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 Features

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.

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:Amgen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding; Astellas: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Xencor: 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.