The Experts below are selected from a list of 5157 Experts worldwide ranked by ideXlab platform
Ayalew Tefferi - One of the best experts on this subject based on the ideXlab platform.
-
Refractory Anemia with ring sideroblasts rars and rars with thrombocytosis rars t 2017 update on diagnosis risk stratification and management
American Journal of Hematology, 2017Co-Authors: Mrinal M Patnaik, Ayalew TefferiAbstract:Disease Overview Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include Refractory Anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). Diagnosis MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥ 450 × 10(9)/L and large atypical megakaryocytes (similar to BCR-ABL1 negative MPN). Mutations and Karyotype Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases. Risk stratification Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-IPSS). Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic Treatment Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain.
-
vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis
Leukemia, 2016Co-Authors: Mrinal M Patnaik, Terra L Lasho, Christy Finke, Rhett P Ketterling, C A Hanson, Rebecca King, Naseema Gangat, Ayalew TefferiAbstract:Vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis
-
predictors of survival in Refractory Anemia with ring sideroblasts and thrombocytosis rars t and the role of next generation sequencing
American Journal of Hematology, 2016Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Terra L Lasho, Christy Finke, Rhett P Ketterling, Naseema Gangat, Rebecca L King, Ayalew TefferiAbstract:Refractory Anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), Anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model.
-
vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis rars t
Blood, 2015Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Terra L Lasho, Christy Finke, Rhett P Ketterling, Naseema Gangat, Pooja Vijayvargiya, Ayalew TefferiAbstract:Background: Refractory Anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity in the MDS/MPN overlap syndromes, with diagnostic features of RARS, along with a platelet count > 450 x 10(9)/L and large atypical megakaryocytes. Mutations involving SF3B1 (~80%), JAK2 (~60%), TET2 (~25%) and ASXL1 (~15%) have been reported. The frequency of thrombotic events in RARS-T is thought to be similar to that of essential thrombocytosis (ET) (3.6 vs 3.9/100 patient years; Hematologica 2012; 1036-41). However, unlike in ET, it remains unclear as to whether thrombotic events in RARS-T impact overall (OS) or thrombosis-free (TFS) survival. Methods: 82 patients with WHO-defined RARS-T were included in the study. All patients had bone marrow (BM) biopsies, iron stains for detection of BM ring sideroblasts (RS) and cytogenetics performed at diagnosis. Mutational analysis for JAK2, CALR, MPL, SF3B1, SRSF2 and ASXL1 was carried out on BM DNA obtained at the time of diagnosis. Details of type of thrombotic event and cardiovascular (CV) risk factors including; hypertension, diabetes, smoking and dyslipidemia were obtained by careful review of the medical record. OS was calculated from time of initial diagnosis to the time of last follow-up or death. TFS was calculated from the time of diagnosis of RARS-T to development of thrombosis in uncensored patients and date of last follow up or death in patients censored for thrombosis. Conventional statistics were utilized for all analyses. Results: Among the 82 study patients, 46 (56%) were males and median age was 72 years (range, 48-93). At a median follow-up of 26.5 months; 48 (59%) deaths and 2 leukemic transformations were documented. Median OS was 44 months. Karyotype was diploid in 61 (74%) and analyzed mutational frequencies were; SF3B1 67% (28/42), JAK2 V617F 40% (25/61), ASXL1 21% (9/41), SRSF2 6% (2/31), MPL 1% (2/41) and CALR 0, respectively. Cardiovascular risk factors were present in 52 (63%). a) Thrombotic events and their impact on thrombosis free survival: Eight (10%) patients had a thrombotic event prior to or at the time of diagnosis of RARS-T (venous-8, arterial-0). Nine (11%) patients developed subsequent thrombotic events (venous-7, arterial-2), with no fatalities. In univariate analysis, lower hemoglobin level (p=0.008), lower BM RS % (p=0.04), history of thrombosis (p=0.02), and absence of SF3B1 mutations (p=0.017) were associated with an inferior TFS. Age (p=0.07), JAK2 mutation status (p=0.56) and CV risk factors (p=0.95) did not have prognostic impact. Given the association between SF3B1 mutations and BM RS, in a multivariable model that included these two as covariates, only the absence of SF3B1 mutations retained prognostic significance (p=0.02). Absence of SF3B1 mutation remained significant when history of thrombosis or lower hemoglobin level were introduced into the multivariable model. b) Risk factors for overall survival: In univariate analysis, hemoglobin Conclusions: In contrast to what is observed in ET, thrombosis history does not appear to affect either overall or thrombosis-free survival in RARS-T. The current study suggests a lower thrombosis risk in SF3B1 -mutated patients with RARS-T, compared to their SF3B1 wild-type counterparts. Disclosures No relevant conflicts of interest to declare.
