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Patient-Specific Measurable Residual Disease Markers Predict Outcome in Patients With Myelodysplastic Syndrome and Related Diseases After Hematopoietic Stem-Cell Transplantation
Tobiasson, M., Pandzic, T., Illman, J., Nilsson, L., Weström, S., Ejerblad, E., Olesen, G., Björklund, A., Olsnes Kittang, A., Werlenius, O., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024;:Jco2301159
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Editor's Choice
Abstract
PURPOSE Clinical relapse is the major threat for patients with myelodysplastic syndrome (MDS) undergoing hematopoietic stem-cell transplantation (HSCT). Early detection of measurable residual disease (MRD) would enable preemptive treatment and potentially reduced relapse risk. METHODS Patients with MDS planned for HSCT were enrolled in a prospective, observational study evaluating the association between MRD and clinical outcome. We collected bone marrow (BM) and peripheral blood samples until relapse, death, or end of study 24 months after HSCT. Patient-specific mutations were identified with targeted next-generation sequencing (NGS) panel and traced using droplet digital polymerase chain reaction (ddPCR). RESULTS Of 266 included patients, estimated relapse-free survival (RFS) and overall survival (OS) rates 3 years after HSCT were 59% and 64%, respectively. MRD results were available for 221 patients. Relapse was preceded by positive BM MRD in 42/44 relapses with complete MRD data, by a median of 71 (23-283) days. Of 137 patients in continuous complete remission, 93 were consistently MRD-negative, 39 reverted from MRD+ to MRD-, and five were MRD+ at last sampling. Estimated 1 year-RFS after first positive MRD was 49%, 39%, and 30%, using cutoff levels of 0.1%, 0.3%, and 0.5%, respectively. In a multivariate Cox model, MRD (hazard ratio [HR], 7.99), WHO subgroup AML (HR, 4.87), TP53 multi-hit (HR, 2.38), NRAS (HR, 3.55), and acute GVHD grade III-IV (HR, 4.13) were associated with shorter RFS. MRD+ was also independently associated with shorter OS (HR, 2.65). In a subgroup analysis of 100 MRD+ patients, presence of chronic GVHD was associated with longer RFS (HR, 0.32). CONCLUSION Assessment of individualized MRD using NGS + ddPCR is feasible and can be used for early detection of relapse. Positive MRD is associated with shorter RFS and OS (ClinicalTrials.gov identifier: NCT02872662).
PICO Summary
Population
Adults with myelodysplastic syndrome planned for HSCT, from centres in Denmark, Norway and Sweden (n=266)
Intervention
Assessment of the prognistic impact of measurable residual disease (MRD) and patient-specific mutations
Comparison
None
Outcome
Estimated relapse-free survival (RFS) and overall survival (OS) rates 3 years after HSCT were 59% and 64%, respectively. MRD results were available for 221 patients. Relapse was preceded by positive BM MRD in 42/44 relapses with complete MRD data, by a median of 71 (23-283) days. Of 137 patients in continuous complete remission, 93 were consistently MRD-negative, 39 reverted from MRD+ to MRD-, and five were MRD+ at last sampling. Estimated 1 year-RFS after first positive MRD was 49%, 39%, and 30%, using cutoff levels of 0.1%, 0.3%, and 0.5%, respectively. In a multivariate Cox model, MRD (hazard ratio [HR], 7.99), WHO subgroup AML (HR, 4.87), TP53 multi-hit (HR, 2.38), NRAS (HR, 3.55), and acute GVHD grade III-IV (HR, 4.13) were associated with shorter RFS. MRD+ was also independently associated with shorter OS (HR, 2.65). In a subgroup analysis of 100 MRD+ patients, presence of chronic GVHD was associated with longer RFS (HR, 0.32).
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Proteomics to predict relapse in patients with myelodysplastic neoplasms undergoing allogeneic hematopoietic cell transplantation
Guru Murthy, G. S., Zhang, T., Bolon, Y. T., Spellman, S., Dong, J., Auer, P., Saber, W.
Biomarker research. 2024;12(1):10
Abstract
Disease relapse remains a major barrier to success after allogeneic hematopoietic cell transplantation (allo-HCT) in myelodysplastic neoplasms (MDS). While certain high risk genomic alterations are associated with increased risk of relapse, there is a lack of clinically applicable tools to analyze the downstream cellular events that are associated with relapse. We hypothesized that unique proteomic signatures in MDS patients undergoing allo-HCT could serve as a tool to understand this aspect and predict relapse. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 52 MDS patients who underwent allo-HCT and analyzed their proteomic profile from pretransplant blood samples in a matched case-control design. Twenty-six patients without disease relapse after allo-HCT (controls) were matched with 26 patients who experienced relapse (cases). Proteomics assessment was conducted using the Slow Off-rate Modified Aptamers (SOMAmer) based assay. In gene set enrichment analysis, we noted that expression in the hallmark complement, and hallmark allograft rejection pathways were statistically enriched among patients who had disease relapse post-transplant. In addition, correlation analyses showed that methylation array probes in cis- and transcription regulatory elements of immune pathway genes were modulated and differentially sensitize the immune response. These findings suggest that proteomic analysis could serve as a novel tool for prediction of relapse after allo-HCT in MDS.
