods:

EA4151 is a four arm trial conducted through the U.S. National Clinical Trials Network (NCTN) and Blood and Marrow Transplant Clinical Trials Network (BMT-CTN). Pts with MCL between the ages of 18 and 70 and in first remission were eligible. After induction, pts underwent PET/CT, bone marrow biopsy, and the clonoSEQ® MRD assay from peripheral blood. Pts in CR with uMRD at 1 in 10-6 sensitivity (uMRD6) were randomized 1:1 to Arm A (auto-HCT + 3 years of maintenance rituximab [MR]) or Arm B (3 years of MR alone), stratified by MIPI-c score and intensive vs non-intensive induction. Pts with either MRD-positive (MRD+) CR or MRD-indeterminate CR (Arm C and Arm D, respsectively) both received auto-HCT + 3 years of MR. Pts who were MRD+ pre-transplant had MRD repeated at day 100. Primary endpoint was to compare overall survival (OS) in Arms A and B, with secondary endpoints including progression-free survival (PFS). Primary analysis population included all randomized pts. As some pts refused their assigned treatment (N=65 [25.3%] for arm A and N=2 [0.8%] for arm B), a “treated as assigned” analysis was also performed. Stratified logrank test was used to compare survival distributions. P-values are two-sided.

Results:

From Aug 2017 to July 2024, 650 pts were assigned to a treatment arm with 257, 259, 49, and 85 pts enrolled on Arms A, B, C, and D, respectively. Pts were 79% male and 92% white race. Median age was 60 years (range 27-70). MIPI-c was low/low-intermediate (LI) in 63% and high/ high-intermediate (HI) in 37%. Induction was intensive (defined as high-dose cytarabine-containing) in 73% and non-intensive in 27%. A BTK inhibitor was given during induction in 7.2% of pts, and during maintenance in 0.3% of pts.

The third pre-planned interim analysis was based on data as of 7/15/24, with median follow up of 2.7 years. The futility boundary was an OS hazard ratio (HR) of 0.984 for Arm A vs B. The estimated OS HR for Arm A vs B in all randomized (n=516) and pts treated as assigned (n=375) were 1.11 (CI 0.71-1.74, p=0.66) and 1.00 (CI 0.58-1.74, p=0.99), respectively and crossed the futility boundary. The 3 year (yr) OS for Arms A and B were 82.1% and 82.7% in all randomized pts, and 86.2% and 84.8% in pts treated as assigned. The estimated PFS HR for Arm A vs B in all randomized and pts treated as assigned were 1.05 (CI 0.71-1.56, p=0.79) and 0.95 (CI 0.59-1.54, p=0.84), respectively. The 3 yr PFS for Arms A and B were 76.6% and 77.4% in all randomized pts, and 81.5% and 80.4% in pts treated as assigned.

For Arm C, 3 yr OS and PFS were 81.9% (CI 69.6-96.4%) and 76.9% (CI 64.4-91.7%), respectively. For Arm D, 3 yr OS and PFS were 85.1% (CI 76.0%-95.4%) and 73.4% (62.7-85.9%), respectively. For the MIPI-c low/LI group, 3 yr OS was 84.6% vs 85.7% for Arm A vs B (p=0.96), while in the MIPI-c high/HI group, 3 yr OS was 77.4% vs 77.6% for Arm A vs B (p=0.71). For the intensive induction group, 3 yr OS was 83.0% vs 86.2% for Arm A vs B (p=0.30), while in the non-intensive induction group, 3 yr OS was 79.5% vs 72.8% for Arm A vs B (p=0.48).

Exploratory analysis of MRD+ pts (Arm C) showed that pts who converted to uMRD6 post auto-HCT (n=17) had 3 yr OS of 100% and PFS of 100%, whereas those who remained MRD+ (n=13) post auto-HCT had 3 yr OS of 63.6% and PFS of 48.8%. Causes of death (COD) in Arm A were 4.7% lymphoma, 5.1% COVID-19, and 5.0% other/unknown. COD in Arm B were 3.5% lymphoma, 6.6% COVID-19, and 4.6% other/unknown. In Sept 2024, the DSMC recommended termination of accrual and release of trial findings based on these results.

