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

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.

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TET2 Mutation and High miR-22 Expression as Biomarkers to Predict Clinical Outcome in Myelodysplastic Syndrome Patients Treated with Hypomethylating Therapy

Current Issues in Molecular Biology ◽

10.3390/cimb43020065 ◽

2021 ◽

Vol 43 (2) ◽

pp. 917-931

Author(s):

Jina Yun ◽

Young Sok Ji ◽

Geum Ha Jang ◽

Sung Hee Lim ◽

Se Hyung Kim ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Odds Ratio ◽

Lower Risk ◽

Genetic Mutations ◽

Dna Hypermethylation ◽

Leukemic Transformation ◽

Mutation Status ◽

Similar Tendency ◽

Tet2 Mutation ◽

Expression Status

Tet methylcytosine dioxygenase 2 (TET2) is one of the most frequently mutated genes in myelodysplastic syndrome (MDS). TET2 is known to involve a demethylation process, and the loss of TET2 is thought to cause DNA hypermethylation. Loss of TET2 function is known to be caused by genetic mutations and miRNA, such as miR-22. We analyzed 41 MDS patients receiving hypomethylating therapy (HMT) to assess whether TET2 mutation status and miR-22 expression status were associated with their clinical characteristics and treatment outcomes. Responsiveness to HMT was not affected by both TET2 mutation (odds ratio (OR) 0.900, p = 0.909) and high miR-22 expression (OR 1.548, p = 0.631). There was a tendency for TET2 mutation to be associated with lower-risk disease based on IPSS (Gamma = −0.674, p = 0.073), lower leukemic transformation (OR 0.170, p = 0.040) and longer survival (Hazard ratio 0.354, p = 0.059). Although high miR-22 expression also showed a similar tendency, this tendency was weaker than that of TET2 mutation. In summary, the loss of TET2 function, including both TET2 mutation and high miR-22 expression, was not a good biomarker for predicting the response to HMT but may be associated with lower-risk disease based on IPSS, lower leukemic transformation and longer survival.

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High Residual Allelic Burden Increases Leukemic Transformation Irrespective of Clinical Response in Patients with Lower Risk Myelodysplastic Syndrome Treated with Azacitidine

Blood ◽

10.1182/blood-2019-130428 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4263-4263

Author(s):

Joon Ho Moon ◽

Hee Jeong Cho ◽

Dong Won Baek ◽

Sang Kyun Sohn ◽

Jae-Sook Ahn ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Clinical Response ◽

Cumulative Incidence ◽

Lower Risk ◽

Conflicts Of Interest ◽

Rank Test ◽

Leukemic Transformation ◽

Mutation Group ◽

Allelic Burden

Background: Hypomethylating agents (HMAs) are used to treat patients with lower-risk myelodysplastic syndrome (LR-MDS) relapsing after the use of hematopoietic cytokines or presenting initially with more than two lineages of cytopenias. However, the significance of underlying genetics and allelic burden changes after HMAs are still under investigation. This study investigated the effects of allelic burden changes on the long-term outcomes in LR-MDS patients treated with HMAs. Methods: This study included 61 patients with LR-MDS treated with azacitidine. Bone marrow samples were taken at diagnosis and follow-up after median 4 cycles. Targeted deep sequencing on a custom myeloid gene panel of 84 genes (Agilent SureSelect) was performed on trios of T-cell, pre-HMA, and post-HMA samples on 61 LR-MDS patients. Patients were divided into groups according to the post-HMA variant allele frequency (VAF): low-VAF (< 2%), high-VAF (≥ 2%), and no-mutation group (absence of mutations at diagnosis and follow-up). Overall survival (OS) was defined as the time from the azacitidine treatment until death from any cause, which was analyzed using the Kaplan-Meier method and the groups were compared using the log-rank test. The cumulative incidence of AML was calculated using the Gray method, considering death without AML as a competing risk. Fine-Gray proportional hazard regression with a competing event was used to identify risk factors for the incidence of AML. Results: Median age was 67 years (range 31-81), and 41 patients (67%) were male. IPSS risk group were low in 2 patients (3%) and intermediate-1 in 59 (97%). At diagnosis, 38 patients harbored at least one mutation. Most frequently mutated genes were ASXL1 (n=11, 18%), TET2 (n=10, 16%), and SRSF2 (n=7, 11%) followed by RUNX1, SF3B1, U2AF1, IDH2, and DNMT3A. Azacitidine was administered median 8 cycles (range 2-44). The overall response (CR, PR, HI) was achieved in 18 patients (30%). With median follow-up duration of 31 months (range 4.7-135 months), leukemic transformation occurred in 11 patients (18%). Mutational allelic burdens were decreased from median 20.9% (range 0.1-67.2) to 11.0% (range 0.0-74.9%). At follow-up, 5 patients were low-VAF group and 33 were high-VAF group. OS rate was not different between the low-VAF and high-VAF group (50% vs 46% at 3 years; p=0.80). Three-year cumulative incidence of AML was higher in high-VAF group compared to low-VAF (0%) and no-mutation group (4.8%, p=0.02). However, non-leukemic mortality was higher in low-VAF group than no-mutation group (60% vs 23%, p=0.09), which explains similar OS rate between low-VAF and high-VAF group. In the multivariate analysis, high-VAF was an independent predictive factor for an AML transformation in LR-MDS patients treated with azacitidine (HR 5.20, p=0.04). Conclusion: The current study showed that the high residual allelic burden is associated with an increased AML transformation in LR-MDS patients treated with azacitidine, irrespective of the clinical response. The higher non-leukemic mortality explains inferior OS in low-VAF group compared to no-mutation group. Figure Disclosures No relevant conflicts of interest to declare.

