From Pages to Practice

Published February 8, 2017


Myelodysplastic syndrome (MDS) is a heterogenous collection of myeloid malignancies characterized by marrow failure with peripheral blood cytopenias. Underlying causes can range from inherited conditions or treatment-related complications from chemotherapy, radiotherapy, or both. MDS usually affects patients older than 60 years, but congenital mutations can affect children and young adults. Although allogeneic stem-cell transplantation can be curative, it is associated with high risk for transplant-related morbidity and mortality. Genetic profiling might improve the nosology of this condition and help identify patients with MDS who are most likely to benefit from stem-cell transplantation.

In this week’s issue of NEJM, Lindsley and colleagues sought to identify genetic mutations that predict clinical outcomes following allogeneic stem-cell transplantation. Before the preparative conditioning regimen and transplantation, the authors performed targeted mutational analysis of 129 genes in whole blood samples from 1514 patients with MDS from 130 transplant centers. They then analyzed the associations of particular gene mutations with transplantation outcomes, including overall survival, relapse, and death without relapse.

At least one mutation was found in 79% of patients with MDS treated with an allogeneic stem-cell transplant; 32 genes mutated in at least 20 patients were analyzed to investigate associations with overall survival. Mutation in tumor protein 53 (TP53), a well-known tumor-suppressor gene, was associated with shorter overall survival (hazard ratio for death, 1.96; 95% CI, 1.69-2.28; adjusted P<0.0001). The effect of this mutation on survival was independent of the intensity or type of conditioning regimen used. Other mutations that were associated with shorter survival were PPM1D and JAK2.

Prognostic nongenetic variables included age >40 years, Karnofsky performance status score < 90, HLA mismatch, severe thrombocytopenia, and elevated percentage of bone marrow blasts. Mutations in PPM1D were more common in patients with therapy-related MDS than in patients with primary MDS (15% vs. 3%, P<0.001). A multivariable model demonstrated that the presence of a TP53 mutation was predictive of a high risk of relapse after stem-cell transplantation and poor survival.

The authors used recursive partitioning analysis of genetic mutations, clinical variables, and survival outcomes to create a hierarchical prognostic model. In this model, among patients ≥40 years without TP53 mutations, those with a RAS pathway mutation had shorter survival than those without a RAS pathway mutation (median, 0.9 vs. 2.2 years; P=0.004). The shorter survival was also associated with a high risk of relapse. Among patients ≥40 years without a RAS pathway mutation or TP53 mutation, those with a JAK2 mutation had shorter survival than those without a JAK2 mutation (median, 0.5 vs. 2.3 years, P=0.001), but without a high risk of relapse (i.e., nonrelapse death). Among patients younger than 40, more than one high-risk clinical feature (e.g., therapy-related MDS, thrombocytopenia, >15% bone marrow blasts at diagnosis) was predictive of poor response.

Considerable uncertainty remains about the benefits of genetic sequencing techniques in directing therapy. However, this study highlights how identification of molecular subgroups of patients with MDS undergoing stem-cell transplantation can provide greater prognostic information, contribute to the choice of conditioning regimen (myeloablative or immunosuppressive), and help identify new targets for therapy.

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Ramya Ramaswami is a 2016-2017 NEJM editorial fellow. She is a medical oncologist within the National Health Services of the United Kingdom. Ramya received her medical degree, postgraduate medical and oncology training from Imperial College London, and a masters in public health from Columbia University, Mailman School of Public Health. Her clinical and research interests include cancer prevention, viral driven cancers, as well as disparities and access issues in global oncology.