Genetic profiling can be used to determine which patients with myelodysplastic syndrome (MDS) are likely to benefit from allogeneic hematopoietic stem cell transplant (HSCT), according to research published in NEJM.
Targeted sequencing of 129 genes revealed mutations that, after adjustment for clinical variables, were associated with shorter survival and/or relapse after HSCT.
Patients with mutations in TP53, JAK2, and the RAS pathway tended to have worse outcomes after HSCT than patients without such mutations.
“Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself,” said study author R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts.
“As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse.”
Researchers have long known that specific genetic mutations are closely related to the course MDS takes. With this study, Dr Lindsley and his colleagues sought to discover whether mutations can be used to predict how patients will fare following allogeneic HSCT.
The team analyzed blood samples from 1514 MDS patients, performing targeted sequencing of 129 genes. The genes were selected based on their known or suspected involvement in the pathogenesis of myeloid cancers or bone marrow failure syndromes.
Dr Lindsley and his colleagues then evaluated the association between mutations and HSCT outcomes, including overall survival, relapse, and death without relapse.
After adjusting for significant clinical variables, the researchers found that having mutated TP53 was significantly associated with shorter survival and shorter time to relapse after HSCT (P<0.001 for both comparisons). This was true whether patients received standard conditioning or reduced-intensity conditioning.
In patients age 40 and older who did not have TP53 mutations, mutations in RAS pathway genes (P=0.004) or JAK2 (P=0.001) were significantly associated with shorter survival.
The shorter survival in patients with mutated RAS pathway genes was due to a higher risk of relapse, while the shorter survival in patients with JAK2 mutations was due to a higher risk of death without relapse.
In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in patients who received reduced-intensity conditioning (P<0.001). This suggests these patients may benefit from higher intensity conditioning regimens, the researchers said.
This study also yielded insights about the biology of MDS in specific groups of patients.
For example, the researchers found that 4% of MDS patients between the ages of 18 and 40 had mutations associated with Shwachman-Diamond syndrome (in the SBDS gene), but most of them had not previously been diagnosed with the syndrome.
In each case, the patients had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after HSCT.
The researchers also analyzed patients with therapy-related MDS. The team found that TP53 mutations and mutations in PPM1D, a gene that regulates TP53 function, were far more common in these patients than in those with primary MDS (15% and 3%, respectively, P<0.001).
“In deciding whether a stem cell transplant is appropriate for a patient with MDS, it’s always necessary to balance the potential benefit with the risk of complications,” Dr Lindsley noted.
“Our findings offer physicians a guide—based on the genetic profile of the disease and certain clinical factors—to identifying patients for whom a transplant is appropriate, and the intensity of treatment most likely to be effective.”
