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2950 Measurable Residual Mutated NPM1 before Allogeneic Transplant for Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 619. Acute Myeloid Leukemias: Disease Burden and Minimal Residual Disease in Prognosis and Treatment: Poster II
Hematology Disease Topics & Pathways:
Measurable Residual Disease
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Rasha W Al-Ali1*, Gege Gui1*, Niveditha Ravindra, MD2*, Georgia Andrew, BSc2*, Devdeep Mukherjee, PhD2*, Zoë Wong, BSc2*, Ying Huang, PhD3*, Jason Gerhold4*, Matthew Holman, BSc3*, Austin Jacobsen5*, Julian D'Angelo5*, Jeffrey E Miller, PhD3, Karina Elias5*, Jeffery J. Auletta, MD6, Firas El Chaer, MD7*, Steven Michael Devine, MD8, Antonio M. Jimenez Jimenez, MD, MSc9*, Marcos de Lima10*, Mark R. Litzow, MD11, Partow Kebriaei, MD12, Wael Saber, MD, MS13,14, Stephen R. Spellman6*, Scott L. Zeger, PhD15*, Kristin Page16, Coleman Lindsley, MD, PhD17, Jerald P. Radich, MD18, Christopher S. Hourigan, DM, DPhil1,2 and Laura W Dillon, PhD2*

1Fralin Biomedical Research Institute, Virginia Tech FBRI Cancer Research Center, Washington, DC
2Laboratory of Myeloid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD
3Invivoscribe, Inc., San Diego, CA
4VP, Global Regulatory, Quality, & Clinical Affairs, Invivoscribe, Inc., San Diego, CA
5Invivoscribe, Inc, San Diego, CA
6CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN
7University of Virginia Health System, Charlottesville, VA
8Center for International Blood and Marrow Transplant Research, NMDP, Minneapolis, MN
9Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, FL
10Division of Hematology, The Ohio State University, Columbus, OH
11Division of Hematology, Mayo Clinic, Rochester, MN
12M.D. Anderson Cancer Center, Houston, TX
13Center for International Blood and Marrow Transplant Research, Minneapolis, MN
14Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI
15Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
16Medical College of Wisconsin, Milwaukee, WI
17Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
18Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Rsch. Ctr., Seattle, WA

Introduction: NPM1 mutations, seen in up to 30% of adults with acute myeloid leukemia (AML), often co-occur with FLT3 internal tandem duplication (FLT3-ITD). Measurable residual disease (MRD) testing before allogeneic hematopoietic cell transplant (alloHCT) for persistence of mutated NPM1 and/or FLT3-ITD can identify patients with AML in complete remission (CR) at highest risk of relapse and death. Quantitative RT-PCR assays are currently recommended for NPM1 MRD testing, while FLT3-ITD MRD testing is DNA-based using next generation sequencing (NGS). DNA-based NGS assays for mutated NPM1 MRD testing may have several advantages but require validation. We performed NPM1 MRD detection in blood collected from patients with AML during first CR (CR1) prior to alloHCT on a subset of patients from the Pre-MEASURE study (PMID: 36881031) using a highly-sensitive, commercially available DNA-based NPM1 NGS MRD assay.

Methods: Of the 531 patients aged 18 or older from the Pre-MEASURE study who received an alloHCT for NPM1mutated AML during CR1 at a CIBMTR reporting site in the USA between the years of 2013-2019, a subset of 190 were randomly selected to be included in this analysis. A commercially available research testing kit (IVS, Invivoscribe, San Diego, CA), which can detect DNA-based NPM1 MRD, was used to establish a workflow following clinical testing standards and validated to detect NPM1 insertion variants down to a variant allele fraction (VAF) of at least 0.005%. Results were compared to those previously reported using an anchored multiplex PCR-based (AMP) targeted NGS assay (detection limit 0.01%) and FLT3-ITD MRD results, where applicable. Overall survival (OS) and cumulative incidence of relapse were estimated with the day of transplant as time 0 using Kaplan-Meier estimation (log-rank tests), Fine and Gray model, and Cox proportional hazards models.

Results: NPM1 NGS MRD testing was successful for 186 (98%) patients, of which 48 (26%) relapsed (median: 4.0 months; range: 0.7-52.5) and 64 (34%) died (median: 9.7 months; range: 0.4-58.9) post-alloHCT. The IVS assay detected NPM1 insertion variants in 71 patients with a median VAF of 0.0026% (range:0.0002-2.1%).

