Clinical Significance Of SF3B1, U2AF1 and SRSF2 Spliceosomal Gene Mutations For The Treatment Of Hypomethylating Agents In Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2802-2802
Author(s):  
Jae-Sook Ahn ◽  
Hye-Ran Kim ◽  
Hyeoung-Joon Kim ◽  
Yeo-Kyeoung Kim ◽  
Sung-Hoon Jung ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Gene Mutation ◽  
Clinical Features ◽  
Somatic Mutations ◽  
Splicing Factor ◽  
Hypomethylating Agents ◽  
Wild Type ◽  
Leukemic Transformation ◽  
Treatment Indications

Abstract Background Many reports state that hematopoietic malignancies mostly result from somatic mutations in HSCs in the bone marrow. Somatic mutations of spliceosomal gene such as SF3B1, U2AF1 and SRSF2 have been widely described in myelodysplastic syndrome (MDS). Some studies presented that MDS patient with splicing factor mutations influence the clinical outcomes. However, the clinical significances for the treatment of hypomethylating agents (HMA) in splicing factor mutation were not reported. Therefore, this study investigated the influences of the SF3B1, U2AF1 and SRSF2 splice gene mutation in MDS patients who received the HMAs. Materials and Methods MDS harboring ring sideroblast and association with somatic spliceosomal gene mutation was well demonstrated but, comparatively rare and showed good prognosis. So, we excluded MDS harboring ring sideroblast in this study. The study cohort of 133 MDS patients without harboring ring sideroblast was examined for somatic mutations in SF3B1, U2AF1 and SRSF2 splicing gene using direct sequencing method and 59 out of 133 patients received the treatment of HMAs (43 of Azacitidine and 16 of decitabine) for the treatment of MDS. Using the international prognostic scoring system(IPSS), the treatment indications for the HMA were as follows, 1) inermediate-1 with anemia and no response for the treatment of erythropoietin, 2) intermediate-1 with anemia accompanying other cytopenia ( neutrophil <1,000/uL or PLT <100,000/uL), 3) intermediate-2 or high risk. The response analysis was followed the modified IWG MDS response criteria. Results In 59 patients, mutations in K700E of SF3B1; S34T, S34P or Q157P of U2AF1; P95H or P95R of SRSF2 were found in 6 (10.2%), 7 (11.8%), and 4 (6.8%) patients, respectively. The 17 patients were observed any mutation (SF3B1, U2AF1 or SRSF2) in 59 patients. We compared the clinical features, treatment responses and survivals according to the somatic mutations of spliceosomal gene vs wild type (WT) in each mutation. The disease composition of 59 patients was like as follows; 1 of MDS with del(5q), 6 of RCUD, 24 of RCMD, 9 of RAEB-1, 19 of RAEB-2. In the clinical features, lower risk (according to IPSS, WPSS and revised-IPSS) patients was included in the group with SF3B1 mutation (P<0.05). The hematologic improvement or more response for the HMA was observed in 33% vs 47% in SF3B1 mutation vs WT, 29% vs 48% in U2AF1 and 75% vs 44% in SRSF2, respectively. There was no difference in the response rates for the HMA therapy according to the mutation or wild type (P>0.05). Overall survival did not show the statistical differences in each mutation (P>0.05). The leukemia free survival in patients with SRSF2 mutation was inferior to the WT (p=0.001). However, anyone showed the leukemic transformation in the patients with SF3B1 mutation without statistical significance (p=0.247) (Fig. 1). Conclusion Our results show that mutation of SF3B1, U2AF1 and SRSF2 spliceosomal gene in MDS patients without harboring ring sideroblast did not influence the treatment response and overall survival for the HMAs. However, alteration of SRSF2 splice gene may be regarded as a risk factor of leukemic transformation. So, the patients with SRSF2 mutation treated with HMA have to consider the aggressive therapy such as allogeneic stem cell transplantation before leukemic transformation. To confirm this result, it will be needed more study for large number of patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

2021 ◽  
Vol 22 (19) ◽  
pp. 10232
Author(s):  
Paul Lee ◽  
Rita Yim ◽  
Yammy Yung ◽  
Hiu-Tung Chu ◽  
Pui-Kwan Yip ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Molecular Targeted Therapy ◽  
Somatic Mutations ◽  
Standard Of Care ◽  
Hypomethylating Agents ◽  
Mechanisms Of Resistance ◽  
Leukemic Transformation ◽  
Combinational Therapies

Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40–60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance.

