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Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide
Ravindra, N., Dillon, L. W., Gui, G., Smith, M., Gondek, L. P., Jones, R. J., Corner, A., Hourigan, C. S., Ambinder, A. J.
Bone marrow transplantation. 2024
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2.
Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes
Pasca, S., Guo, M. Z., Wang, S., Stokvis, K., Shedeck, A., Pallavajjala, A., Shams, C., Pallavajjala, R., DeZern, A., Varadhan, R., et al
Blood advances. 2023
Abstract
The measurable residual disease (MRD) assessment provides an attractive predictor of alloHCT outcomes. Cell-free DNA (cfDNA) has been applied to diagnosis, early detection, and disease burden monitoring in various tumors but its utility as an MRD test in myeloid malignancies has not been systematically evaluated. We sought to determine the differential sensitivity between bone marrow (BM) and cfDNA MRD and to assess the effect of cfDNA MRD on alloHCT outcomes. The technical and clinical validation cohort including 82 patients participating in clinical trials (BMT CTN-0201 and 0402) were utilized. Ultra-deep error-corrected targeted sequencing was performed on plasma and bone marrow-derived DNA. We demonstrated that 94.6% (range 93.9-95.3%) of cfDNA was derived from hematopoietic tissue. The mutant allele fraction was congruent between BM and cfDNA (rho = 0.8, p<0.0001), however, cfDNA appeared to be more sensitive in detecting clones with variant allele frequency (VAF) <0.26%. CfDNA-MRD clearance by day 90 post-alloHCT (D90) was associated with improved relapse-free survival (RFS, median survival not reached vs 5.5 months, p <0.0001) and overall survival (OS, median survival not reached vs 7.3 months, p < 0.0001) when compared to patients with persistent MRD. Irrespective of pre-alloHCT MRD, D90 cfDNA MRD was associated with inferior 2-year OS (16.7% vs. 84.8%, p <0.0001) and RFS (16.7% vs. 80.7%, p <0.0001). CfDNA appears to be an accurate, minimally invasive alternative to BM aspirates in MRD assessment and confers important prognostic implications in patients with myeloid malignancies undergoing alloHCT.
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Impact of diagnostic genetics on remission MRD and transplantation outcomes in older AML patients
Murdock, H. M., Kim, H. T., Denlinger, N., Vachhani, P., Hambley, B. C., Manning, B. S., Gier, S., Cho, C., Tsai, H. K., McCurdy, S. R., et al
Blood. 2022
Abstract
Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (VAFâ„2%) on diagnostic samples from 295 AML patients age 60 or older who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at the time of remission in 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS 85%), intermediate (55%), high (35%), and very high risk (7%). Prior to HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 mutations (DT) and 61.4% with other mutations (MRDpositive). In univariable analysis, MRD-positivity was associated with increased relapse and inferior LFS compared with DT and MRDnegative patients. However, in a multivariable model accounting for baseline risk, MRD-positivity had no independent impact on LFS, likely due to its significant association with diagnostic genetic characteristics including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In conclusion, molecular associations with MRD positivity and transplant outcomes in older AML patients are driven primarily by baseline genetics, and not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are required.
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4.
Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission
Murdock, H. M., Kim, H. T., Hambley, B., Vachhani, P., Denlinger, N., Gier, S. H., Cho, C., Perales, M. A., Koreth, J., Ho, V. T., et al
Blood. 2019;134(Supplement_1):48
Abstract
DISCLOSURES Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.