Optimizing Post-Transplant Outcomes for Patients With MDS

Two analyses from the European Society for Blood and Marrow Transplantation (EBMT) reported on post-allogeneic hematopoietic cell transplantation (alloHCT) among patients with myelodysplastic syndromes (MDS), with a goal of identifying patient and procedural factors that could help clinicians better select patients who would benefit most from alloHCT.

Examining Excess Mortality Risk in Post-Transplant MDS
In the first study, Johannes Schetelig, MD, MSc, from the University Hospital Dresden in Germany, and colleagues compared outcomes of patients diagnosed with MDS who received alloHCT with matched controls in the general population to define the excess mortality risk associated with the disease.1

The authors included data from adult patients with MDS who had received a first alloHCT between January 2000 and December 2012 and were registered with the EBMT database. Patients who received unmatched related alloHCT or cord-blood transplantation and those with >20 percent bone marrow blasts at any point during their treatment history were excluded from the analysis. They then calculated excess mortality in patients with MDS relative to age-, sex-, country-, and calendar year-matched members of the general population.

A total of 3,813 patients were included in the analysis (60% male), and patients were followed for a median of 49 months (range not provided).

The number of alloHCTs performed each year increased substantially during the study period – from 56 in 2000 to 660 in 2012. The median age at the time of transplant also rose – from 47 years (range = 18-66 years) in 2000 to 57 years (range = 18-74 years) in 2012.

Thirty-nine percent of patients had a human leukocyte antigen (HLA)-matched sibling donor and 58 percent received reduced-intensity conditioning.

In the overall patient cohort, 5-year overall survival (OS) was 46 percent (95% CI 45-48) and 10-year OS was 40 percent (95% CI 37-42). Age and the presence of excess blasts affected the post-transplant survival outcomes, with 10-year OS probabilities highest in young patients and those with a lower disease burden:

  • patients <55 years of age versus ≥55 years of age: 48% (95% CI 45-51) and 31% (95% CI 28-34)
  • with versus without excess blasts: 33% (95% CI 30-37) and 46% (95% CI 43-49)

Two years after alloHCT, the probability of event-free survival was 52 percent (95% CI 50-54). Among patients who were alive at 2 years, the likelihood of surviving to 10 years post-alloHCT was even greater for younger patients and those with a lower disease burden: 82 percent (95% CI 78-86) and 65 percent (95% CI 59-72) for patients <55 years of age or ≥55 years of age, and 68 percent (95% CI 62-74) and 81 percent (95% CI 77-85) for patients with or without excess blasts at alloHCT.

For patients ≥65 years of age, compared with age-matched controls in the general population, the probability of survival at 5 years was 70 percent (95% CI 58-85) for older male patients and 88 percent for their matched controls, and 65 percent (95% CI 49-86) and 93 percent for older female patients.

“Long-term follow-up data derived from the EBMT registry show that patients experience excess mortality, compared with the general population, also beyond the 2-year landmark,” Dr. Schetelig and co-authors concluded, noting that the post-transplant mortality risk from causes also relevant to the matched population, such as cardiovascular disease, were similar. “However, for elderly patients this background, mortality should be considered when interpreting results after alloHCT.”

Haplo-Identical and Mismatched Transplant
In the second trial, Marie Robin, MD, PhD, from Saint-Louis Hospital in Paris, France, and researchers analyzed outcomes among patients with intermediate- and high-risk MDS who received an alloHCT from an HLA-mismatched related donor or haplo-identical donors, finding similar survival rates between both cohorts.2 They were also able to identify several factors associated with post-transplant outcome in each group.

Dr. Robin and co-authors included 230 consecutive patients with a primary diagnosis of MDS who received alloHCT from an HLA-mismatched related donor (<4 mismatches) and haploidentical donors (5 HLA mismatches) between 2007 and 2014 who were included in the EBMT registry.

The median age at transplant was 56 years (range = 46-64 years), and patients had the following MDS classifications, according to 2008 World Health Organization criteria:

  • refractory cytopenia with multilineage dysplasia: 31 (13.5%)
  • refractory anemia with ring sideroblasts and del5q: 12 (5.2%)
  • refractory anemia with excess blasts-1: 36 (15.7%)
  • refractory anemia with excess blasts-2: 67 (29.1%)
  • MDS transformed to acute myeloid leukemia (AML): 84 (36.6%)

More than three-quarters of patients (n=181; 78.7%) had ≥2 HLA mismatches with the donor, while other patients had only one HLA mismatch (n=49; 21.3%). The majority of patients received a reduced-intensity conditioning (RIC) regimen pre-transplant (n=117; 51.5%), while 62 (27.3%) received a total body irradiation. In vivo T-cell depletion was performed in 105 (46.1%) patients, while ex vivo T-cell depletion was performed in 34 (14.9%) patients.

The rates of 3-year OS and disease-free survival (DFS) were 32 percent (95% CI 26-41) and 29 percent (95% CI 23-37), respectively. The cumulative incidence of non-relapse mortality (NRM) at 3 years was 49 percent (95% CI 41-56), and NRM was particularly high in patients who received a myeloablative conditioning regimen, compared with those who received RIC (59% vs. 40%; p value not provided), the authors noted.

Rates of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 31 percent (95% CI 25-38) and 30 percent (95% CI 23-36), respectively.

When restricting the analysis to patients who received cyclophosphamide as GVHD prophylaxis (n=102; 44.7%), rates of 3-year OS and DFS were slightly higher than the overall patient population (38% and 34%), and the rate of NRM was reduced (41%).

The researchers identified several factors associated with OS, DFS, and NRM, including transformation to AML, not in complete remission at time of transplant, a female donor for a male recipient, myeloablative conditioning regimen, and no use of cyclophosphamide (TABLE). The authors attributed the improvement in DFS over time to an increase in the use of prophylactic cyclophosphamide treatment, but noted that rates of NRM remain “relatively high,” even with cyclophosphamide treatment.

Authors of both analyses noted that missing data in the registries could have affected the study results.


References

  1. Schetelig J, de Wreede L, van Gelder M, et al. Long-term survival of patients with MDS after allogeneic transplantation: a report from the Chronic Malignancies Working Party of EBMT. Oral abstract presented at the 43rd Annual Meeting of the European Society for Blood and Marrow Transplantation, March 28, 2017; Marseilles, France.
  2. Robin M, Porcher R, Ciceri F, et al. Haplo-identical transplantation (haplo-HSCT) in patients with myelodysplastic syndrome (MDS): a report from the European Society of Blood and Marrow Transplantation. Oral abstract presented at the 43rd Annual Meeting of the European Society for Blood and Marrow Transplantation, March 28, 2017; Marseilles, France.

 

TABLE. Factors Associated With DFS, OS, and NRM (According to Multivariable Analyses)2
DFS OS NRM
Hazard ratio P value Hazard ratio P value Hazard ratio P value
Transformation to AML 1.84 0.033 2.19 0.01 1.83 0.069
Not in complete remission at time of transplant 1.93 0.001 1.90 0.002 1.76 0.017
Female donor for male recipient 1.53 0.062 1.67 0.030 1.94 0.016
Myeloablative conditioning 1.47 0.048 1.56 0.026 1.70 0.023
Prophylactic cyclophosphamide treatment 0.49 0.038 0.44 0.025 0.40 0.027
DFS = disease-free survival; OS = overall survival; NRM = non-relapse mortality; AML = acute myeloid leukemia

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