Identifying Genetic Mutations That Can Predict Transplant Outcome in Patients With Myelodysplastic Syndromes

Though allogeneic hematopoietic cell transplantation (alloHCT) is the only curative option for myelodysplastic syndromes (MDS), transplant-related mortality, complication rates, and available, suitable donors preclude many patients from being able to undergo alloHCT.

Two reports published in the New England Journal of Medicine (NEJM) and Blood suggest that TP53 and RAS-pathway mutations – in the presence of a complex karyotype – predict poor post-alloHCT survival in patients with MDS. The results confirm that clinical sequencing provides vital information for accurate prognostication in alloHCT, the researchers noted.

“The genetic lesions that drive the pathogenesis of MDS predict overall survival (OS) and many aspects of clinical phenotype and may contribute to the outcome of patients after alloHCT,” wrote the authors of the NEJM paper, led by R. Coleman Lindsley, MD, PhD, from Dana-Farber Cancer Institute in Boston, Massachusetts.1 Current prognostic models, however, do not incorporate molecular genetic characteristics that may help predict post-transplant outcomes.

Dr. Lindsley and co-authors performed targeted mutational analyses of pre-alloHCT samples from 1,514 patients (age range = 6 months-70 years) with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014, then evaluated the association between mutations and post-alloHCT outcomes (OS, relapse, and death without relapse). Patients were excluded if the percentage of blasts in the bone marrow or blood was >20 percent or if they had a diagnosis of chronic myelomonocytic leukemia or overlap MDS/myeloproliferative neoplasms (MPNs).

Seventy-nine percent of patients (n=1,196) had at least one mutation, with a median of two driver mutations per patient (range = 0-15 mutations). “Mutations, including TP53 and DNMT3A, that are associated with higher-risk MDS according to the International Prognostic Scoring System were more prevalent in our cohort than in published cohorts of patients with MDS who had not undergone transplantation,” the authors wrote, “whereas mutations that are associated with lower-risk MDS, such as SF3B1, were less prevalent – findings that were consistent with the clinical practice to prioritize higher-risk cases for transplantation.”

TP53 mutations were the most common and were present in 19 percent of all patients (n=289). These were the only mutations independently associated with shorter survival and shorter time to relapse compared with the absence of these mutations (after adjustment for performance status, age, and hematologic variables):

  • hazard ratio (HR) for death = 1.71 (95% CI 1.45-2.02; p<0.001)
  • HR for shorter time to relapse = 2.03 (95% CI 1.60-2.58; p<0.001)

RAS pathway mutations (including NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT) were associated with shorter time to relapse (HR=1.56; 95% CI 1.18-2.05; p=0.002). JAK2 V617F mutations were associated with a higher rate of death without relapse (HR=2.10; 95% CI 1.36-3.24; p<0.001) but not a higher rate of relapse (HR=0.68; 95% CI 0.35-1.33; p=0.26).

Among patients without TP53 mutations (n=1,225; 1,011 patients ≥40 years of age), RAS pathway and JAK2 mutations remained significant predictors of shorter survival, when compared with patients without these mutations (median survival = 0.9 and 0.5 months vs. 2.2 and 2.3 years, respectively; p=0.004 and 0.001). Among the 214 patients <40 years of age, RAS pathway and JAK2 mutations were also associated with shorter survival, but only among patients with high-risk clinical features (therapy-related MDS, platelet count of <30×109/L at the time of alloHCT; OS = 2.6 years vs. not reached; p<0.001).

Notably, the adverse prognostic effect of TP53 mutations was similar in patients who received reduced-intensity conditioning regimens and those who received myeloablative conditioning regimens (OS = 7.5 months and 9.2 months, respectively; p=0.19), “calling into question the benefit of conventional myeloablative conditioning over reduced-intensity approaches” in these patients, Dr. Lindsley and colleagues observed. “By contrast, the adverse effect of RAS pathway mutations on the risk of relapse was evident only with reduced-intensity conditioning.”

In the second study, Tetsuichi Yoshizato, MD, PhD, from the Department of Pathology and Tumor Biology at Kyoto University in Japan, and co-authors published similar results, validating the prognostic role of TP53 and RAS pathway mutations in a large cohort of patients who had an initial diagnosis of MDS and received unrelated alloHCT through the Japan Marrow Donor Program.2 Unlike the paper led by Dr. Lindsley, this analysis included patients with MDS, MDS/MPN, and secondary acute myeloid leukemia.

Dr. Yoshizato and co-authors performed targeted-capture sequencing in 797 patients (median age = 53 years; range = 16-66 years), identifying 1,776 oncogenic driver mutations in 597 patients (75%).

TP53 mutations were, again, the most common mutation in this patient population (12.7%), followed by RAS pathway mutations (6.8%); 27.4 percent of patients had complex karyotype (detected by conventional cytogenetics), and 38.1 percent had high-risk cytogenetic abnormalities.

Eighty-eight percent of the 98 patients with TP53 mutations also had complex karyotype, whereas only 42 percent of patients with complex karyotype had mutated TP53. Together with complex karyotype, the presence of TP53 and RAS pathway mutations negatively affected post-alloHCT survival independently of clinical factors. Patients with both TP53 mutations and complex karyotype had a poorer prognosis than those without complex karyotype: OS was 4.8 months in the TP53-mutated and complex karyotype group, whereas 73 percent of TP53-mutated patients were alive at 60 months post-alloHCT. “Consideration for therapies other than alloHCT should be made for patients with [TP53 mutations and complex karyotype], whereas those with TP53 mutations without complex karyotype do comparatively well with alloHCT,” Dr. Yoshizato and co-authors wrote. Notably, the effects of RAS-pathway mutations depended on disease subtype and were confined to MDS/MPN.

“Our results confirm the significant effects of genetic abnormalities on the outcome of alloHCT for patients with these myeloid malignancies, independent of clinical factors,” Dr. Yoshizato and co-authors concluded. Their multivariate analyses determined that genetic factors explained 30 percent of the total hazards for OS; however, “70 percent of the risk associated with alloHCT in myelodysplasia is still associated with clinical factors, … and recommendations for alloHCT should be based on both clinical and molecular factors.”

Both sets of researchers cautioned that the results of their analyses should be validated in prospective cohorts and compared with outcomes of MDS patients with these mutations in the non-transplant setting.


References

  1. Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536-47.
  2. Yoshizato T, Nannya Y, Atsuta Y, et al. Impact of genetic alterations in stem-cell transplantation for myelodysplasia and secondary acute myeloid leukemia. Blood. 2017 February 8. [Epub ahead of print]

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