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Role Of Hypomethylating Agents For Patients With Lower-Risk Myelodysplastic Syndrome Defined By IPSS and IPSS-R

Blood ◽

10.1182/blood.v122.21.2782.2782 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2782-2782

Author(s):

Joon Ho Moon ◽

Sang Kyun Sohn ◽

Jae Sook Ahn ◽

Yeo-Kyeoung Kim ◽

Hyeoung Joon Kim ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Lower Risk ◽

Conflicts Of Interest ◽

Risk Groups ◽

International Prognostic Scoring System ◽

Hypomethylating Agents ◽

Risk Patients ◽

Very High ◽

Prognostic Power

Abstract Background International Prognostic Scoring System (IPSS) is commonly used to distinguish various subgroups of myelodysplastic syndrome (MDS) patients with different prognosis and to make a therapeutic decision. However, the classic IPSS, defining lower-risk as low and intermediate-1 IPSS, seems to be insufficient to discriminate the prognostic groups of lower-risk MDS. Recently, IPSS was updated into the revised score (IPSS-R) to refine the IPSS by reassessing the major predictive features of MDS. The hypomethylating agents (HMA) are usually recommended for patients with lower-risk MDS who is not responsive to other therapies. However the role of HMA for the patients with lower-risk IPSS are still on debate. This study was conducted to find the rationale to treat HMA for the patients with lower-risk IPSS and to know whether IPSS-R further discriminate the prognosis of patients treated with HMA. Methods The data of 334 patients diagnosed with MDS lower-risk defined by IPSS after Jan 2006 were retrospectively reviewed. Lower-risk IPSS was revised into IPSS-R to know whether it could further discriminate the prognosis of this group of patients. The prognosis of lower-risk by IPSS and IPSS-R were analyzed in terms of overall survival (OS) and prognostic power was calculated with time-dependent Cox-hazard models. To define the role of HMA for patients with lower-risk IPSS, we categorized the lower risk patients into No-HMA group, early HMA group (HMA within 2 mo.), and late HMA group (HMA after 2 mo). Results Out of 334 lower-risk patients (39 low and 295 intermediate-1), 195 patients (58.4%) were treated with HMA (azacitidine 163, decitabine 32). Median time to HMA treatment was 43 days (range 0-1778 days). 3yr-OS rate was not significantly different between HMA group (43.1¡¾4.2%) and non-HMA group (62.3¡¾5.9%) (p=0.099). Early HMA treatment (3yr-OS 36.4¡¾5.4%) didn't show survival benefits compared to late HMA group (54.6¡¾6.3%) or no-HMA group (62.3¡¾5.9%) (p=0.003). Plus, HMA response (CR/PR/HI) didn't guarantee OS benefits: 3yr-OS of 45.2¡¾7.4% in responders (CR/PR/HI, n=74) and 43.4¡¾5.0 in non-responders (SD/PD, n=121) (p=0.239). Among 39 patients with IPSS low, 11 patients (28.2%) were revised into IPSS-R very low, 24 (61.5%) into low, 3 (7.7%) into intermediate, and 1 (2.6%) into high. Among 295 patients with IPSS intermediate-1, 4 patients (1.4%) were revised into IPSS-R very low, 84 (28.5%) into low, 133 (45.1%) into intermediate, 71 (24.1%) into high and 3 (1.0%) into very high. IPSS-R could further discriminate the IPSS lower-risk patients with regard to OS: 3yr-OS rates of 100% in very low, 64.5¡¾5.9% in low, 46.1¡¾5.5% in intermediate, 26.1¡¾6.6% in high, and 0% in very high (p<0.001). The survival benefits of HMA for lower risk groups (very low and low) defined by IPSS-R (n=123) was not defined in the current study, where 3yr-OS was 83.8¡¾6.4% in no-HMA group (n=60) vs. 60.5¡¾7.1% in HMA group (n=63) (p=0.198). Conclusion The prognosis of the patients with lower-risk IPSS (low and intermediate-1) were successfully refined by IPSS-R. The IPSS intermediate-1 risk was heterogeneous group, which subdivided into very low to very high by IPSS-R. However, the beneficial effect of HMA for patients with lower-risk MDS, defined by IPSS (low and intermedite-1) and IPSS-R (very low and low), should be elucidated in the future studies. Disclosures: No relevant conflicts of interest to declare.

