Abdullah Ali

Severely impaired terminal erythroid differentiation as an independent prognostic marker in myelodysplastic syndromes

Anemia is the defining feature in most patients with myelodysplastic syndromes (MDS), yet defects in erythropoiesis have not been well characterized. We examined freshly obtained bone marrow (BM) samples for stage-specific abnormalities during terminal erythroid differentiation (TED) from 221 samples (MDS, n = 205 from 113 unique patients; normal, n = 16) by measuring the surface expression of glycophorin A, band 3, and integrin α-4. Clinical and biologic associations were sought with presence or absence of TED and the specific stage of erythroid arrest. In 27% of MDS samples (56/205), there was no quantifiable TED documented by surface expression of integrin α-4 and band 3 by terminally differentiating erythroblasts. Absence of quantifiable TED was associated with a significantly worse overall survival (56 vs 103 months, P = .0001) and SRSF2 mutations (7/23, P < .05). In a multivariable Cox proportional hazards regression analysis, absence of TED remained independently significant across International Prognostic Scoring System-Revised (IPSS-R) categories, myeloid/erythroid ratio, and mutations in several genes. In 149/205 MDS samples, the proportion of cells undergoing TED did not follow the expected 1:2:4:8:16 doubling pattern in successive stages. Absence of TED emerged as a powerful independent prognostic marker of poor overall survival across all IPSS-R categories in MDS, and SRSF2 mutations were more frequently associated with absence of TED.

Rigosertib in myelodysplastic syndromes (MDS)

ABSTRACT Introduction: Therapeutic options for myelodysplastic syndromes (MDS) are limited to hypomethylating agents (HMA) and lenalidomide. Rigosertib, a small molecule which blocks RAS-mediated activation of proteins containing a common RAS binding domain, appears to be a promising novel drug. Areas covered: Discovery, mechanism of action of rigosertib, and results of clinical trials are described. More than 500 patients have been treated and the safety, pharmacokinetics, and efficacy of rigosertib are summarized. These studies are placed in the context of the history of therapeutic development in MDS and the promise of new, tailored treatments based on emerging knowledge of the heterogeneity and molecular biology of the disease. Expert opinion: In summary, the Phase III study failed to meet the primary endpoint but clearly showed significant improvement in survival in a subset of very high risk MDS patients who were primary HMA failures. A new Phase III trial designed to validate these findings is now ongoing. Oral rigosertib, in a Phase II trial, produced transfusion independence in ~35% patients with lower risk MDS with or without recombinant erythropoietin. A methylation based signature appears to distinguish between the two groups. Validation of these early encouraging observations through future clinical trials is eagerly anticipated.

Two different “tales” of ATG7: Clinical relevance to myelodysplastic syndromes

ABSTRACT Somatic mutations in U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) are associated with various cancers including myelodysplastic syndrome (MDS). Mutant U2AF1 promotes malignant transformation by inhibiting autophagy, partly as a result of alterations in the 3′ tail of ATG7. This results in altered mitochondrial function, increased reactive oxygen species production, and genomic instability.