TP53 and IDH2 Somatic Mutations Are Associated With Inferior Overall Survival After Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

doi:10.1016/j.clml.2017.06.003

Clinical Lymphoma Myeloma and Leukemia

Volume 17, Issue 11, November 2017, Pages 753-758

https://doi.org/10.1016/j.clml.2017.06.003 Get rights and content

Abstract

Background

Next-generation sequencing has identified somatic mutations that are prognostic of cancer.

Patients and Methods

We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen.

Results

The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival.

Conclusion

This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.

Introduction

Despite growing understanding of the genetic and molecular basis of myelodysplastic syndrome (MDS) as well as availability of epigenetic therapy, the disease remains incurable unless eligible patients are offered an allogeneic hematopoietic cell transplantation (allo-HCT).1, 2, 3, 4, 5, 6 Nevertheless, only approximately half of the patients who undergo the procedure achieve durable remissions.5, 6 Significant morbidity and mortality occurs despite efforts to optimize patient selection using disease-specific hematopoietic cell transplantation comorbidity indices.7, 8

No randomized data exist for comparisons of allo-HCT versus nontransplant therapies in patients with MDS. Presently, the decision to offer an allo-HCT is on the basis of published decision models that have shown a significant benefit favoring an allo-HCT earlier in the disease course, for patients with intermediate- or higher-risk MDS whether allografted from histocompatible siblings or unrelated donors.9, 10 Published retrospective single-institution or registry studies have also supported the benefit of an allo-HCT to eligible patients with MDS.11, 12, 13, 14 Various clinical models have been developed aimed at improving outcomes in patients who undergo an allo-HCT for MDS by identifying patient's comorbidities7, 15 and clinical characteristics of the disease.¹⁶ These models, however, are unable to predict outcomes in individual cases.

Availability of next-generation sequencing (NGS) has helped identify somatic mutations capable of prognosticating outcomes of patients with MDS and acute myeloid leukemia (AML).1, 17, 18 Bejar et al evaluated, retrospectively, 87 subjects who underwent an allo-HCT for MDS, median age 58 (range, 19-73) years, and identified the presence of at least 1 somatic mutations in 80 of 87 (92%) of cases.¹⁹ In their series, mutated ASXL1 was the most frequently observed mutation (n = 25/87, 29%).¹⁹ Moreover, mutations in TP53, TET2, and DNMT3A were associated with an inferior overall survival (OS) after allo-HCT; and presence of mutated TP53 was described as the most significant predictor of mortality after transplantation with a short median survival of 4.6 months.¹⁹ This study highlights the importance of identifying strong predictors of adverse outcomes in patients with MDS who undergo allo-HCT to develop therapeutic strategies aimed at improving outcomes.¹⁹ Integrating NGS as a prognostic tool represents a step in the right direction aimed at moving MDS therapeutics to a more personalized approach.

Section snippets

Patient and Treatment Characteristics

Patients were considered eligible for inclusion in this study if they were ≥ 18 years of age, received an allo-HCT for MDS between January 2005 and June 2012, and had available formalin-fixed paraffin embedded (FFPE) bone marrow (BM) samples from the pretransplant workup, which was performed within approximately 30 days from initiation of the preparative regimen. All samples were collected according to a protocol approved by the institutional review board of the University of South Florida.

Patient, Disease, and Transplant-Related Characteristics

Initially, we identified 139 patients who received an allo-HCT during the specified time period. However, 38 were excluded for inability to isolate DNA because of poor quality of FFPE BM samples and 12 because of diagnoses other than MDS (AML = 4, chronic myelomonocytic leukemia = 8). Accordingly, 89 patients (male = 52%), median age 58 (range, 22-74) years, were included in this cohort. The 3 most common MDS types at the time of diagnosis, defined according to the 2008 World Health

Discussion

The presence of mutated TP53 is associated with an inferior OS and a strong trend for worse PFS in patients with MDS who undergo an allo-HCT (Table 2). In our study, the median survival of patients harboring TP53 mutations was only 6.1 months and the 3-year PFS and OS were 0. Lindsley et al showed that TP53 mutations are associated with shorter survival and a shorter time to relapse.²² These findings are comparable with a previous single-institution study that reported a median survival of 4.6

Conclusion

Rapidly expanding knowledge pertaining to the prognostic significance of various gene mutations has only begun to augment disease risk prognostication for MDS. This study furthers the implementation of clinical genomics in this disease and will help incorporate novel therapies, for example IDH2 inhibitors or others, in the post-transplant setting aimed at reducing the risk associated with these mutations.