-
Refractory Anemia with ring sideroblasts and rars with thrombocytosis
American Journal of Hematology, 2015Co-Authors: Mrinal M Patnaik, Ayalew TefferiAbstract:Disease Overview: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include Refractory Anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T). Diagnosis: RARS is a lower risk myelodysplastic syndrome (MDS) with dysplasia limited to the erythroid lineage, <5% bone marrow (BM) blasts and ≥15% BM RS. RARS-T is a provisional entity in the MDS/MPN (myeloproliferative neoplasm) overlap syndromes, with diagnostic features of RARS, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes similar to those observed in BCR-ABL1 negative MPN. Mutations and Karyotype: Mutations in the SF3B1 gene are seen in ≥80% of patients with RARS and RARS-T, and strongly correlate with the presence of BM RS; RARS-T patients have additional mutations such as, JAK2V617F (∼60%), MPL (<5%), and CALR (<5%). Cytogenetic abnormalities are uncommon in both RARS and RARS-T. Risk stratification: Most patients with RARS are stratified into lower risk groups by the International Prognostic Scoring System (IPSS) for MDS and the revised IPSS. Disease outcome in RARS-T is better than that of RARS, but worse than that of essential thrombocytosis. Both RARS and RARS-T have a low risk of leukemic transformation. Treatment: Anemia and iron overload are complications in both diseases and are managed similar to lower risk MDS. Aspirin therapy is reasonable in RARS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain. Case reports of RARS-T therapy with lenalidomide warrant additional studies. Am. J. Hematol. 90:550–559, 2015. © 2015 Wiley Periodicals, Inc.
Mrinal M Patnaik - One of the best experts on this subject based on the ideXlab platform.
-
Refractory Anemia with ring sideroblasts rars and rars with thrombocytosis rars t 2017 update on diagnosis risk stratification and management
American Journal of Hematology, 2017Co-Authors: Mrinal M Patnaik, Ayalew TefferiAbstract:Disease Overview Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include Refractory Anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). Diagnosis MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥ 450 × 10(9)/L and large atypical megakaryocytes (similar to BCR-ABL1 negative MPN). Mutations and Karyotype Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases. Risk stratification Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-IPSS). Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic Treatment Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain.
-
vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis
Leukemia, 2016Co-Authors: Mrinal M Patnaik, Terra L Lasho, Christy Finke, Rhett P Ketterling, C A Hanson, Rebecca King, Naseema Gangat, Ayalew TefferiAbstract:Vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis
-
predictors of survival in Refractory Anemia with ring sideroblasts and thrombocytosis rars t and the role of next generation sequencing
American Journal of Hematology, 2016Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Terra L Lasho, Christy Finke, Rhett P Ketterling, Naseema Gangat, Rebecca L King, Ayalew TefferiAbstract:Refractory Anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), Anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model.
-
imetelstat therapy in Refractory Anemia with ring sideroblasts with or without thrombocytosis
Blood Cancer Journal, 2016Co-Authors: A Tefferi, Mrinal M Patnaik, Terra L Lasho, Aref Alkali, Kebede H Begna, A Rizo, Ying Wan, C A HansonAbstract:Imetelstat therapy in Refractory Anemia with ring sideroblasts with or without thrombocytosis
-
vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis rars t
Blood, 2015Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Terra L Lasho, Christy Finke, Rhett P Ketterling, Naseema Gangat, Pooja Vijayvargiya, Ayalew TefferiAbstract:Background: Refractory Anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity in the MDS/MPN overlap syndromes, with diagnostic features of RARS, along with a platelet count > 450 x 10(9)/L and large atypical megakaryocytes. Mutations involving SF3B1 (~80%), JAK2 (~60%), TET2 (~25%) and ASXL1 (~15%) have been reported. The frequency of thrombotic events in RARS-T is thought to be similar to that of essential thrombocytosis (ET) (3.6 vs 3.9/100 patient years; Hematologica 2012; 1036-41). However, unlike in ET, it remains unclear as to whether thrombotic events in RARS-T impact overall (OS) or thrombosis-free (TFS) survival. Methods: 82 patients with WHO-defined RARS-T were included in the study. All patients had bone marrow (BM) biopsies, iron stains for detection of BM ring sideroblasts (RS) and cytogenetics performed at diagnosis. Mutational analysis for JAK2, CALR, MPL, SF3B1, SRSF2 and ASXL1 was carried out on BM DNA obtained at the time of diagnosis. Details of type of thrombotic event and cardiovascular (CV) risk factors including; hypertension, diabetes, smoking and dyslipidemia were obtained by careful review of the medical record. OS was calculated from time of initial diagnosis to the time of last follow-up or death. TFS was calculated from the time of diagnosis of RARS-T to development of thrombosis in uncensored patients and date of last follow up or death in patients censored for thrombosis. Conventional statistics were utilized for all analyses. Results: Among the 82 study patients, 46 (56%) were males and median age was 72 years (range, 48-93). At a median follow-up of 26.5 months; 48 (59%) deaths and 2 leukemic transformations were documented. Median OS was 44 months. Karyotype was diploid in 61 (74%) and analyzed mutational frequencies were; SF3B1 67% (28/42), JAK2 V617F 40% (25/61), ASXL1 21% (9/41), SRSF2 6% (2/31), MPL 1% (2/41) and CALR 0, respectively. Cardiovascular risk factors were present in 52 (63%). a) Thrombotic events and their impact on thrombosis free survival: Eight (10%) patients had a thrombotic event prior to or at the time of diagnosis of RARS-T (venous-8, arterial-0). Nine (11%) patients developed subsequent thrombotic events (venous-7, arterial-2), with no fatalities. In univariate analysis, lower hemoglobin level (p=0.008), lower BM RS % (p=0.04), history of thrombosis (p=0.02), and absence of SF3B1 mutations (p=0.017) were associated with an inferior TFS. Age (p=0.07), JAK2 mutation status (p=0.56) and CV risk factors (p=0.95) did not have prognostic impact. Given the association between SF3B1 mutations and BM RS, in a multivariable model that included these two as covariates, only the absence of SF3B1 mutations retained prognostic significance (p=0.02). Absence of SF3B1 mutation remained significant when history of thrombosis or lower hemoglobin level were introduced into the multivariable model. b) Risk factors for overall survival: In univariate analysis, hemoglobin Conclusions: In contrast to what is observed in ET, thrombosis history does not appear to affect either overall or thrombosis-free survival in RARS-T. The current study suggests a lower thrombosis risk in SF3B1 -mutated patients with RARS-T, compared to their SF3B1 wild-type counterparts. Disclosures No relevant conflicts of interest to declare.
Claudia Haferlach - One of the best experts on this subject based on the ideXlab platform.
-
Refractory Anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in sf3b1 or other spliceosome genes accompanied by jak2v617f and asxl1 mutations
Haematologica, 2015Co-Authors: Sabine Jeromin, W Kern, T Haferlach, Sandra Weissmann, Manja Meggendorfer, Christiane Eder, Nirsoshan Nadarajah, Tamara Alpermann, Alexander Kohlmann, Claudia HaferlachAbstract:Refractory Anemia with ring sideroblasts and marked thrombocytosis (RARS-T) is a rare entity with characteristics of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN).[1][1] Patients have been shown to be frequently JAK2 V617F and SF3B1 , and less commonly MPL W515, mutated
-
high frequencies of sf3b1 and jak2 mutations in Refractory Anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic myeloproliferative neoplasms
Haematologica, 2013Co-Authors: Sabine Jeromin, Claudia Haferlach, W Kern, T Haferlach, Tamara Alpermann, Vera Grossmann, Andreas Kowarsch, Susanne SchnittgerAbstract:Mutations of spliceosome genes were shown to occur frequently in different entities.[1][1] Remarkably, mutations in SF3B1 (splicing factor 3b, subunit 1) were associated with the morphological feature of ring sideroblasts[1][1]-[3][2] and were also found in Refractory Anemia with ring sideroblasts
-
mutations of jak2 and tet2 but not cbl are detectable in a high portion of patients with Refractory Anemia with ring sideroblasts and thrombocytosis
Haematologica, 2010Co-Authors: Johanna Flach, Susanne Schnittger, T Haferlach, Alexander Kohlmann, Frank Dicker, Claudia HaferlachAbstract:The WHO classification of 2008 characterized Refractory Anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) by the presence of less than 5% marrow blasts, 15% or more ring sideroblasts and a persistent platelet count over 450×109/L to be in line with the revised
-
detection of an mplw515 mutation in a case with features of both essential thrombocythemia and Refractory Anemia with ringed sideroblasts and thrombocytosis
Leukemia, 2008Co-Authors: S Schnittger, Ulrike Bacher, Claudia Haferlach, Robert Dengler, A Krober, W Kern, T HaferlachAbstract:Detection of an MPL W515 mutation in a case with features of both essential thrombocythemia and Refractory Anemia with ringed sideroblasts and thrombocytosis
T Haferlach - One of the best experts on this subject based on the ideXlab platform.
-
Refractory Anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in sf3b1 or other spliceosome genes accompanied by jak2v617f and asxl1 mutations
Haematologica, 2015Co-Authors: Sabine Jeromin, W Kern, T Haferlach, Sandra Weissmann, Manja Meggendorfer, Christiane Eder, Nirsoshan Nadarajah, Tamara Alpermann, Alexander Kohlmann, Claudia HaferlachAbstract:Refractory Anemia with ring sideroblasts and marked thrombocytosis (RARS-T) is a rare entity with characteristics of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN).[1][1] Patients have been shown to be frequently JAK2 V617F and SF3B1 , and less commonly MPL W515, mutated
-
high frequencies of sf3b1 and jak2 mutations in Refractory Anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic myeloproliferative neoplasms
Haematologica, 2013Co-Authors: Sabine Jeromin, Claudia Haferlach, W Kern, T Haferlach, Tamara Alpermann, Vera Grossmann, Andreas Kowarsch, Susanne SchnittgerAbstract:Mutations of spliceosome genes were shown to occur frequently in different entities.[1][1] Remarkably, mutations in SF3B1 (splicing factor 3b, subunit 1) were associated with the morphological feature of ring sideroblasts[1][1]-[3][2] and were also found in Refractory Anemia with ring sideroblasts
-
mutations of jak2 and tet2 but not cbl are detectable in a high portion of patients with Refractory Anemia with ring sideroblasts and thrombocytosis
Haematologica, 2010Co-Authors: Johanna Flach, Susanne Schnittger, T Haferlach, Alexander Kohlmann, Frank Dicker, Claudia HaferlachAbstract:The WHO classification of 2008 characterized Refractory Anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) by the presence of less than 5% marrow blasts, 15% or more ring sideroblasts and a persistent platelet count over 450×109/L to be in line with the revised
-
detection of an mplw515 mutation in a case with features of both essential thrombocythemia and Refractory Anemia with ringed sideroblasts and thrombocytosis
Leukemia, 2008Co-Authors: S Schnittger, Ulrike Bacher, Claudia Haferlach, Robert Dengler, A Krober, W Kern, T HaferlachAbstract:Detection of an MPL W515 mutation in a case with features of both essential thrombocythemia and Refractory Anemia with ringed sideroblasts and thrombocytosis
Terra L Lasho - One of the best experts on this subject based on the ideXlab platform.
-
vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis
Leukemia, 2016Co-Authors: Mrinal M Patnaik, Terra L Lasho, Christy Finke, Rhett P Ketterling, C A Hanson, Rebecca King, Naseema Gangat, Ayalew TefferiAbstract:Vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis
-
predictors of survival in Refractory Anemia with ring sideroblasts and thrombocytosis rars t and the role of next generation sequencing
American Journal of Hematology, 2016Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Terra L Lasho, Christy Finke, Rhett P Ketterling, Naseema Gangat, Rebecca L King, Ayalew TefferiAbstract:Refractory Anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), Anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model.
-
imetelstat therapy in Refractory Anemia with ring sideroblasts with or without thrombocytosis
Blood Cancer Journal, 2016Co-Authors: A Tefferi, Mrinal M Patnaik, Terra L Lasho, Aref Alkali, Kebede H Begna, A Rizo, Ying Wan, C A HansonAbstract:Imetelstat therapy in Refractory Anemia with ring sideroblasts with or without thrombocytosis
-
vascular events and risk factors for thrombosis in Refractory Anemia with ring sideroblasts and thrombocytosis rars t
Blood, 2015Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Terra L Lasho, Christy Finke, Rhett P Ketterling, Naseema Gangat, Pooja Vijayvargiya, Ayalew TefferiAbstract:Background: Refractory Anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity in the MDS/MPN overlap syndromes, with diagnostic features of RARS, along with a platelet count > 450 x 10(9)/L and large atypical megakaryocytes. Mutations involving SF3B1 (~80%), JAK2 (~60%), TET2 (~25%) and ASXL1 (~15%) have been reported. The frequency of thrombotic events in RARS-T is thought to be similar to that of essential thrombocytosis (ET) (3.6 vs 3.9/100 patient years; Hematologica 2012; 1036-41). However, unlike in ET, it remains unclear as to whether thrombotic events in RARS-T impact overall (OS) or thrombosis-free (TFS) survival. Methods: 82 patients with WHO-defined RARS-T were included in the study. All patients had bone marrow (BM) biopsies, iron stains for detection of BM ring sideroblasts (RS) and cytogenetics performed at diagnosis. Mutational analysis for JAK2, CALR, MPL, SF3B1, SRSF2 and ASXL1 was carried out on BM DNA obtained at the time of diagnosis. Details of type of thrombotic event and cardiovascular (CV) risk factors including; hypertension, diabetes, smoking and dyslipidemia were obtained by careful review of the medical record. OS was calculated from time of initial diagnosis to the time of last follow-up or death. TFS was calculated from the time of diagnosis of RARS-T to development of thrombosis in uncensored patients and date of last follow up or death in patients censored for thrombosis. Conventional statistics were utilized for all analyses. Results: Among the 82 study patients, 46 (56%) were males and median age was 72 years (range, 48-93). At a median follow-up of 26.5 months; 48 (59%) deaths and 2 leukemic transformations were documented. Median OS was 44 months. Karyotype was diploid in 61 (74%) and analyzed mutational frequencies were; SF3B1 67% (28/42), JAK2 V617F 40% (25/61), ASXL1 21% (9/41), SRSF2 6% (2/31), MPL 1% (2/41) and CALR 0, respectively. Cardiovascular risk factors were present in 52 (63%). a) Thrombotic events and their impact on thrombosis free survival: Eight (10%) patients had a thrombotic event prior to or at the time of diagnosis of RARS-T (venous-8, arterial-0). Nine (11%) patients developed subsequent thrombotic events (venous-7, arterial-2), with no fatalities. In univariate analysis, lower hemoglobin level (p=0.008), lower BM RS % (p=0.04), history of thrombosis (p=0.02), and absence of SF3B1 mutations (p=0.017) were associated with an inferior TFS. Age (p=0.07), JAK2 mutation status (p=0.56) and CV risk factors (p=0.95) did not have prognostic impact. Given the association between SF3B1 mutations and BM RS, in a multivariable model that included these two as covariates, only the absence of SF3B1 mutations retained prognostic significance (p=0.02). Absence of SF3B1 mutation remained significant when history of thrombosis or lower hemoglobin level were introduced into the multivariable model. b) Risk factors for overall survival: In univariate analysis, hemoglobin Conclusions: In contrast to what is observed in ET, thrombosis history does not appear to affect either overall or thrombosis-free survival in RARS-T. The current study suggests a lower thrombosis risk in SF3B1 -mutated patients with RARS-T, compared to their SF3B1 wild-type counterparts. Disclosures No relevant conflicts of interest to declare.
-
differential prognostic effect of idh1 versus idh2 mutations in myelodysplastic syndromes a mayo clinic study of 277 patients
Leukemia, 2012Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Janice M Hodnefield, Terra L Lasho, Christy Finke, Ryan A Knudson, Rhett P Ketterling, Animesh Pardanani, Ayalew TefferiAbstract:Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in Refractory Anemia with ring sideroblasts, 12% (16 of 130) in Refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in Refractory Anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P=0.0004; hazard ration 4.0, 95% confidence interval 1.9-8.8), revised International Prognostic Scoring System risk category (P<0.0001), and red cell transfusion need (P=0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P=0.001; hazard ration 7.0, 95% confidence interval 2.3-20.8). The presence of IDH2R140Q did not affect the overall (P=0.54) or leukemia-free (P=0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.
