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 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 FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Michael Schieber ◽  
Christian Marinaccio ◽  
Lyndsey C. Bolanos ◽  
Wendy D. Haffey ◽  
Kenneth D. Greis ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Leukemic Transformation ◽  
Secondary Acute Myeloid Leukemia ◽  
Ubiquitin Ligase Complex ◽  
Genetic Abnormalities ◽  
Scf Ubiquitin Ligase ◽  
Cellular Pathways ◽  
F Box Protein

Abstract Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.

scholarly journals Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: a systematic review of hypomethylating agents trials

2016 ◽  
Vol 8 (1) ◽  
Author(s):  
Seongseok Yun ◽  
Nicole D. Vincelette ◽  
Ivo Abraham ◽  
Keith D. Robertson ◽  
Martin E. Fernandez-Zapico ◽  
...  
Keyword(s):  
Systematic Review ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Hypomethylating Agents ◽  
Acute Myeloid

scholarly journals Anaplastic Thyroid Carcinoma: Treatment in the Age of Molecular Targeted Therapy

2016 ◽  
Vol 12 (6) ◽  
pp. 511-518 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Mark Zafereo ◽  
G. Brandon Gunn ◽  
Renata Ferrarotto
Keyword(s):  
Targeted Therapy ◽  
Thyroid Carcinoma ◽  
Molecular Targeted Therapy ◽  
Standard Of Care ◽  
Anaplastic Thyroid Carcinoma ◽  
Novel Therapies ◽  
Current Standard ◽  
Major Barrier

Anaplastic thyroid carcinoma is one of the most aggressive and deadly cancers in humans and accounts for one to two cases per million persons annually. The rarity of this malignancy and the rapidity by which it grows has been a major barrier to progress in finding effective therapies. Thus, the treatment that is the current standard of care for these patients is largely palliative, and few are cured; however, novel therapies and approaches are being studied in patients with anaplastic thyroid carcinoma and are delineated herein.

scholarly journals Inflammation-related genes S100s, RNASE3, and CYBB and risk of leukemic transformation in patients with myelodysplastic syndrome with myelofibrosis

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Minghua Hong ◽  
Junqing Wu ◽  
Lifeng Ma ◽  
Xiaoping Han ◽  
Ting Lu ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemic Transformation ◽  
Genetic Characteristics ◽  
Expression Levels ◽  
Single Cell Sequencing ◽  
Before And After ◽  
Gene Expression Levels ◽  
Acute Myeloid

AbstractMyelodysplastic syndrome with myelofibrosis (MDS-MF) has been associated with an inferior prognosis compared with MDS without MF. However, MDS-MF is not listed independently as a subtype of MDS, and its clinical and genetic characteristics remain poorly understood. We retrospectively compared 53 patients with MDS-MF (44 MF grade 1/MF1; 9 MF grade 2–3/MF2 − 3) and 31 with de novo MDS without MF (MDS). The leukemic transformation risks of both MDS-MF2 − 3 and MDS-MF1 were increased compared with the MDS group. To identify the potential mechanisms responsible for the leukemic transformation of MDS-MF, we performed single-cell sequencing for one MDS-MF2 − 3 patient before and after leukemic transformation to explore the variations in gene expression levels. In addition to upgraded expression levels of acute myeloid leukemia-related genes during leukemic transformation, expression levels of some inflammation-related genes (such as S100s, RNASE3, and CYBB) were also increased, and inflammation-related pathways were up-regulated. These results suggest that inflammation-related genes and pathways may play an important role in the leukemic transformation of MDS-MF.

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 Response to Venetoclax and Hypomethylating Agents Among Prognostic Risk Groups and Genetic Subtypes of Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 334-334 ◽  
Author(s):  
Ibrahim Aldoss ◽  
Dongyun Yang ◽  
Raju Pillai ◽  
James F Sanchez ◽  
Ahmed Aribi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
De Novo ◽  
Recursive Partitioning ◽  
Response To Therapy ◽  
Intermediate Risk ◽  
Hypomethylating Agents ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract The combination of venetoclax and hypomethylating agents (HMA) has demonstrated potent activity in acute myeloid leukemia (AML), both in newly diagnosed patients (pts) and those with relapsed/refractory (r/r) disease. We analyzed the association between response to therapy and leukemic somatic mutations, cytogenetics, and other pertinent patient- and leukemia-related features in a large series of newly diagnosed and r/r AML in adults treated with venetoclax in combination with HMA at City of Hope between October 2016 and May 2018. We identified 107 evaluable adults with AML treated with the combination of venetoclax and HMA. Sixty-one (57%) pts had r/r AML at the time of initiating treatment (median prior lines of therapy: 2; range: 1-10), while 46 (43%) were treated in the frontline setting. The median age of pts was 68 years (range: 19-86). AML was de novo in 57 (53%), therapy-related in 23 (21%) and secondary in 27 (25%) pts. Thirty-six (34%) pts had prior exposure to HMA, and 21 (20%) pts had relapsed following prior allogeneic hematopoietic cell transplantation (HCT). The majority of treated pts had unfavorable (52%) or intermediate-risk (39%) AML based on combined cytogenetics and molecular profiles. The most common detected somatic mutations (majority by next generation sequencing) were FLT3 (17%), followed by DNMT3A (15%), RAS and TET2 (each 14%), RUNX1 (13%), TP53 (12%), and IDH1/2 (11%). Most pts received decitabine in combination with venetoclax (N=97, 91%); only 10 (9%) pts received 5-azacitidine together with venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved in 57 (53%) pts after a median of 2 (range 1-4) cycles. For 36 pts who achieved CR/CRi and had available minimal residual disease (MRD) assessment by multicolor flow cytometry (MFC), 23 (64%) became MRD-. CR/CRi was higher in pts carrying favorable- or intermediate-risk AML compared to poor-risk AML (100% vs. 60% vs. 45%, P=0.029). CR/CRi was 48% in those with complex cytogenetics (N = 31), 45% in monosomal karyotype (N = 22), 36% in KMT2A gene rearrangement (N = 11), 74% in normal karyotype (N = 19), and 25% in inversion 3 (N =4). The CR/CRi rate was not significantly different between newly diagnosed or r/r AML (61% vs. 48%, P = 0.17), nor was there a difference associated with AML type (de novo vs. therapy-related vs. secondary, P= 0.26), patient age (> or ≤ 65 years) at time of therapy (P = 0.13), prior allogeneic HCT (P = 0.29), prior administration of HMA (P = 0.37) and the type or schedule (5- or 10-day decitabine) of HMA (P = 0.52). In multivariate analysis, only favorable- or intermediate-risk cytogenetics was associated with better CR/CRi (P = 0.036). CR/CRi was also comparable regardless of the presence or absence of various analyzed somatic AML mutations. However, in recursive partitioning analysis of detectable somatic mutations and response to therapy, the combined lack of RAS, TP53 and RUNX1 mutations was linked to an improved rate of CR/CRi. When AML cases were stratified into functional gene alteration subgroups (according to the TCGA data set), there was no significant difference in CR/CRi according to the presence or absence of certain functional genes/fusions. Median overall survival (OS) for all pts was 12.5 months and was 14.6 months for pts who achieved CR/CRi, in contrast to 4.6 months for non-responders (P <0.001). Only AML subtype (de novo vs. therapy-related vs. secondary) (P <0.001) and AML genetic risk (favorable/intermediate vs. high) (P = 0.042) independently impacted OS in multivariate analysis. None of the AML individual somatic mutations influenced OS for this cohort, however, in recursive partitioning analysis of detectable mutations, the presence of any of SRSF2, IDH1/2 or RUNX1 were associated with improved OS. Furthermore, the presence of myeloid transcription factor (P = 0.033) and spliceosome complex mutations (P = 0.004) predicted superior OS, whereas the presence of a chromatin modifying mutation predicted inferior OS (P = 0.004). Thirteen (23%) responders subsequently underwent allogeneic HCT. We report remarkable activity with venetoclax and HMA across various high-risk genetics and clinical features in AML patients. Prospective studies are warranted to compare this combination directly with chemotherapy in all AML subsets. This is particularly true for high risk AML where response to conventional chemotherapy is poor. Disclosures Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Khaled:Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding; Daiichi: Consultancy. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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