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727 Early Achievement of Deep Measurable Residual Disease (MRD) Negativity Identifies Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) Who Have Excellent Long-Term Outcomes and Do Not Benefit from Allogeneic Stem Cell Transplant, Irrespective of Baseline High-Risk Cytomolecular FeaturesClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Look into the Crystal B-ALL: Genetic, Phenotypic and Dynamic Outcome Predictors in Lymphoblastic Leukemia
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Adult, Clinical Research, Diseases, Lymphoid Malignancies, Study Population, Human, Measurable Residual Disease
Monday, December 9, 2024: 10:30 AM

Walid Macaron, MD, MSc1,2*, Elias Jabbour, MD2, Nitin Jain, MD2, Fadi G. Haddad, MD2, Jayastu Senapati, MD, DM, MBBS2, Partow Kebriaei, MD3, Eitan Kugler, MD PhD2*, Kelly S. Chien, MD4, Ghayas C. Issa, MD2, Jairo Matthews, BA5*, Rebecca Garris2*, Farhad Ravandi, MBBS6, Hagop M. Kantarjian, MD2 and Nicholas J. Short, MD2

1Department of Medicine, Baylor College of Medicine, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, MD Anderson, Houston, TX
5The University of Texas at MD Anderson Cancer center, Houston, TX
6Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX

Background: MRD is strongly prognostic in ALL. However, it is largely unknown whether achievement of MRD negativity below 1x10-6 using newer, highly sensitive assays can overcome the poor prognosis associated with high-risk (HR) cytogenetic or molecular features.

Methods: This is a retrospective analysis of patients (pts) with B-cell ALL undergoing frontline therapy who underwent assessment of high-throughput next-generation sequencing (NGS)-based MRD for IG/TR (sensitivity 1x10-6) using clonoSEQ (Adaptive Biotechnologies). Pts who achieved CR/CRi with frontline therapy and had at least one NGS MRD assessment in the first 6 months of frontline therapy were included. “Early MRD response” was defined as NGS MRD negativity within 1.5 months from the start of frontline therapy.

Results: 161 pts had at least 1 NGS MRD assessment in the first 6 months of frontline therapy for B-cell ALL. The median age of the cohort was 46 years (range, age 18-87 years). 80 pts (50%) were female. 51 pts (32%) had Ph+ ALL and 110 pts (68%) had Ph- ALL. Frontline therapy was hyper-CVAD-based ± immunotherapy (e.g. inotuzumab ozogamicin and/or blinatumomab) in 43% (n=69), mini-hyper-CVD-based ± immunotherapy in 28% (n=45), and chemotherapy-free in 29% (n=47, all of whom were Ph+). Among the 110 Ph- pts, 59 (54%) had at least 1 HR feature (i.e. low hypodiploidy/near triploidy or complex cytogenetics, KMT2Ar, Ph-like ALL, and/or TP53 mutation). The median duration of follow-up for the entire cohort was 22 months.

In the entire cohort, the rates of MRD negativity increased with time. At 1.5 months, 3 months, and 6 months from the start of therapy, rates of MRD negativity were 35% (29/82), 68% (84/123), and 85% (79/93), respectively. Among pts with Ph- ALL, no differences in rates of MRD negativity were observed between HR and non-HR pts. “Early” MRD negativity was achieved in 9/25 (36%) of HR pts vs 8/29 (28%) of non-HR pts (P=0.71), and cumulative 6-month MRD negativity was 42/59 (72%) and 36/51 (71%), respectively.

NGS MRD negativity was associated with superior outcomes at all times assessed (i.e. 1.5, 3, and 6 months from the start of frontline therapy). Among the 29 pts who achieved early MRD negativity, only 1 pt relapsed (3% relapse rate in early MRD responders), and the 2-year RFS for pts who were MRD-negative vs. MRD-positive at 1.5 months was 83% and 66% (P=0.06), at 3 months was 84% and 65% (P=0.04), and at 6 months was 82% and 62% (P=0.01), respectively. The impact of MRD negativity was most pronounced in Ph- ALL. Among 17 pts with Ph- ALL who achieved early MRD negativity, none relapsed. Comparing MRD negative and positive pts with Ph- ALL, the 2-year RFS at 1.5 months was 100% and 69% (P=0.03), at 3 months was 84% and 60% (P=0.03) and at 6 months was 88% and 50% (P<0.001), respectively.

Among pts with non-HR Ph- ALL, outcomes were excellent regardless of early MRD response (2-year RFS for negative and positive pts: 100% vs. 94%, respectively; P=0.50). However, for HR Ph- ALL, a dramatic difference in survival was observed according to early MRD response (2-year RFS 100% vs. 38%, respectively; P=0.01). In HR pts, those who were MRD-positive at 1.5 months and converted to MRD-negative within 6 months (i.e. “late” MRD negativity) still had poor outcomes (2-year RFS 100% for early MRD response vs 34% for late MRD response; P=0.009), suggesting that only early MRD response was protective for relapse in HR pts.

In a landmark analysis, there was no benefit with allogeneic stem cell transplant (SCT) consolidation in pts with HR Ph- ALL who achieved NGS MRD negativity within the first 3 months (2-year RFS 75% for SCT vs 77% for no SCT; P=0.80) or first 6 months of frontline therapy (2-year RFS 67% for SCT vs 74% for no SCT; P=0.72). However, SCT appeared to benefit HR pts with poor MRD response (2-year RFS 100% for transplanted pts who remained MRD positive at 6 months vs. 20% for non-transplanted pts; P=0.003).

Conclusions: Early achievement of NGS MRD negativity identifies pts with excellent outcomes after frontline therapy. Importantly, no relapses were observed in pts with HR cytogenetic/molecular features who achieved early NGS MRD negativity, suggesting that early MRD dynamics should be included in ALL risk stratification systems. Pts with HR Ph- ALL who achieve deep MRD negativity within the first 6 months of frontline therapy do not appear to benefit from allogeneic SCT.

Disclosures: Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Jain: Servier: Research Funding; TransThera Sciences: Research Funding; MingSight: Honoraria, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Research Funding; Incyte: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Loxo Oncology: Research Funding; Medisix: Research Funding; Newave: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; Pfizer: Research Funding; NovalGen: Research Funding; Dialectic Therapeutics: Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Kebriaei: Jazz Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Chien: Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Issa: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Astex: Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Celgene: Research Funding; Merck: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees. Ravandi: Xencor: Research Funding; Amgen: Research Funding; BMS: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Syndax: Honoraria; Astyex/Taiho: Research Funding. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Short: Astellas Pharma, Inc.: Honoraria, Research Funding; NextCure: Research Funding; Takeda Oncology: Honoraria, Research Funding; Xencor: Research Funding; Novartis: Honoraria; Stemline Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Autolus: Honoraria; GSK: Consultancy, Research Funding; Pfizer Inc.: Honoraria; BeiGene: Honoraria.

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