Using a VAF threshold of 0.01% for MRD positivity, the IVS test showed that 24 patients tested positive for NPM1 MRD pre-alloHCT, which was associated with significantly increased rates of relapse (52% vs 20% at 3yrs; HR=4.3; P<0.001) and decreased OS (34% vs 71% at 3yrs; HR=3.6; P<0.001) compared to testing negative, in close alignment with those previously reported using the AMP assay. After removing the VAF threshold, an additional 47 patients were classified as NPM1 MRD positive, which remained associated with increased rates of relapse (40% vs 15% at 3yrs; HR=3.4; P<0.001) and decreased OS (50% vs 75% at 3yrs; HR=2.9; P<0.001). In multivariable analysis, residual NPM1 MRD burden prior to alloHCT was associated with risk of relapse and death in a dose-dependent manner.

Patients were further subdivided based on their reported FLT3-ITD mutational status at baseline. Increased risk of relapse was seen for NPM1 MRD positive patients regardless of baseline FLT3-ITD. 123 (66%) patients were co-mutated for FLT3-ITD at baseline and previously tested for FLT3-ITD MRD using the IVS assay (PMID: 38696205). Defining MRD based on the presence of NPM1 vs NPM1 and/or FLT3-ITD revealed equivalent levels of relapse (45% vs 44%) and OS (45% vs 46%) at 3 years, with NPM1 MRD evaluation identifying 5 additional relapses. These results were confirmed in the full Pre-MEASURE cohort (n=317) using the AMP assay.

NPM1 MRD positive patients receiving nonmyeloablative conditioning or reduced-intensity conditioning (RIC) without melphalan (mel) had increased risk of relapse or death compared to patients receiving myeloablative conditioning or RIC with mel, regardless of FLT3-ITD co-mutational status (3yrs: relapse 87% vs 55%, P=0.006; OS 15% vs 42%, P=0.013).

Conclusions: In patients with NPM1 mutated AML from the Pre-MEASURE study, we show that detection of residual NPM1 variants in pre-transplant blood during CR1 using a highly sensitive DNA-based assay is associated in a dose-dependent manner with a significantly increased risk of relapse and death after allo-HCT, which can be mitigated in part by conditioning regimen. In patients co-mutated for both FLT3-ITD and NPM1 at diagnosis, NPM1 should be prioritized as a target for NGS-MRD if only one test is available.

Disclosures: Huang: Invivoscribe, Inc.: Current Employment, Current equity holder in private company. Gerhold: Invivoscribe, Inc.: Current Employment, Current equity holder in private company. Holman: Invivoscribe, Inc.: Current Employment, Current equity holder in private company. Jacobsen: Invivoscribe, Inc.: Current Employment, Current equity holder in private company. D'Angelo: Invivoscribe, Inc.: Current Employment, Current equity holder in private company. Miller: Invivoscribe, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Elias: Invivoscribe, Inc: Current Employment, Current equity holder in private company. Auletta: AscellaHealth: Membership on an entity's Board of Directors or advisory committees. El Chaer: FibroGen: Research Funding; BioSight: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; DAVA Oncology: Consultancy, Other: Travel grant; Sobi: Consultancy; Geron: Consultancy; Bristol Myers Squib: Consultancy, Research Funding; PharmaEssentia: Consultancy, Research Funding; Association of Community Cancer Centers: Consultancy; MorphoSys: Consultancy; AbbVie: Consultancy; CTI BioPharma: Consultancy; Amgen: Consultancy, Research Funding; SPD Oncology: Consultancy, Research Funding; Arog Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding. Devine: National Marrow Donor Program: Current Employment. Jimenez Jimenez: Orca Bio: Research Funding. de Lima: Pfizer: Consultancy; Autolous: Consultancy; Bristol Myers Squibb: Consultancy. Litzow: Abbvie: Research Funding; Amgen: Research Funding, Speakers Bureau; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Sanofi: Research Funding; Beigene: Speakers Bureau; Biosight: Other: Data Safety Monitoring Committee. Kebriaei: Jazz Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Radich: ThermoFisher: Honoraria.

*signifies non-member of ASH