Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation

Porta, Matteo Giovanni Della; Gallì, Anna; Bacigalupo, Andrea; Zibellini, Silvia; Bernardi, Massimo; Rizzo, Ettore; Allione, Bernardino; Lint, Maria Teresa Van; Pioltelli, Pietro; Marenco, Paola; Bosi, Alberto; Voso, Maria Teresa; Sica, Simona; Cuzzola, Mariella; Angelucci, Emanuele; Rossi, Marianna; Ubezio, Marta; Malovini, Alberto; Limongelli, Ivan; Ferretti, Virginia Valeria; Spinelli, Orietta; Tresoldi, Cristina; Pozzi, Sarah; Luchetti, Silvia; Pezzetti, Laura Anna; Catricalà, Silvia; Milanesi, Chiara; Riva, Alberto; Bruno, Benedetto; Ciceri, Fabio; Bonifazi, Francesca; Bellazzi, Riccardo; Papaemmanuil, Elli; Santoro, Armando; Alessandrino, Emilio Paolo; Rambaldi, Alessandro; Cazzola, Mario

doi:10.1200/jco.2016.67.3616

Cited by 215 publications

(105 citation statements)

References 28 publications

(25 reference statements)

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“…Assessment of gene mutations may help predict survival among patients with MDS undergoing allogeneic stem-cell transplantation, 3,9 but previous studies have not evaluated a large number of genetic risks or the extent to which genetic risk interacts with clinical variables. In this study, we paired genetic analysis with comprehensive clinical annotation in a large, registry-based cohort.…”

Section: Discussionmentioning

confidence: 99%

“…6–8 Recently, somatic mutations have been linked to survival outcomes after transplantation, but previous studies have not comprehensively evaluated the effect of clinical and transplantation variables. 3,9 Here we report a comprehensive analysis of genes related to MDS and bone marrow failure in a broadly representative cohort of patients of all ages with rigorously defined MDS who underwent allogeneic stem-cell transplantation.…”

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confidence: 99%

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Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation

Lindsley¹,

et al. 2017

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BACKGROUND Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation. METHODS We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. We evaluated the association of mutations with transplantation outcomes, including overall survival, relapse, and death without relapse. RESULTS TP53 mutations were present in 19% of the patients and were associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations, after adjustment for significant clinical variables (P<0.001 for both comparisons). Among patients 40 years of age or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with shorter survival than was the absence of RAS pathway mutations (P= 0.004), owing to a high risk of relapse, and the presence of JAK2 mutations was associated with shorter survival than was the absence of JAK2 mutations (P = 0.001), owing to a high risk of death without relapse. The adverse prognostic effect of TP53 mutations was similar in patients who received reduced-intensity conditioning regimens and those who received myeloablative conditioning regimens. By contrast, the adverse effect of RAS pathway mutations on the risk of relapse, as compared with the absence of RAS pathway mutations, was evident only with reduced-intensity conditioning (P<0.001). In young adults, 4% of the patients had compound heterozygous mutations in the Shwachman–Diamond syndrome–associated SBDS gene with concurrent TP53 mutations and a poor prognosis. Mutations in the p53 regulator PPM1D were more common among patients with therapy-related MDS than those with primary MDS (15% vs. 3%, P<0.001). CONCLUSIONS Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen. (Funded by the Edward P. Evans Foundation and others.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation

Lindsley¹,

et al. 2017

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“…Complex karyotype MDS patients have fewer mutations in other genes, but roughly half will carry a TP53 mutation and have the worst overall outcomes, even after treatment. (6, 8, 15, 16) Complex karyotype patients without TP53 mutations appear to do as well as MDS patients without a complex karyotype, highlighting the importance of TP53 mutation status in this group. (12)…”

Section: Prognostic Valuementioning

confidence: 96%

“…(2) These lesions often carry prognostic significance that is independent of existing risk stratification tools and to a lesser extent, can help predict response to certain therapies. (5–8) In some cases, the presence of a somatic mutation in cytopenic patients may also aid in establishing a diagnosis. This brief review will give examples of how somatic mutations detected in MDS patients might impact their clinical care and reshape how we classify these disorders.…”

Section: Introductionmentioning

confidence: 99%

Implications of molecular genetic diversity in myelodysplastic syndromes

Bejar

2017

Current Opinion in Hematology

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Purpose of review Myelodysplastic syndromes (MDS) have remarkably diverse somatic mutation patterns that are challenging to interpret clinically. Yet, genetic information is increasingly available to physicians. This review will examine several implications of genetic diversity in MDS. Recent findings Somatic mutations can serve as clinically relevant biomarkers in MDS. Molecular subtypes may exist that share clinical features including risk of progression to acute myeloid leukemia (AML), response to treatment, and overall survival. Several mutated genes are known to have prognostic value that is independent of common risk stratification tools. Mutations of several genes identify low-blast percentage patients with greater than predicted disease risk while only SF3B1 mutations predict lower disease risk than expected. Mutations of TP53 are associated with adverse features, yet demonstrate inferior outcomes than predicted by these risk factors. SF3B1 and TP53 mutations may identify clinically relevant subtypes of MDS and allow for better refinement of risk within these groups. Using somatic mutations to diagnose MDS is more challenging since they can occur in healthy individuals. Yet, patients with unexplained cytopenias have a high rate of clonal hematopoiesis that may be an important risk factor to identify clinically. Summary Patterns of somatic mutations are diverse in MDS, but can inform the prediction of prognosis and aid in its diagnosis.

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“…Although some patients receive myeloablative conditioning regimens [G] , recent studies showing equivalent success rates with reduced-intensity regimens suggest that the primary mechanism of action is immunological elimination of the MDS stem cell clone 156 . The efficacy is far from complete, however, and specific mutations have been associated with poor survival following alloHSCT, including TP53 , owing to increased rates of post-transplant relapse 35,157 . TP53 mutation is a powerful marker of poor survival after transplant: in a retrospective analysis of 87 patients, not one of the 18 with a TP53 mutation was still alive five years following alloHSCT with reduced intensity conditioning regimens 35 .…”

Section: Genetics and Mds Managementmentioning

confidence: 99%

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

2016

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Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated hematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal hematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic hematopoietic differentiation, and the absence of features that define acute leukemia. Over 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation, and transcription. In this review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems, and therapeutic approaches.

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Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation

Cited by 215 publications

References 28 publications

Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation

Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation

Implications of molecular genetic diversity in myelodysplastic syndromes

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

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