Clinical Features and Prognosis of MDS Patients with Chromosome 5 Abnormalities Other Than ‘5q-Syndrome’: Results of Multi-Center Analysis in Korea.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4618-4618
Author(s):  
June-Won Cheong ◽  
Inho Kim ◽  
Sung-Soo Yoon ◽  
Dong Soon Lee ◽  
Chul Won Jung ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Features ◽  
Chromosomal Abnormalities ◽  
Normal Chromosome ◽  
Retrospective Evaluation ◽  
Chromosome 5 ◽  
Good Responder ◽  
Mosaic Pattern ◽  
Leukemic Transformation ◽  
5Q Deletion

Abstract Introduction: The myelodysplastic syndrome (MDS) is frequently associated with various chromosomal abnormalities. ‘5q− syndrome’ is low-risk MDS known as good responder of lenalidomide recently. However, the patients with other abnormalities in chromosome 5 showed quite different clinical features from those with ‘5q− syndrome’. The aim of this study was a retrospective evaluation for Korean MDS patients with abnormalities in chromosome 5 other than ‘5q− syndrome’. Materials and Methods: Among 456 patients with MDS diagnosed at 16 hospitals in Korea between 1996 and 2006, 370 with available cytogenetic data entered the study. Univariate and multivariate analysis were performed. Results: Ninety three patients (25.1%) showed abnormalities in chromosome 5 and the ‘5q− syndorme’ was only 10 patients (2.7%). Among the rest, 39 patients (10.5%) had various abnormalities other than 5q deletion such as translocation or 5 monosomy, 38 (10.3%) had complex abnormalities with 5q−, and 2 had mosaic pattern with normal chromosome. Four patients had isolated 5q− but blasts in marrow were over 5%. The deletion of 5q was interstitial but with a predominance for 5q13-33 deletions (34.8%). MDS patients with chromosome 5 abnormalities other than ‘5q− syndrome’ didn’t share the clinical features with ‘5q− syndrome’. There was no leukemic transformation in ‘5q− syndrome’ group, but 18 (21.7%) with other abnormalities in chromosome 5 finally transformed to acute leukemia. Five year overall survival was significantly inferior in non-’5q− syndrome’ patients than ‘5q− syndrome’ (14.3% vs. 79.6%, P=0.0115). Conclusions: Patients with isolated 5q− and excess blast (>5%), other abnormalities than isolated 5q−, or mosaic chromosome with isolated 5q− and normal chromosome didn’t share the clinical features such as lower rate of leukemic transformation and long survival.

Genetic Polymorphism of Cytochrome P450 1B1 (C432G) Is Associated with An Increased Treatment-Related Mortality and Lower Overall Survival in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3287-3287
Author(s):  
Michael Koldehoff ◽  
Ahmet H. Elmaagacli ◽  
Dietrich W. Beelen
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Gene Mutation ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Cytochrome P450 1B1 ◽  
Genotype C ◽  
Type Gene ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Background. The human cytochrome P450 1B1 (CYP 1B1) is a key enzyme involved in the production of reactive metabolites and in the activation of environmental carcinogens. Several polymorphisms were identified in CYP 1B1 gene; four of them are single nucleotide polymorphisms and give rise to amino acidic substitutions. The CYP 1B1 codon 432 polymorphism leads to a three-fold higher 4-hydroxylase activity for the variant CYP 1B1 isozymes than the wild types. Never before the influence of genetic polymorphisms of CYP 1B1 (C432G) on patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT), was evaluated. Methods. Here we genotyped in a retrospective study 384 recipients (R) (and their donors (D)) for CYP 1B1 (C432G) expression that underwent allogeneic HSCT for various diseases and analyzed their outcome. Genotyping of CYP 1B1 (C432G) was performed by real-time PCR. Results. 170 R (44.3%) were genotyped as homozygous wild-type gene C/C, 157 R (40.9%) were genotyped as heterozygous genotype C/G and 57 R (14.8%) were genotype as homozygous gene mutation G/G. From the 167 D (43.5%) were C/C, 164 D (42.7%) were C/G, and 53 D (13.8%) had a homozygous gene mutation G/G. A homozygous CYP 1B1 gene mutation G/G was found on 18 R/D side (4.7%). Calculated genotype frequencies did not differ from that reported earlier by other studies for Caucasians. Five-year estimate for treatment-related mortality (TRM) and overall survival (OS) were statistically different in genotype C/G- and G/G- R with 33 ± 4%, and 49 ± 4% compared to homozygous wild-type gene C/C- R (18 ± 3%, and 59 ± 4%, respectively, [p<0.03]), whereas the five-year estimate for relapse rate (RR) was not different between the groups. No differences for five-year estimates for TRM, RR, or OS were seen in R with either genotype C/C-, C/G- or G/G- D. No statistic differences were found in the incidence of acute GVHD grade 2–4 on R- or on D- side with variant CYP 1B1 (C432G) polymorphisms. Surprisingly, the five-year estimate for TRM, RR, and OS were statistically different in homozygous gene mutation G/G on R/D site with 57 ± 2%, 81 ± 2%, and 16 ± 1% compared to all other CYP 1B1 genotypes with 28 ± 3%, 26 ± 2%, and 55 ± 3%, respectively [TRM, p<0.01; RR and OS, p<0.001]). Multivariate analysis confirmed that CYP 1B1 (C432G) homozygous gene mutation G/G on R/D site had an increased risk for TRM and RR (p<0.02), whereas the mutation G/G on R/D site revealed a worse OS (p<0.01). Conclusions. These results suggest that recipients with genetic polymorphism of CYP 1B1 do have an increased TRM, RR and lower OS after transplantation. Genotyping for CYP 1B1 (C432G) might help to identify patients with higher risk for allogeneic transplantation.