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

The authors acknowledge Moffitt tissue core and genomics core and Core Grant P30-CA076292. This work was supported by a grant from Moffitt Cancer Center Foundation to M.A.K-D.

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Cited by (18)

Outcomes with allogeneic hematopoietic stem cell transplantation in TP53-mutated myelodysplastic syndrome: A systematic review and meta-analysis
2024, Critical Reviews in Oncology/Hematology
We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in TP53-mutated myelodysplastic syndromes (MDS). A literature search was performed on PubMed, Cochrane, Embase, and Clinicaltrials.gov. After screening 626 articles, eight studies were included. Data were extracted following the PRISMA guidelines and analyzed using the meta-package by Schwarzer et al. We analyzed 540 patients. The pooled median 3 (1−5) year overall survival was 21% (95% CI 0.08–0.37, I2=91%, n=540). The pooled relapse rate was 58.9% (95% CI 0.38–0.77, I2=93%, n=487) at a median of 1.75 (1−3) years. The pooled 4-year progression- free survival was 34.8% (95% CI 0.15–0.57, I2=72%, n=105). Outcomes of Allo-HSCT for TP53-mutated MDS patients remain poor, with 21% OS at three years; however, Allo-HSCT confers a survival advantage as compared to non-transplant palliative therapies. Our findings suggest the need to explore novel therapeutic agents in prospective clinical trials.
Moving toward a conceptualization of measurable residual disease in myelodysplastic syndromes
2023, Blood Advances
Approximately 90% of patients with myelodysplastic syndromes (MDSs) have somatic mutations that are known or suspected to be oncogenic in the malignant cells. The genetic risk stratification of MDSs has evolved substantially with the introduction of the clinical molecular international prognostic scoring system, which establishes next-generation sequencing at diagnosis as a standard of care. Furthermore, the International Consensus Classification of myeloid neoplasms and acute leukemias has refined the MDS diagnostic criteria with the introduction of a new MDS/acute myeloid leukemia category. Monitoring measurable residual disease (MRD) has historically been used to define remission status, improve relapse prediction, and determine the efficacy of antileukemic drugs in patients with acute and chronic leukemias. However, in contrast to leukemias, assessment of MRD, including tracking of patient-specific mutations, has not yet been formally defined as a biomarker for MDS. This article summarizes current evidence and challenges and provides a conceptual framework for incorporating MRD into the treatment of MDS and future clinical trials.
Clinical Characteristics, Prognosis, and Treatment Strategies of TP53 Mutations in Myelodysplastic Syndromes
2022, Clinical Lymphoma, Myeloma and Leukemia
Citation Excerpt :
As is shown in Figure 1, the initial literature search included 634 articles. After excluding 62 duplicates and other 552 pieces for the reasons of reviews, case reports, animals or cells experiment, and insufficient data, we finally enrolled 20 primary studies compromising 5067 patients in this Analysis.17,18,8,19-23,9,24-33,34 The sample sizes ranged from 39 to 1514, while the frequency of mutations in TP53 ranged from 5.3% to 74.6%.
TP53 gene mutations are common in myelodysplastic syndromes (MDS). Previous studies have reported their detrimental effects on patient survival. However, current treatment strategies mainly based on hypomethylating agent therapy (HMA) and hematopoietic stem cell transplantation (HSCT) still leave a lot to be desired. And there is also a lack of studies on large sample with a view to the refinement of specific characteristics and disease progression. So we performed a meta-analysis including 20 studies compromising 5067 patients to assess the prognostic impact and clinical characteristics of TP53 mutations in MDS patients. The overall hazard ratio for overall survival (OS) was 2.14 (95% confidence interval 1.94-2.37, P < .00001) compared with patients with MDS without TP53 mutations. Lower progression-free survival and leukemia-free survival were associated with TP53 mutations. Subgroup analysis revealed that TP53 mutations were significantly associated with high levels of blast cells and karyotypic aberrations. And among Asian population, the adverse impact on OS of TP53 mutations seemed worse than those in Western countries. (HR 2.87 vs. 2.02, P = .01). In addition, TP53 mutations had no effect on response to HMA therapy, and HSCT improved OS in patients carrying TP53 mutations.
Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myelogenous Leukemia and Myelodysplastic Syndromes with Low/Intermediate but not High Disease Risk Index: A Center for International Blood and Marrow Transplant Research Study
2020, Biology of Blood and Marrow Transplantation
Citation Excerpt :