Conclusion:

In this interim analysis, in the era of highly effective induction and maintenance regimens, MCL pts in first CR with uMRD6 did not benefit from consolidative auto-HCT. Pts who remain MRD+ after induction may benefit from auto-HCT. Longer follow-up will be important to confirm these findings.

Disclosures

Fenske:AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Beigene, Janssen, Kite, Lilly, Ono Pharmaceuticals: Consultancy, Honoraria; AstraZeneca, Beigene, Kite, SeaGen: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria. Till:Mustang Bio: Consultancy, Patents & Royalties, Research Funding; Bristol Myers Squibb: Research Funding; Proteios Technology: Consultancy, Honoraria. Lunning:Daiichi Sankyo, Fate Therapeutics, Genentech, Genmab, Ipsen, Janssen: Consultancy, Honoraria; AbbVie, Bristol Myers Squibb, Fate Therapeutics, Sana Therapeutics, Kite: Consultancy, Research Funding; Abbvie, Acrotech, ADC Therapeutics, Astrazeneca, Britsol-Myers Squibb, Caribou, CRISPR,: Consultancy, Honoraria; Kite, Lilly, Incyte, Recordati, Regeneron, SeaGen, ViTToria: Consultancy, Honoraria. Lazarus:Actinium Pharmaceuticals, Inc: Consultancy, Honoraria; Partner Therapeutics: Consultancy, Current holder of stock options in a privately-held company; Pluristem Therapeutics, Inc: Consultancy, Honoraria; CSL Behring: Consultancy; GlycoMimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; BioSight: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Geron: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Fishkin:Novartis: Current equity holder in publicly-traded company. Kostakoglu Shields:Roche: Consultancy; Point Biopharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scott:Nanostring: Patents & Royalties: use of gene expresssion to subtype aggressive lymphoma; Genmab: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Roche/Genentech: Research Funding; Veracyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZenenca: Consultancy, Honoraria. LaCasce:Genmab: Consultancy, Honoraria. Johnston:Miltenyi: Consultancy, Other: Honoaria paid to Mayo Clinic. Cashen:SecuraBio: Research Funding. Popplewell:Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria; Hoffmann-La Roche: Consultancy, Honoraria. Ahmed:BMS: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria. Shah:Tundra Therapeutics: Current holder of stock options in a privately-held company; Miltenyi Biomedicine, Lilly Oncology: Research Funding; Gilead-Kite, BMS-Juno, Miltenyi, Lilly Onclogy, Novartis, Seattle Genetics, Janssen, Abbvie, Cargo, Beigene, Galapagos, AstraZeneca: Consultancy, Honoraria. Wagner-Johnston:Genentech: Research Funding; Merck: Research Funding; AstraZeneca: Research Funding; Beigene: Consultancy. Hu:ImmPACT Bio, Caribou Biosciences, Genentech, CRISPR Therapeutics, Morphosys AG, Repare Therapeutics, Artiva Biosciences, Newave, Astrazeneca: Research Funding; Eli Lilly, Genmab, ADC Therapeutics, ImmPACT Bio, SeaGen, Regeneron, Caribou Biosciences, Abbvie, Kite Pharma, Bristol-Myers Squibb: Consultancy, Honoraria. Dholaria:Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, Adicet, BMS, Molecular template, Atara: Research Funding; MJH BioScience, Arivan Research, Janssen, ADC therapeutics, Gilead, GSK, Caribou, Roche, Autolus, Sanofi.: Consultancy, Honoraria. Leonard:AbbVie, AstraZeneca, Astellas, Bayer, BeiGene,BMS, Calithera, Caribou Bioscences, Constellation, Eisai, Epizyme,GenMab, Grail, Incyte, Janssen, Karyopharm, Lilly, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro, Treelin: Consultancy, Honoraria. Kahl:Bristol Myers Squibb: Consultancy, Honoraria; BeiGene: Consultancy, Research Funding; Lilly: Consultancy, Honoraria; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; Genentech: Consultancy; Roche: Consultancy, Research Funding; ADCT: Consultancy.

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2024
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