Lenalidomide As a Second-Line Therapy after Failure of Hypomethylating Agents in Patients with Myelodysplastic Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1687-1687 ◽  
Author(s):  
Hawk Kim ◽  
Je-Hwan Lee ◽  
Won-Sik Lee ◽  
Inho Kim ◽  
Joon Ho Moon ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Who Classification ◽  
Median Overall Survival ◽  
Hematopoietic Cell Transplantation ◽  
Objective Response ◽  
Primary Objective ◽  
Hypomethylating Agents ◽  
5Q Deletion

Abstract Background: There is no standard therapy after the failure of hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) without only providing supportive cares including transfusion or cytokine therapies when the patient is not eligible for allogeneic hematopoietic cell transplantation. Lenalidomide is the treatment of choice in case of MDS with 5q deletion. A study of lenalidomide for non-5q deletion MDS patients showed that transfusion independency rate was 26% which was relatively acceptable and suggested that lenalidomide could be used for non-5q deletion MDS patients. Method: We conducted the prospective phase II trial to evaluate the efficacy of lenalidomide for patients who failed to HMA (ClinicalTrials.gov Identifier: NCT01673308). Patients took lenalidomide 10mg daily for 3 weeks and rested for a week. New cycle began every 4 weeks. The primary objective was the objective response rate (ORR; CR+PR+marrow CR+HI). Unknown or not evaluable response were regarded as failure. The planed sample size was 29 (P0: 10%, P1: 30%, α-error:0.5, β-error:0.2) patients. The major inclusion criteria were adult MDS by WHO classification and they should be treatment failure after HMAs (azacitidine or decitabine) which were defined as either intolerant to HMAs or progressive disease after HMA. Results: Total 31 patients were included in this analysis. Among them, 1 patient didn't receive study drug at all. Male was 21 (67.7%) patients. Median age was 68 (range 40-82) years. Reasons for stopping HMA were no response in 10, progression in 14, adverse events in 3 and other causes in 4 patients. WHO classification was follows; RA in 4, RARS in 1, RCMD in 8, RAEB-1 in 4, RAEB-2 in 8, MDS with 5q deletion in 2 and not known in 4 patients. IPSS at study enrollment were low (n=4), INT-1 (n=12), INT-2 (n=9), high risk (n=3) and unknown (n=3) risk. Revised IPSS were very low (n=3), low (n=3), intermediate (n=5), poor (n=2), very poor (n=8) and unknown risk (n=3). Median cycles of lenalidomide was 3 (range 0-21). The responses after 4 cycles were CR in 5, PR in 2, SD in 5, failure in 12, unknown in 7 patients. The maximal responses were CR in 5, marrow CR in 1, PR in 4, HI-E in 1, SD in 5, failure in 14 patients. Best ORR was 11/31 (35.5%) patients, with 16/31 receiving clinical benefit (52%, inclusive of SD). The toxicity profile was tolerable except for hematological toxicities including neutropenia and thrombocytopenia. Among 2 patients with 5q deletion, 1 patient achieved CR but 1 patient failed. Median overall survival was 8.936 (95% CI 0.0-19.685) months which compares with a historical estimate in HMA failures of 4.3-5.6 months. Two patients received alloHCT after progression or failure to lenalidomide. Causes of death were infection (n=8) and bleeding (n=1). Patients who failed to benefit from lenalidomide showed significantly poorer survival when comparing with patients who achieved ORR or SD (median overall survival 2.990 vs. 17.774 months; p=0.010). Among 17 patients who had achieved ORR or SD, 6 patients didn't progress while 8 patients progressed and 3 patients were lost to follow up. Conclusion: Lenalidomide showed reasonable response and excellent overall survival after failure of HMA in adult MDS with tolerable toxicities. Therefore, lenalidomide can be a promising option after failure of HMA even in non-5q deletion MDS. Disclosures Kim: Alexion Pharmaceuticals: Research Funding; Celgene: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