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Survival Advantage with Hypomethylating Agents In Patients with Higher Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v116.21.1859.1859 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1859-1859

Author(s):

Young-Hoon Park ◽

Je-Hwan Lee ◽

Kyoo Hyung Lee ◽

Jung-Hee Lee ◽

Dae-Young Kim ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Survival Data ◽

Lower Risk ◽

Conflicts Of Interest ◽

Cox Model ◽

Immunosuppressive Treatment ◽

Complete Response ◽

Risk Category ◽

Hypomethylating Agents ◽

Treatment Groups

Abstract Abstract 1859 Background: Two hypomethylating agents, azacitidine and decitabine, are active in myelodysplastic syndrome (MDS) and both drugs have been approved for the treatment of MDS in Korea. In this retrospective analysis, we tried to analyze the effects of hypomethylating agents on the clinical outcomes of the patients with MDS. Methods: A total of 385 patients, who were diagnosed as MDS at the Asan Medical Center between July 1992 and March 2010, were included in this study. We divided the patients into three treatment groups such as hypomethylating therapy (HMT, n=92), intensive chemotherapy (IC, n=15), and supportive care (including low-dose cytarabine and immunosuppressive treatment, SC, n=278). Primary end points of this study were overall survival (OS) and progression-free survival (PFS). PFS was defined as time from diagnosis to AML progression or death. All survival data were censored at the time of hematopoietic cell transplantation (HCT) to eliminate the influence of HCT on survivals. The difference of survivals was compared using time updated Cox model because times from diagnosis of MDS to treatment (HMT or IC) were various. Results: Baseline clinico-laboratory features were not significantly different between 3 treatment groups (HMT vs. IC vs. SC) in regard to sex, age, WHO subtype, and IPSS risk category. Among 83 patients in the HMT group, 39 (47.0%) attained any response to HMT including complete response, partial response, marrow complete response, and hematologic improvement. Survival data were the followings: OS, HMT vs. IC vs. SC, median 62.5 vs. 16.7 vs. 21.0 months; PFS, median 37.7 vs. 13.8 vs. 17.8 months. Multivariate analyses by stratified time updated Cox model showed that hazard ratio (HR) of HMT compared to SC was 1.029 (95% CI, 0.670–1.582, P=0.895) for OS and 0.539 (95% CI, 0.362–0.803, P=0.002) for PFS. When we performed subgroup analyses in lower risk disease (IPSS Low/Intermediate-1) and higher risk disease (IPSS Intermediate-2/High), the effects of HMT on survivals were different by the risk stratification of MDS. In lower risk MDS, there were no survival benefits of HMT compared to SC (OS, median 53.9 vs. 39.8 months, HR 1.570, P=0.108; PFS, median 37.7 vs. 52.5 months, HR 0.880, P=0.633), whereas both OS and PFS were significantly longer in HMT compared to SC (OS, median 137.9 vs. 5.9 months, HR 0.289, P=0.043; PFS, median 80.2 vs. 0.9 months, HR 0.154, P<0.001). Conclusion: Our data suggested that hypomethylating therapy could improve the survivals (OS and PFS) of the patients with higher risk MDS. Disclosures: No relevant conflicts of interest to declare.

