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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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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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Allogeneic Blood or Marrow Transplantation with High-Dose Post-transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Aged ≥55
Webster, J. A., Reed, M., Tsai, H. L., Ambinder, A., Jain, T., Dezern, A. E., Levis, M. J., Showel, M. M., Prince, G. T., Hourigan, C. S., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Patients ≥55 years-old with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy with 5-year overall survival of ∼20%. Tyrosine kinase inhibitors and novel B-cell targeted therapies improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (AlloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplants with low rates of non-relapse mortality (NRM) and graft-versus-host disease (GVHD). METHODS The transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received alloBMT for ALL using PTCy. FINDINGS The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% CI 34-57) and 49% (95% CI 37-60). Grade 3-4 acute GVHD occurred in only 3% of patients and chronic GVHD in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (HR 4.65, p=0.001); while transplant in CR1 (HR 0.30, p=0.004), and transplant for Ph+ ALL vs. T ALL (HR 0.29, p=0.03) improved RFS. Of the 54 patients who received RIC alloBMT in CR1 for B ALL, 5-year RFS and OS were 62% (95% CI 47-74) and 65% (95% CI 51-77), respectively, with a 5-year relapse incidence of 16% (95% CI 7-27) and NRM of 24% (95% CI 13-36). INTERPRETATION RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. FUNDING NIH grants P01 CA225618 and P30 CA06973.
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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 (VAF≥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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Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide
Webster, J. A., Luznik, L., Tsai, H. L., Imus, P. H., DeZern, A. E., Pratz, K. W., Levis, M. J., Gojo, I., Showel, M. M., Prince, G., et al
Blood advances. 2020;4(20):5078-5088
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Editor's Choice
Abstract
Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
PICO Summary
Population
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing allogeneic transplantation (n=76)
Intervention
Myeloablative conditioning in first complete remission (CR1 MAC, n=26); Non-myeloablative conditioning in first complete remission (CR1 NMAC, n=43)
Comparison
Patients in second or subsequent remission (CR2+, n=12)
Outcome
For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%.
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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.