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The prognosis and risk factors for patients with complex karyotype myelodysplastic syndrome undergoing allogeneic haematopoietic stem cell transplantation
Shimomura, Y., Komukai, S., Kitamura, T., Tachibana, T., Kurosawa, S., Itonaga, H., Tsukamoto, S., Doki, N., Katayama, Y., Ito, A., et al
British journal of haematology. 2023
Abstract
Allogeneic haematopoietic stem cell transplantation (HCT) is the curative treatment for myelodysplastic syndrome with a complex karyotype (CK-MDS). However, only a few studies have been limited to patients with CK-MDS undergoing allogeneic HCT. This study aimed to identify the risk factors for patients with CK-MDS undergoing allogeneic HCT. We included 691 patients with CK-MDS who received their first allogeneic HCT. The overall survival (OS) was the primary end-point, estimated using the Kaplan-Meier method. Prognostic factors were identified using a Cox proportional hazards model. The 3-year OS was 29.8% (95% confidence interval [CI]: 26.3-33.3). In the multivariable analysis, older age (hazard ratio [HR]: 1.44, 95% CI: 1.11-1.88), male sex (HR: 1.38, 95% CI: 1.11-1.71), poor haematopoietic cell transplant comorbidity index (HR: 1.47, 95% CI: 1.20-1.81), red blood cell transfusion requirement (HR: 1.58, 95% CI: 1.13-2.20), platelet transfusion requirement (HR: 1.85, 95% CI: 1.46-2.35), not-complete remission (HR: 1.55, 95% CI: 1.16-2.06), a high number of karyotype abnormality (HR: 1.63, 95% CI: 1.18-2.25) and monosomal karyotype (HR: 1.49, 95% CI: 1.05-2.12) were significantly associated with OS. Thus, the 3-year OS of allogeneic HCT was 29.8% in patients with CK-MDS, and we identified risk factors associated with poor OS.
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Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups: Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study
Versluis, J., Saber, W., Tsai, H. K., Gibson, C. J., Dillon, L. W., Mishra, A., McGuirk, J., Maziarz, R. T., Westervelt, P., Hegde, P., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;:Jco2300866
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Abstract
PURPOSE Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study. METHODS We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53(multihit) if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity). RESULTS The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). Among those with a TP53 mutation, OS was similar between TP53(single) versus TP53(multihit) (22% ± 8% v 20% ± 6% at 3 years; P = .31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P = .001). CONCLUSION HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.
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Progress in survival following three decades of allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: a real-world registry study in Japan
Konuma, T., Itonaga, H., Ishiyama, K., Hamamura, A., Uchida, N., Ozawa, Y., Katayama, Y., Sakurai, M., Ueda, Y., Matsuoka, K. I., et al
American journal of hematology. 2023
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Comparison of the prognostic predictive value of Molecular International Prognostic Scoring System and Revised International Prognostic Scoring System in patients undergoing allogeneic hematopoietic stem cell transplantation for myelodysplastic neoplasms
Yang, T., Jiang, B., Luo, Y., Zhao, Y., Ouyang, G., Yu, J., Lan, J., Lu, Y., Lai, X., Ye, B., et al
American journal of hematology. 2023
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Prognostic landscape of mitochondrial genome in myelodysplastic syndrome after stem-cell transplantation
Dong, J., Buradagunta, C. S., Zhang, T., Spellman, S., Bolon, Y. T., DeZern, A. E., Gadalla, S. M., Deeg, H. J., Nazha, A., Cutler, C., et al
Journal of hematology & oncology. 2023;16(1):21
Abstract
Despite mitochondrial DNA (mtDNA) mutations are common events in cancer, their global frequency and clinical impact have not been comprehensively characterized in patients with myelodysplastic neoplasia (also known as myelodysplastic syndromes, MDS). Here we performed whole-genome sequencing (WGS) on samples obtained before allogenic hematopoietic cell transplantation (allo-HCT) from 494 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research. We evaluated the impact of mtDNA mutations on transplantation outcomes, including overall survival (OS), relapse, relapse-free survival (RFS), and transplant-related mortality (TRM). A random survival forest algorithm was applied to evaluate the prognostic performance of models that include mtDNA mutations alone and combined with MDS- and HCT-related clinical factors. A total of 2666 mtDNA mutations were identified, including 411 potential pathogenic variants. We found that overall, an increased number of mtDNA mutations was associated with inferior transplantation outcomes. Mutations in several frequently mutated mtDNA genes (e.g., MT-CYB and MT-ND5) were identified as independent predictors of OS, RFS, relapse and/or TRM after allo-HCT. Integration of mtDNA mutations into the models based on the Revised International Prognostic Scores (IPSS-R) and clinical factors related to MDS and allo-HCT could capture more prognostic information and significantly improve the prognostic stratification efforts. Our study represents the first WGS effort in MDS receiving allo-HCT and shows that there may be clinical utility of mtDNA variants to predict allo-HCT outcomes in combination with more standard clinical parameters.