scholarly journals Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia

2018 ◽  
Vol 2 (21) ◽  
pp. 2937-2946 ◽  
Author(s):  
Zachary R. Hunter ◽  
Lian Xu ◽  
Nickolas Tsakmaklis ◽  
Maria G. Demos ◽  
Amanda Kofides ◽  
...  
Keyword(s):  
Dna Damage ◽  
Overall Survival ◽  
Somatic Mutations ◽  
Morphological Characteristics ◽  
B Cell Lymphoma ◽  
Wild Type ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Increased Risk ◽  
The Many

Abstract Activating MYD88 mutations are present in 95% of Waldenström macroglobulinemia (WM) patients, and trigger NF-κB through BTK and IRAK. The BTK inhibitor ibrutinib is active in MYD88-mutated (MYD88MUT) WM patients, but shows lower activity in MYD88 wild-type (MYD88WT) disease. MYD88WT patients also show shorter overall survival, and increased risk of disease transformation in some series. The genomic basis for these findings remains to be clarified. We performed whole exome and transcriptome sequencing of sorted tumor samples from 18 MYD88WT patients and compared findings with WM patients with MYD88MUT disease. We identified somatic mutations predicted to activate NF-κB (TBL1XR1, PTPN13, MALT1, BCL10, NFKB2, NFKBIB, NFKBIZ, and UDRL1F), impart epigenomic dysregulation (KMT2D, KMT2C, and KDM6A), or impair DNA damage repair (TP53, ATM, and TRRAP). Predicted NF-κB activating mutations were downstream of BTK and IRAK, and many overlapped with somatic mutations found in diffuse large B-cell lymphoma. A distinctive transcriptional profile in MYD88WT WM was identified, although most differentially expressed genes overlapped with MYD88MUT WM consistent with the many clinical and morphological characteristics that are shared by these WM subgroups. Overall survival was adversely affected by mutations in DNA damage response in MYD88WT WM patients. The findings depict genomic and transcriptional events associated with MYD88WT WM and provide mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population.

scholarly journals microRNA-22 and TET-2 Mutation in Myelodysplastic Syndrome Patients Treated with Hypomethylating Agents

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5127-5127
Author(s):  
Seong Kyu Park ◽  
Se Hyung Kim ◽  
Sung Hee Lim ◽  
Chan Kyu Kim ◽  
Jong-Ho Won ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Lower Risk ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Hypomethylating Agents ◽  
Poor Survival ◽  
Leukemic Transformation ◽  
Clinical Role ◽  
Aberrant Expression ◽  
Tet2 Mutation

