Allo-HSCT did not improve survival outcomes in patients with lower-risk myelodysplastic syndrome who had some higher-risk features.
Receipt of allogeneic hematopoietic stem cell transplant (allo-HSCT) failed to improve overall survival (OS) compared with no transplant in patients with lower-risk myelodysplastic syndromes (MDS) harboring some higher-risk features, according to data from the phase 2 MDS-ALLO-RISK trial (NCT02757989) published in Blood.1
Findings demonstrated that at a median follow-up of 35.5 months, including a median follow-up of 50 months (IQR, 38.8-57.2) for patients who were still alive, patients who had a donor (n = 62) experienced a 3-year OS rate of 57.6% (95% CI, 46.2%-71.7%) compared with 64.3% (95% CI, 43.5%-95.0%) for those who did not have a donor (n = 15; HR, 0.75; 95% CI, 0.31-1.82; P = .53).
Among the 28 patients in the donor group who died, 7 died due to disease progression. Disease progression led to death in 3 of 6 patients who died in the no-donor group. In 17 patients who underwent allo-HSCT and died without disease progression, 11 died after experiencing grade 3/4 acute graft-vs-host disease (GVHD), and 1 died following severe chronic GVHD. In the 11 patients who died after severe acute GVHD, 5 deaths were due to infection.
Allo-HSCT in Lower-Risk MDS With Higher-Risk Features: Key Takeaways
“OS did not statistically differ among patients with lower-risk MDS harboring some high-risk features with or without transplantation, with the limitation of a low number of patients in this study,” lead study author Marie Sébert, MD, PhD, of Hôpital Saint-Louis in Paris, France, and colleagues wrote in the publication. “However, patients who had received a transplant were more often in remission than those who [had] not.”
Although allo-HSCT represents the only potential curative strategy for MDS, Sébert and colleagues noted that the benefit of upfront transplant has been limited to patients with higher-risk disease per International Prognostic Scoring System (IPSS) criteria due to the relative high mortality associated with allo-HSCT, with prior retrospective data underscoring this notion.2
However, the potential benefit of transplant in patients with lower-risk MDS remains under debate, and prior to the release of the Molecular IPSS (IPSS-M) criteria in 2016, the MDS-ALLO-RISK trial was launched to investigate whether allo-HSCT improved survival in patients with lower-risk disease that featured some higher-risk characteristics.1
Investigators enrolled patients 18 to 69 years of age with low- or intermediate-1–risk MDS per World Health Organization 2016 criteria, including chronic myelomonocytic leukemia. Patients also had to have at least 1 of the following high-risk criteria: intermediate- or higher-risk disease per Revised IPSS (IPSS-R) criteria; thrombocytopenia with a platelet level less than 20 x 109/L; neutropenia with an absolute neutrophil count less than 0.5 x 109/L; or progression following 2 prior lines of therapy. The study excluded patients who had standard contraindications for allo-HSCT, those with prior active cancer within 3 years of enrollment, and patients with uncontrolled infection.
Patients who met enrollment criteria were permitted to join the study, and the search for a related or unrelated 10/10 HLA-matched donor began. Patients with a donor identified within 2 months were assigned to the donor group, and those without a donor were assigned to the no-donor cohort.
Allo-HSCT was recommended within 4 months for patients in the donor arm, and those in the no-donor group received investigator’s choice of therapy. In the transplant group, patients underwent a conditioning regimen comprising busulfan at 3.2 mg/kg per day for 2 days, fludarabine at 30 mg/m2 per day for 5 days, and antilymphocyte globulin (Grafalon) at 10 mg/kg per day for 3 days. Patients in the donor arm also received infection prophylaxis via valaciclovir and sulfamethoxazole/trimethoprim or sulfadoxine/pyrimethamine or atovaquone. GVHD prophylaxis consisted of cyclosporine at full doses on days 1 to 120, followed by a 25% decrease per week, along with mycophenolate mofetil from days 1 to 45.
In the trial’s overall population (n = 77), the median age was 62.2 years (range, 58-65), and 67.5% of patients were male. The median time from diagnosis was 17.8 months (range, 5.2-36.3). Patients had a median hematopoietic cell transplantation comorbidity index of 1 (range, 0-2) and an ECOG performance status of 0 (range, 0-1).
Per IPSS-R criteria, patients had very low- to low-risk disease (28%), intermediate-risk disease (51%), and high-risk disease (21%); data were missing for 1 patient. Per IPSS-M criteria, disease risk included very low (2.8%), low (28.9%), moderate low (22.2%), moderate high (15.3%), high (20.8%), and missing (n = 5).
Among the 62 patients in the donor group, 58 underwent allo-HSCT; reasons for not receiving transplant included death (n = 2) and disease progression (n = 2). In the no-donor group, 4 of 15 patients received allo-HSCT with an alternate donor due to disease progression, with transplants performed at 4.7, 5.2, 5.4, and 35 months, respectively, following study inclusion.
Data demonstrated that patients in the donor arm achieved a 36-month complete remission rate of 67.8% (95% CI, 53.9%-78.3%) vs 21.4% (95% CI, 4.8%-45.8%) in the no-donor arm (P = .002). Progression to acute myeloid leukemia by 36 months occurred in 3.4% (95% CI, 0.6%-10.2%) of patients in the donor group vs 0% of patients in the no-donor arm (P = .49).
The rates of disease progression at 36 months were 27.8% (95% CI, 17.2%-39.5%) in the donor arm compared with 42.6% (95% CI, 16.4-66.8) in the no-donor arm. The respective 36-month rates of no-relapse mortality were 24.7% (95% CI, 14.6%-36.1%) and 7.2% (95% CI, 0.4%-29%).
Quality-of-life (QOL) outcomes were not significantly different between the 2 treatment groups at baseline (81.2% in the donor group vs 77.9% in the no-donor group; P = .81) or at 36 months (89.7% vs 78.8%; P = .64).
Regarding safety, severe infections were reported at 12 months in 38.9% (95% CI, 26.4%-51.1%) of patients in the donor arm vs 21.0% (95% CI, 4.7%-45.1%) of patients in the no-donor arm (P = .69). The rates of hemorrhages were 21% and 13%, respectively. Grade 3 cardiovascular adverse effects were reported in 7.2% of patients in the donor group vs 28.6% of patients in the no-donor group.
Ultimately, due to slow recruitment and the estimated low probability of reaching the OS primary end point, the study was stopped in 2021.
The study authors explained that improvements in allo-HSCT administration and prophylaxis may have occurred since the study period, but they noted it was difficult to estimate whether these improvements could have affected the study’s outcomes.
“The strategy for patients with lower-risk MDS to undergo transplantation when they progress to a higher risk is still valuable. More investigations should be done to reduce posttransplant mortality and complications to improve survival and QOL in patients in the specific population studied in this trial,” Sébert and colleagues concluded.
