Transplantation for therapy-related, TP53-mutated myelodysplastic syndrome - not because we can, but because we should.
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ABSTRACT:
SUBMITTER: Cutler C
PROVIDER: S-EPMC5709095 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
Publications
Transplantation for therapy-related, <i>TP53</i>-mutated myelodysplastic syndrome - <i>not because we can, but because we should</i>.
Haematologica 20171201 12
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Project description:TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches for this entity.SignificanceEmerging data on the impact of cytogenetic aberrations, TP53 allelic burden, immunobiology, and tumor microenvironment of TP53-mutated MDS and AML are further unraveling the complexity of this disease. An improved understanding of the functional consequences of TP53 mutations and immune dysregulation in TP53-mutated AML/MDS coupled with dismal outcomes has resulted in a shift from the use of cytotoxic and hypomethylating agent-based therapies to novel immune and nonimmune strategies for the treatment of this entity. It is hoped that these novel, rationally designed combinations will improve outcomes in this area of significant unmet need.
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Project description:Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.
| S-EPMC9064046 | biostudies-literature
Project description:TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate (ORR) (odds ratio, 0.3; P = .021), and lower TP53 VAF correlated with higher ORR to HMAs. Increase in TP53 VAF at the time of transformation was observed in 13 patients (61%), and previously undetectable mutations were observed in 15 patients (65%). TP53 VAF was associated with worse prognosis (hazard ratio, 1.02 per 1% VAF increase; 95% confidence interval, 1.01-1.03; P < .001). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups within TP53-mutant MDS. We developed a multivariable model for overall survival that included the revised International Prognostic Scoring System (IPSS-R) categories and TP53 VAF. Total score for each patient was calculated as follows: VAF TP53 + 13 × IPSS-R blast score + 16 × IPSS-R cytogenetic score + 28 × IPSS-R hemoglobin score + 46 × IPSS-R platelet score. Use of this model identified 4 prognostic subgroups with median survival times of not reached, 42.2, 21.9, and 9.2 months. These data suggest that outcomes of patients with TP53-mutated MDS are heterogeneous and that transformation may be driven not only by TP53 but also by other factors.
| S-EPMC7013259 | biostudies-literature
Project description:Mutations of TP53 are observed in 5-10% of patients in myelodysplastic syndrome (MDS) and are associated with adverse outcomes. Previous studies indicate that the TP53 allelic state and variant allele frequency of TP53 mutation impact patient outcomes, but there is significant heterogeneity within this MDS subgroup. We performed retrospective review of clinicopathologic and genomic information of 107 patients with TP53-mutated MDS. We assessed each mutation according to the phenotypic annotation of TP53 mutations (PHANTM) and analyzed the associations between predicted TP53 mutant function, represented by the PHANTM combined phenotype score, and overall survival (OS) using the log rank test and Cox regression. Our results indicated that patients with PHANTM combined phenotype score above the median (>1) had significantly shorter OS compared to those with scores below the median (median OS: 10.59 and 16.51 months, respectively, p = 0.025). This relationship remained significant in multivariable analysis (HR (95%CI): 1.62 (1.01-2.58), p = 0.044) and identified to have an independent prognostic influence, accounting for known risk such as IPSS-R and other standard risk variables. Our results suggest that the functional information of TP53 mutations, represented by PHANTM combined phenotype score, are associated with the clinical outcome of patients with TP53-mutated MDS.
| S-EPMC8582962 | biostudies-literature
Project description:There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.
| S-EPMC9837415 | biostudies-literature
Project description:Targeting TP53 mutated myelodysplastic syndromes and acute myeloid leukemia remains a significant unmet need. Recently, new drugs have attempted to improve the outcomes of this poor molecular subgroup. The aim of this article is to review all the current knowledge using active agents including hypomethylating agents with venetoclax, eprenetapopt or magrolimab. We include comprehensive analysis of clinical trials to date evaluating these drugs in TP53 myeloid neoplasms as well as discuss future novel combinations for consideration. Additionally, further understanding of the unique clinicopathologic components of TP53 mutant myeloid neoplasms versus wild-type is critical to guide future study. Importantly, the clinical trajectory of patients is uniquely tied with the clonal burden of TP53, which enables serial TP53 variant allele frequency analysis to be a critical early biomarker in investigational studies. Together, significant optimism is now possible for improving outcomes in this patient population.
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Project description:BackgroundAfter successful treatment of malignant diseases, therapy-related myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems.Design and methodsThe aim of this study was to investigate outcome and risk factors in patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia who underwent allogeneic stem cell transplantation. Between 1981 and 2006, 461 patients with therapy-related myelodysplastic syndrome or acute myeloid, a median age of 40 years and a history of solid tumor (n=163), malignant lymphoma (n=133), or other hematologic diseases (n=57) underwent stem cell transplantation and their data were reported to the European Group for Blood and Marrow Transplantation.ResultsThe cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 31%, respectively. In a multivariate analysis significant factors for relapse were not being in complete remission at the time of transplantation (p=0.002), abnormal cytogenetics (p=0.005), higher patients' age (p=0.03) and therapy-related myelodysplastic syndrome (p=0.04), while higher non-relapse mortality was influenced by higher patients' age. Furthermore, there was a marked reduction in non-relapse mortality per calendar year during the study period (p<0.001). The 3-year relapse-free and overall survival rates were 33% and 35%, respectively. In a multivariate analysis significant higher overall survival rates were seen per calendar year (p<0.001), for younger age (<40 years) and normal cytogenetics (p=0.05). Using age (<40 years), abnormal cytogenetics and not being in complete remission at the time of transplantation as risk factors, three different risk groups with overall survival rates of 62%, 33% and 24% could be easily distinguished.ConclusionsAllogeneic stem cell transplantation can cure patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia and has markedly improved over time. Non-complete remission, abnormal cytogenetics and higher patients' age are the most significant factors predicting survival.
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Project description:TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the myeloid malignancies with the poorest prognosis. In this review, we analyze the prognosis of these two diseases, focussing particularly on the extent of the mono or biallelic mutation status of TP53 mutation, which is largely correlated with cytogenetic complexity. We discuss the possible/potential improvement in outcome based on recent results obtained with new drugs (especially eprenetapopt and magrolimab). We also focus on the impact of allogeneic hematopoietic stem cell transplantation (aHSCT) including post aHSCT treatment.
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Project description:GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2mut) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (-7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and -7 (DFS 67%). Comparing outcome of GATA2mut with GATA2wt patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with -7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
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