Abstract Background: MicroRNAs are small RNA species that regulate gene expression post-transcriptionally and are aberrantly expressed in many cancers including hematological malignancies. Some reports suggested that aberrations in the miR-22-TET2 regulatory network are common in myelodysplastic syndrome (MDS) and leukemia, and its aberrant expression correlates with poor survival. We attempted to identify the clinical role of miR-22 and TET-2 in patients with myelodysplastic syndrome. Materials and Methods: A total of 41 MDS patients who treated with hypomethylating agents were recruited. Real time RT-PCR was performed to assess the expression levels of miR-22 and TET-2 mutation in bone marrow samples at the time of diagnosis. And we investigated the relationship between its results and clinical outcomes. Results: TET2 mutation frequency in the higher risk group based the IPSS and IPSS-R was lower than that of lower risk group (11.1% vs 38.1%). miR22 expression was also down-regulated in higher risk group (higher risk: 1.70 ± 0.96 vs lower risk: 3.14 ± 1.38, p=0.006). TET2 mutation seemed to be different according to the responsiveness to hypomethylating agents. TET2 mutation, IPSS, and IPSS-R were significantly associated with the risk of leukemic transformation. Patients with an decreased value in the consecutive assessment of miR-22 at the time of diagnosis and 3 months after initial treatment tended to be associated with poor survival outcome (survival rate at 3 years: 18.2% vs 35.1% for patients with an increase, p=0.168). Prognostic factors for survival included TET-2 mutation, cytogenetics, IPSS or IPSS-R, and leukemic transformation. Conclusion: miR-22 expression and TET2 mutation had a clinical impact on outcomes in MDS patients treated with hypomethylating agents. And these biomarkers might have a potential as a prognostic factor for MDS patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals NFE2 Mutations Impact AML Transformation and Overall Survival in Patients with Myeloproliferative Neoplasms (MPN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Clemence Marcault ◽  
Lin-Pierre Zhao ◽  
Rafael Daltro De Oliveira ◽  
Juliette Soret ◽  
Nicolas Gauthier ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Somatic Mutations ◽  
Response To Therapy ◽  
Age At Diagnosis ◽  
Prognostic Impact ◽  
Leukemic Transformation ◽  
Advisory Committees ◽  
Increased Risk

Introduction: MPN are a heterogeneous group of chronic hematological malignancies often resulting from a combination of a driver gene mutation (JAK2, MPL or CALR) and a variety of somatic mutations harboring diverse prognosis values. A subset of MPN patients carry somatic mutations in the hematopoietic transcription factor NFE2 (nuclear factor erythroid 2) resulting in a functionally enhanced truncated form of NFE2 (Jutzi JS et al., JEM, 2013). Moreover, epigenetically induced overexpression of NFE2 has recently been reported in the majority of MPN patients (Peeken JC et al., Blood, 2018). In transgenic murine models, NFE2 overexpression results in an MPN phenotype (thrombocytosis, leukocytosis, EPO-independent colony formation, characteristic bone marrow histology and expansion of stem and progenitor compartments) and has recently been shown to predispose to the acquisition of additional genetic abnormalities and subsequent leukemic transformation (Kaufmann KB et al., JEM, 2012) (Jutzi JS et al., Blood, 2019). However, clinical impact of NFE2 mutations in MPN patients remains unknown. The aim of this study was to evaluate the phenotypic characteristics and prognostic impact of NFE2 somatic mutations in a large mono-centric cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and May 2020. This study included 707 of them in whom a next-generation sequencing (NGS) molecular analysis targeting 36 myeloid genes was performed at diagnosis and/or during follow-up. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Statistical analyses were performed using the STATA software (STATA 15.0 Corporation, College Station, TX). Results: In our cohort, 411 patients presented with polycythemia vera (PV), 577 with essential thrombocythemia (ET), 184 with primary or pre-fibrotic myelofibrosis (PMF), 59 with unclassified MPN and 12 with MDS/MPN. Median age at diagnosis was 51 years [40-63]. 73.1% patients had a JAK2V617F mutation, 14.1% a CALR mutation and 3.3% a MPL mutation. Overall, 64 (9.05%) patients harbored a NFE2 mutation with a variant allelic frequency (VAF) ≥ 0.5% and 36 had a VAF ≥ 5%, the latest were considered as NFE2 mutated for the rest of the study as VAF &lt;5% may refer to a minor clone without clinical relevance. NFE2 mutations were present in 7.3%, 5.3% and 3.6% of PV, PMF and ET patients respectively. No significant association between the presence of NFE2 mutation and clinical/molecular MPN characteristics (driver mutation, constitutional symptoms, splenomegaly, blood counts, cytogenetic and other molecular features) was observed using a logistic regression association model. Median follow-up was 103.8 months, IQR [47.2; 175.6]. In terms of response to therapy, 52.8% of patients achieved complete response, complete hematological response or clinical improvement in NFE2 mutated vs 61.7% in non-mutated patients (p= 0.026). Interestingly, presence of a NFE2 mutation (HR 9.92, 95%CI[3.21; 30.64], p&lt; 0.001), age at diagnosis (HR 1.09, 95%CI[1.05; 1.12], p&lt; 0.001), PMF subtype (HR 6.92, 95%CI[2.81; 17.06], p &lt; 0.001) and high-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1) (HR 2.45, 95%CI[1.14; 5.28], p=0.021) were independently associated with AML/MDS transformation free survival (TFS) in a COX regression multivariate analysis (Figure A). Presence of a NFE2 mutation was also independently associated with overall survival (OS) (HR 9.37, 95%CI [4.18; 21.03], p&lt;0.001) (Figure B). Median TFS were 216.1 months and not reached, while median OS were 144.2 months and not reached for NFE2 mutated and non-mutated patients, respectively. No difference was observed in terms of thrombo-hemorrhagic events (HR 0.73; 95%CI [0.10; 5.21], p=0.752) and secondary myelofibrosis free survivals (HR 0.67; 95%CI [0.09; 4.87], p=0.693). Conclusion: In this retrospective study we show that presence of NFE2 mutations with a VAF ≥5% is independently associated with an increased risk of leukemic transformation and shorter overall survival. These findings are in line with recently reported animal models and suggest that NFE2 mutations screening should be routinely performed in MPN patients. Disclosures Rea: Incyte: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