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Poor pretransplantation minimal residual disease clearance as an independent prognostic risk factor for survival in myelodysplastic syndrome with excess blasts: A multicenter, retrospective cohort study
Ma, Y. Y., Wei, Z. L., Xu, Y. J., Shi, J. M., Yi, H., Lai, Y. R., Jiang, E. L., Wang, S. B., Wu, T., Gao, L., et al
Cancer. 2023
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Editor's Choice
Abstract
BACKGROUND Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS-EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long-term survival. MATERIALS AND METHODS Patients with MDS-EB who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long-term survival was analyzed using univariate and multivariate logistic regression models. RESULTS Of 220 patients with MDS-EB who underwent allo-HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5% (p = .045), respectively, whereas the 3-year OS rates were 91.3% and 66.4% (p = .035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS. CONCLUSION Poor pretransplantation MRD clearance is an independent prognostic risk factor for long-term survival after allo-HSCT for patients with MDS-EB. PLAIN LANGUAGE SUMMARY Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long-term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts.
PICO Summary
Population
Patients with myelodysplastic syndrome with excess blasts (MDS-EB) from eight national study groups in China (n=198)
Intervention
Allogeneic stem cell transplantation
Comparison
None
Outcome
Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of minimal residual disease (MRD) pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5%, respectively, whereas the 3-year OS rates were 91.3% and 66.4%, respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS.
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Whole-genome sequencing identifies novel predictors for hematopoietic cell transplant outcomes for patients with myelodysplastic syndrome: a CIBMTR study
Zhang, T., Auer, P., Dong, J., Cutler, C., Dezern, A. E., Gadalla, S. M., Deeg, H. J., Nazha, A., Carlson, K. S., Spellman, S., et al
Journal of hematology & oncology. 2023;16(1):37
Abstract
Recurrent mutations in TP53, RAS pathway and JAK2 genes were shown to be highly prognostic of allogeneic hematopoietic cell transplant (alloHCT) outcomes in myelodysplastic syndromes (MDS). However, a significant proportion of MDS patients has no such mutations. Whole-genome sequencing (WGS) empowers the discovery of novel prognostic genetic alterations. We conducted WGS on pre-alloHCT whole-blood samples from 494 MDS patients. To nominate genomic candidates and subgroups that are associated with overall survival, we ran genome-wide association tests via gene-based, sliding window and cluster-based multivariate proportional hazard models. We used a random survival forest (RSF) model with build-in cross-validation to develop a prognostic model from identified genomic candidates and subgroups, patient-, disease- and HCT-related clinical factors. Twelve novel regions and three molecular signatures were identified with significant associations to overall survival. Mutations in two novel genes, CHD1 and DDX11, demonstrated a negative impact on survival in AML/MDS and lymphoid cancer data from the Cancer Genome Atlas (TCGA). From unsupervised clustering of recurrent genomic alterations, genomic subgroup with TP53/del5q is characterized with the significant association to inferior overall survival and replicated by an independent dataset. From supervised clustering of all genomic variants, more molecular signatures related to myeloid malignancies are characterized from supervised clustering, including Fc-receptor FCGRs, catenin complex CDHs and B-cell receptor regulators MTUS2/RFTN1. The RSF model with genomic candidates and subgroups, and clinical variables achieved superior performance compared to models that included only clinical variables.
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10.
Clinical and Cytogenetic Characterization of Early and Late Relapses in Patients Allografted for Myeloid Neoplasms with a Myelodysplastic Component
Platte, V., Bergmann, A., Hildebrandt, B., Wieczorek, D., Schuler, E., Germing, U., Kaivers, J., Haas, R., Kobbe, G., Schroeder, T., et al
Cancers. 2022;14(24)
Abstract
An improved understanding of relapse kinetics is required to optimize detection and treatment strategies for the post-transplant relapse of myeloid neoplasms. Therefore, we retrospectively analyzed data from 91 patients allografted for MDS (n = 54), AML-MRC (n = 29) and chronic myelomonocytic leukemia (CMML, n = 8), who relapsed after transplant. Patients with early (<12 months, n = 56) and late relapse (>12 months, n = 35) were compared regarding patient-, disease- and transplant-related factors, including karyotype analyses at diagnosis and relapse. After a median follow-up of 17.4 months after relapse, late relapses showed improved outcomes compared with early relapses (2-yr OS 67% vs. 32%, p = 0.0048). Comparing frequency of distinct patient-, disease- and transplant-related factors among early and late relapses, complex karyotype (p = 0.0004) and unfavorable disease risk at diagnosis (p = 0.0008) as well as clonal evolution at relapse (p = 0.03) were more common in early than in late relapses. Furthermore, patients receiving transplant without prior cytoreduction or in complete remission were more frequently present in the group of late relapses. These data suggest that cytogenetics rather than disease burden at diagnosis and transplant-related factors determine the timepoint of post-transplant relapse and that upfront transplantation may be favored in order to delay relapse.