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Hoxblinc Is Aberrantly Expressed in Acute Myeloid Leukemia and Functions As a Potent Oncogenic Long Non-Coding RNA in Leukemogenesis

Blood ◽

10.1182/blood-2018-99-112232 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 886-886

Author(s):

Ganqian Zhu ◽

Huacheng Luo ◽

Shi Chen ◽

Qian Lai ◽

Ying Guo ◽

...

Keyword(s):

Mononuclear Cells ◽

Conflicts Of Interest ◽

Flow Cytometric Analysis ◽

Three Dimensional ◽

Donor Cell ◽

Lower Percentage ◽

Leukemic Transformation ◽

Aberrant Expression ◽

The Impact

Abstract Aberrant expression of long non-coding RNAs (lncRNAs) might contribute to the development and progression of leukemia. However, functional studies on the actual role of lncRNAs during the development of leukemia remain scarce, and very few lncRNAs have been shown to be involved in leukemogenesis. HoxBlinc is an anterior HoxB gene-associated intergenic lncRNA. It is a cis-acting lncRNA and functions as an epigenetic regulator to coordinate anterior HoxB gene expression. Giving the dysregulation of HOXA/B genes is a dominant mechanism of leukemic transformation, HoxBlinc might be an oncogenic lncRNA of leukemia. To determine whether HOXBLINC lncRNA is aberrantly expressed in human AML samples, we performed RT-qPCR on bone marrow mononuclear cells (BMMNCs) from a cohort of 73 AML patients. A dramatic up-regulation of HOXBLINC was observed in over 60% of the patients. When TCGA-AML datasets of a cohort of 179 AML patients were analyzed for their HOXBLINC expression, a significant portion of these AML patients had high levels of HOXBLINC expression. Interestingly, AML patients with high HOXBLINC expression (the top thirty percentile of patients) had a significantly shortened survival as compared to patients with low HOXBLINC expression (the bottom thirty percentile). To investigate the impact of HoxBlinc overexpression on normal hematopoiesis and the pathogenesis of hematological malignancies in vivo, we generated a HoxBlinc transgenic(Tg) mouse model. Within 1 year of age, 67% of the HoxBlincTg mice (10 of 15) died or were sacrificed because of a moribund condition due to AML. We then assessed whether overexpression of HoxBlinc affects the pools of HSC/HPCs by flow cytometric analysis on the BM cells of young WT and HoxBlincTg mice (8-10 weeks of age). HoxBlincTg BM had a dramatically greater number of LT-HSC, ST-HSC, MPP cells, and a significantly higher percentage of GMP, but a lower percentage of MEP/CMP cell populations as compared to WT group. To determine the effect of HoxBlinc overexpression on the function of HSC/HPCs, we performed paired-daughter cell assay, replating assay and liquid culture on sorted LT-HSC, LSK or LK cells from young WT and HoxBlincTg mice, the results indicate that transgenic expression of HoxBlinc enhances HSC self-renewal and impairs HSC/HPC differentiation. To assess whether HoxBlinc overexpression-mediated changes in HSC/HPC function are cell-autonomous, we performed competitive transplantation assays to examine the repopulating capacity of HoxBlincTg BM cells. When the donor cell chimerism was analyzed kinetically in the PB of recipient mice, the CD45.2 cell population remained ~50% in mice receiving WT BM cells, whereas the CD45.2 chimerism in the recipients transplanted with HoxBlincTg BM cells steadily increased. Interestingly, mice receiving HoxBlincTg BM cells developed AML at 2-6 months after transplantation. Previous data reported that HoxBlinc can recruit the Setd1a/Mll1 histone H3K4 methyltransferase complex to mediate formation of the active topologically associated domain (TAD) in the anterior HoxB locus for transcription of the anterior HoxB genes. In this study, LSK or LK cells sorted from young WT and HoxBlincTg mice were analyzed by RNA-seq, ATAC-seq, H3K4me3 CHIP-seq and 4C analysis. Mechanistically, HoxBlinc overexpression alters HoxB locus chromatin three-dimensional organization to enhance enhancer/promoter chromatin accessibility and coordinate the expression of not only HoxB1-5 but also HoxA9, Runx1, Meis1 and so on, which are critical genes for HSC regulation and/or leukemogenesis. Our study provides novel insights into the HSC regulation by lncRNAs and identifies HOXBLINC, which coordinates to maintain an oncogenic transcription program for leukemic transformation, as a potent oncogenic lncRNA in leukemogenesis. Disclosures No relevant conflicts of interest to declare.

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GDF11 Increased in Patients with Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v126.23.5224.5224 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5224-5224

Author(s):

Yu Han ◽

Huaquan Wang ◽

Zonghong Shao

Keyword(s):

Bone Marrow ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Risk Group ◽

Low Risk ◽

Mean Corpuscular Hemoglobin ◽

Corpuscular Hemoglobin ◽

Normal Controls

Abstract Objective To analyze the concentration of growth differentiation factor 11(GDF11) in peripheral blood of patients with myelodysplastic syndrome (MDS), so as to evaluate the relationships between these changes and erythropoiesis functions and to explore the role of GDF11 in the pathogenesis of MDS. Methods The concentration of GDF 11 in peripheral blood was detected by enzyme-linked immuno sorbent assay in 44 MDS patients and 10 normal controls from September 2014 to June 2015 at our hospital. The percentage of nucleated erythrocyte (CD235a) in bone marrow was detected by flow cytometry. The correlation between these changes and erythropoiesis functions, including red blood cell count, hemoglobin, reticulocyte (RET%), hematokrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular-hemoglobin concentration (MCHC) and late erythroblast in bone marrow were evaluated. Results (1)The concentration of GDF11(128.67±47.62)in high-risk MDS patients was significantly higher than that of low-risk MDS patients (65.96±36.55,p<0.01)and higher than that of normal controls (29.76±10.10,p<0.01); The concentration of GDF11 in low-risk MDS patients was significantly higher than that of normal controls (p<0.05). (2) The expression of CD235a in high-risk group(38.49±5.42)was not different with that in low-risk group(42.64±7.36, p>0.05). (3)In high-risk MDS patients, the expression of GDF11 was negatively correlated with Hb, RET%, RBC, MCHC, Hct in peripheral blood and late erythroblast, CD235a+ cells in bone marrow(r=-0.437,r=-0.428,r=-0.444,r=-0.553,r=-0.661,r=-0.436,r=-0.52,all p<0.05),and the expression of GDF11 was positively correlated with MCV(r=0.52, p <0.05),but it was not correlated with MCH (p >0.05).(4) In low-risk MDS patients, the expression of GDF11 was negatively correlated with Hb, RET% (r=-0.491Ar=-0.606,both p<0.05),it was not correlated with RBC, MCHC, MCV, MCH, Hct, late erythroblast and CD235a+ cells (all p>0.05). Conclusion GDF11 increased in patients with MDS and it was negatively correlated with late erythropoiesis. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.2802.2802 ◽

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.

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Considering Bone Marrow Blasts from Nonerythroid Cellularity Improves the Prognostic Evaluation of MDS in the Context of IPSS-R and Permits a Better Risk Assessment of MDS Patients Classified into the Intermediate Risk Category

Blood ◽

10.1182/blood.v128.22.3185.3185 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3185-3185

Author(s):

Xavier Calvo ◽

Leonor Arenillas ◽

Elisa Luño ◽

Leonor Senent ◽

Esther Alonso ◽

...

Keyword(s):

Bone Marrow ◽

Lower Risk ◽

Risk Group ◽

Intermediate Risk ◽

Leukemic Transformation ◽

Prognostic Evaluation ◽

Prognostic Assessment ◽

Risk Patients ◽

Very High ◽

Risk Categories

Abstract Introduction: Proportion of bone marrow (BM) blasts is a major prognostic factor for outcome in patients with myelodysplastic syndromes (MDS) and is included in the most applied prognostic scoring systems: IPSS and IPSS-R. IPSS-R stratifies patients in five risk categories: very low (VL), low (L), intermediate (I), high (H) and very high (VH). Some concerns exist about the real prognostic significance of intermediate risk group, as these patients showed around 30 months of median overall survival (OS) in different studies. The Spanish Group of myelodysplastic syndromes considers as high-risk patients those with an expected median OS inferior to 30 months. As showed in a recent study of our group, considering BM blasts from nonerythroid cellularity improves the prognostic evaluation of MDS (Arenillas et al, J Clin Oncol 2016) when applying IPSS and WHO classification. Aims: 1) To assess OS and leukemia-free survival (LFS) prediction by IPSS-R by counting BM blast percentage from nonerythroid cells (NECs). 2) To evaluate whether considering BM blasts from NECs rather than from total nucleated cells (TNCs) improves the prognostic assessment of patients classified into the intermediate risk group. 3) To establish which of these methods present the best prediction capacity for survival and leukemic transformation. Methods: We retrospectively analyzed 3,924 denovo MDS diagnosed according to WHO 2008 from the MDS spanish registry. Percentage of BM blasts from NECs was calculated as follows: [%BM blasts from TNCs/(100 - %BM erythroblasts) x 100]. Survival curves were constructed by using the Kaplan-Meier (K-M) method and compared using the log-rank test. C-index was implemented to assess the method with the best predictive value for survival and leukemic transformation. Results: Median age at diagnosis was 75y (16-101y) and 59% were males. Estimated median follow-up, as calculated by reverse K-M method, was 46.5 months (95% CI, 43.9-49) and median OS was 56.97 months. We assessed OS predicted by IPSS-R by considering BM blasts from TNCs and from NECs (recoded IPSS-R) Fig 1A and 1B. As depicted, five groups with significant differences in OS were observed by using both methods. Interestingly, median OS of intermediate risk group patients changed from 32.3 to 40.4 months by considering blasts from NECs instead of TNCs, whereas patients classified in high and very high risk categories showed almost the same survival even though the higher-risk categories were increased in 25.7%. Of 3,285 patients, 164 (5%) classified in the lower-risk IPSS-R categories (VL, L, I) were reclassified into higher-risk categories (H, VH) when BM blasts were enumerated from NECs. OS and LFS of these upgraded patients was significantly shorter to those observed in patients who remained in the initial categories (median OS, 28.2 vs 71.7 months, P<0.001; median LFS, 63 vs N.R. months, P<0.001) Fig 2A and 2B. In the same way, 24% of patients classified into the intermediate IPSS-R risk group were reclassified into higher-risk categories and showed a significantly shorter OS and LFS (median OS, 24 vs 34.3 months, P=0.012; median LFS, 56.8 vs 164.7 months, P=0.005). Thus, by counting BM blasts from NECs we were able to detect a group of patients labeled at present as having lower-risk disease but who presented an outcome much closer to that of higher-risk patients. The worse outcome observed in these reclassified patients was mainly influenced by the difference in the weight of blasts when assessed from NECs, as other prognostic factors that could explain this difference in outcome, as cytogenetics and degree of cytopenias, were adjusted by using the IPSS-R. Finally, C-index was calculated at 2 and 5 years and the recoded IPSS-R showed a slightly higher value for the prediction of survival and leukemic transformation [(survival, recoded IPSS-R vs IPSS-R: 2y, 0.731 vs 0.728; 5y, 0.696 vs 0.695) (leukemic transformation, recoded IPSS-R vs IPSS-R: 2y, 0.731 vs 0.730; 5y, 0.719 vs 0.716)]. Conclusions: calculating the percentage of BM blasts from NECs improves prognostic assessment of MDS in the context of IPSS-R. By using this method, a more comprehensive distribution of patients was observed, as patients now included in the intermediate risk group presented an outcome much closer to that expected in lower-risk patients. This approach could help clinicians in risk-adapted therapeutic decisions by allowing a better definition of this controversial group. Figure Figure. Figure Figure. Disclosures No relevant conflicts of interest to declare.

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Response to hypomethylating agents improves long-term outcomes for lower-risk patients with myelodysplastic syndrome in case-matched cohorts

Annals of Hematology ◽

10.1007/s00277-018-3458-7 ◽

2018 ◽

Vol 97 (12) ◽

pp. 2309-2317 ◽

Cited By ~ 2

Author(s):

Dong Won Baek ◽

Yoo Jin Lee ◽

Hyunjeong Kim ◽

Seo Yeon Ahn ◽

Jae Sook Ahn ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Lower Risk ◽

Hypomethylating Agents ◽

Long Term Outcomes ◽

Risk Patients

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Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms221910232 ◽

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.

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