Owing to an inherent limitation in all retrospective studies, our analysis could not adjust for the clinical decision making factors (eg, specific comorbidities, performance score, disease status, genetic risk) that prompted treating physicians to choose MAC or RIC for each individual study patient. We were unable to adjust for factors such as molecular abnormalities or MRD status that can also affect the risk of relapse and subsequent survival after HCT [5,6,29-36]. However, because no widely used standardized methods for the high-sensitivity quantification of residual disease burden before HCT are yet widely available for patients with AML [5], future studies could prospectively reexamine the role of conditioning intensity on HCT outcomes where both MRD status and molecular genetic risk are considered.
Compared with reduced-intensity conditioning (RIC), myeloablative conditioning (MAC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, disease-specific risk factors in AML/MDS can further inform when MAC and RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the Disease Risk Index (DRI) in 4387 adults (age 40 to 65 years) to identify the impact of conditioning intensity. In the low/intermediate-risk DRI cohort, RIC was associated with lower nonrelapse mortality (NRM) (hazard ratio [HR], .74; 95% confidence interval [CI], .62 to .88; P < .001) but significantly greater relapse risk (HR, 1.54; 95% CI, 1.35 to 1.76; P < .001) and thus inferior disease-free survival (DFS) (HR, 1.19; 95% CI, 1.07 to 1.33; P = .001). In the high/very high-risk DRI cohort, RIC was associated with marginally lower NRM (HR, .83; 95% CI, .68 to 1.00; P = .051) and significantly higher relapse risk (HR, 1.23; 95% CI, 1.08 to 1.41; P = .002), leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for patients with AML/MDS with low/intermediate-risk DRI, but with a similar benefit as RIC in high/very high-risk DRI. Novel MAC regimens with less toxicity could benefit all patients, but more potent antineoplastic approaches are needed for the high/very-high risk DRI group.
Do next-generation sequencing results drive diagnostic and therapeutic decisions in MDS?
2019, Blood Advances
TP53 mutation in allogeneic hematopoietic cell transplantation for de novo myelodysplastic syndrome
2018, Leukemia Research
Citation Excerpt :
However, 21% of the enrolled patients had therapy-related MDS, which prevented the identification of de novo MDS-specific genetic mutations [16]. The other study failed to identify any genetic mutations associated with transplant outcomes, but the sample size was relatively small and the inclusion of therapy-related MDS was not clarified [32]. One recent study investigated the outcomes after allogeneic HCT for therapy-related MDS patients and the authors reported that there was no survival difference according to the presence or absence of TP53 mutation [33].
We investigated the prognostic role of somatic mutations in allogeneic hematopoietic cell transplantation (HCT) for de novo myelodysplastic syndrome (MDS). We performed targeted deep sequencing analysis of 26 genes on bone marrow samples obtained within 6 weeks before HCT from 202 patients with de novo MDS. Overall, 76% of patients carried one or more somatic mutations, and TP53 mutation was present in 23 patients (11.4%). Overall survival (OS) at 5 years was 63.6%, cumulative incidence of relapse (CIR) was 18.6%, event-free survival (EFS) was 58.5%, and non-relapse mortality (NRM) was 22.9%. TP53 mutation was an independent risk factor for lower OS (41% vs. 67%; P = 0.001), higher CIR (49% vs. 15%; P = 0.001), and lower EFS (38% vs. 61%; P = 0.005), but not for NRM (13% vs. 24%). N-RAS mutation was an independent risk factor for higher CIR (HR, 5.91; P = 0.008). TP53 mutation did not have significant interactions with conditioning intensity or the occurrence of graft-versus-host disease with regard to post-transplant outcomes. In conclusion, TP53 mutation was significantly associated with poor outcomes after HCT for patients with de novo MDS, mainly due to a higher incidence of disease relapse.

View all citing articles on Scopus

: This study was presented in part at the 57th annual meeting of the American Society of Hematology on December 7, 2015 (abstract 4382).

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Original StudyTP53 and IDH2 Somatic Mutations Are Associated With Inferior Overall Survival After Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Patient and Treatment Characteristics

Patient, Disease, and Transplant-Related Characteristics

Discussion

Conclusion

Disclosure

Acknowledgments

Blood

Lancet Oncol

Blood

Blood

Blood

Biol Blood Marrow Transplant

Ann Oncol

Blood

Biol Blood Marrow Transplant

Leuk Res

Clinical effect of point mutations in myelodysplastic syndromes

N Engl J Med

Timing of allogeneic stem cell transplantation for myelodysplastic syndromes and aplastic anemia

Hematology Am Soc Hematol Educ Program

Hematopoietic cell transplantation for myelodysplastic syndrome

Am Soc Clin Oncol Educ Book

Original Study
TP53 and IDH2 Somatic Mutations Are Associated With Inferior Overall Survival After Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome