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Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.
The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.
“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.
Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).
In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).
Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.
When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.
Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.
Gene sequencing efforts in myeloid malignancies have largely charted the mutational “landscape.” This map allows us to (1) have some idea of the fundamental biology underlying the disease, (2) define potential drug targets, and (3) refine outcome expectations, especially when there are no “knockout” therapies (as in chronic myeloid leukemia). The consequence is also the further subclassification of myeloid malignancies, thus making relatively rare diseases into extremely rare ones. One obvious challenge is to cleverly design clinical studies given the myriad subcategories of disease. The higher bar is understanding the biology of how the various mutations and pathways merge to cause disease. The work Malcovati et al., along with the other fine studies noted above, gets us one step farther down the road to cures.
Dr. Jerald Radich of Fred Hutchinson Cancer Research Center, Seattle, made his comment in an accompanying editorial.
Gene sequencing efforts in myeloid malignancies have largely charted the mutational “landscape.” This map allows us to (1) have some idea of the fundamental biology underlying the disease, (2) define potential drug targets, and (3) refine outcome expectations, especially when there are no “knockout” therapies (as in chronic myeloid leukemia). The consequence is also the further subclassification of myeloid malignancies, thus making relatively rare diseases into extremely rare ones. One obvious challenge is to cleverly design clinical studies given the myriad subcategories of disease. The higher bar is understanding the biology of how the various mutations and pathways merge to cause disease. The work Malcovati et al., along with the other fine studies noted above, gets us one step farther down the road to cures.
Dr. Jerald Radich of Fred Hutchinson Cancer Research Center, Seattle, made his comment in an accompanying editorial.
Gene sequencing efforts in myeloid malignancies have largely charted the mutational “landscape.” This map allows us to (1) have some idea of the fundamental biology underlying the disease, (2) define potential drug targets, and (3) refine outcome expectations, especially when there are no “knockout” therapies (as in chronic myeloid leukemia). The consequence is also the further subclassification of myeloid malignancies, thus making relatively rare diseases into extremely rare ones. One obvious challenge is to cleverly design clinical studies given the myriad subcategories of disease. The higher bar is understanding the biology of how the various mutations and pathways merge to cause disease. The work Malcovati et al., along with the other fine studies noted above, gets us one step farther down the road to cures.
Dr. Jerald Radich of Fred Hutchinson Cancer Research Center, Seattle, made his comment in an accompanying editorial.
Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.
The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.
“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.
Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).
In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).
Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.
When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.
Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.
Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.
The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.
“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.
Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).
In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).
Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.
When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.
Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.
FROM BLOOD
Key clinical point: Mutations in SF3B1 identify a subset of patients with MDS with favorable prognosis.
Major finding: Patients with SF3B1 had a hazard ratio for death of 0.37, compared with patients with unmutated (wild-type) SF3B1.
Data source: Mutational analysis of 293 patients with myeloid neoplasms with 1% of more ring sideroblasts followed in centers in Italy, Sweden, and Denmark.
Disclosures: The study was supported by grants from Associazione Italiana per la Ricerca sul Cancro, Fondo per gli Investimenti della Ricerca di Base, and Ministero dell’Istruzione, dell’Università e della Ricerca PRIN 2010-2011, Fondazione Veronesi and Regione Lombardia/Fondazione Cariplo, and Associazione Italiana per la Ricerca sul Cancro IG. The authors and Dr. Radich reported no conflicts of interest.