scholarly journals TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients

Blood ◽  
2014 ◽  
Vol 124 (17) ◽  
pp. 2705-2712 ◽  
Author(s):  
Rafael Bejar ◽  
Allegra Lord ◽  
Kristen Stevenson ◽  
Michal Bar-Natan ◽  
Albert Pérez-Ladaga ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Hypomethylating Agents ◽  
Hypomethylating Agent ◽  
Key Points ◽  
Agent Treatment

Key Points Higher abundance TET2 mutations are associated with increased response to hypomethylating agents, particularly when ASXL1 is not mutated. TP53 and PTPN11 mutations are associated with shorter overall survival after hypomethylating agent treatment, but do not predict response.

scholarly journals Impact of splicing mutations in acute myeloid leukemia treated with hypomethylating agents combined with venetoclax

2021 ◽  
Vol 5 (8) ◽  
pp. 2173-2183
Author(s):  
Curtis A. Lachowiez ◽  
Sanam Loghavi ◽  
Ken Furudate ◽  
Guillermo Montalban-Bravo ◽  
Abhishek Maiti ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cohort Analysis ◽  
Cancer Center ◽  
Hypomethylating Agents ◽  
Wild Type ◽  
The Impact ◽  
Acute Myeloid

Abstract Spliceosome mutations (SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary acute myeloid leukemia cases (sAML) and define a molecular subgroup with outcomes similar to sAML in de novo AML patients treated with intensive chemotherapy. Outcomes in patients with spliceosome mutations treated with hypomethylating agents in combination with venetoclax (HMA+VEN) remains unknown. The primary objective was to compare outcomes in patients with spliceosome mutations vs wild-type patients treated with HMA+VEN. Secondary objectives included analysis of the mutational landscape of the spliceosome cohort and assessing the impact of co-occurring mutations. We performed a retrospective cohort analysis of patients treated with HMA+VEN–based regimens at The University of Texas MD Anderson Cancer Center. A total of 119 patients (spliceosome mutated n = 39 [SRSF2, n = 24; SF3B1, n = 8; U2AF1, n = 7]; wild-type, n = 80) were included. Similar responses were observed between spliceosome and wild-type cohorts for composite complete response (CRc; 79% vs 75%, P = .65), and measurable residual disease–negative CRc (48% vs 60%, P = .34). Median overall survival for spliceosome vs wild-type patients was 35 vs 14 months (P = .58), and was not reached; 35 months and 8 months for patients with SRSF2, SF3B1, and U2AF1 mutations, respectively. IDH2 mutations were enriched in patients with SRSF2 mutations and associated with favorable outcomes (1- and 2-year overall survival [OS] of 100% and 88%). RAS mutations were enriched in patients with U2AF1 mutations and associated with inferior outcomes (median OS, 8 months). Comparable outcomes were observed between patients with vs without spliceosome mutations treated with HMA+VEN regimens, with specific co-mutation pairs demonstrating favorable outcomes.

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