Though randomized trials have found that azacitidine prolongs survival in patients with myelodysplastic syndrome (MDS),1,2 few patients achieve complete remission after hypomethylating agent (HMA) therapy, and it is not curative. Conversely, allogeneic hematopoietic stem cell transplantation (HCT) is a path to potential cure for patients with MDS. Historically, this approach was limited by nonrelapse mortality and transplant-related complications. These risks are greater in older, comorbid patient populations, which makes HCT a difficult proposition for many of the typical, older patients with MDS. Advances such as universal antimicrobial prophylaxis and gentler conditioning regimens have made transplants safer and better tolerated, especially in older populations. Two large multicenter prospective trials addressing whether patients with MDS, particularly those who are advancing in years (≥ 65 years), have improved outcomes undergoing HCT have recently been published.
Dr. Ryotaro Nakamura and colleagues of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) enrolled 384 patients with de novo MDS (≥ intermediate-2 by the International Prognostic Scoring System [IPSS]) aged 50 to 75 years between January 2014 and November 2018. Patients were assigned to a donor or no-donor arm based on a matched donor search. Those with a human leukocyte antigen (HLA)–matched donor were expected to undergo HCT with reduced-intensity conditioning within six months of enrollment; those without were expected to receive non-HCT–based therapy. Patients in the donor arm were not prescribed a pre-HCT therapeutic strategy; most patients received HMAs even before trial registration. In an intention-to-treat (ITT) analysis, the donor arm had significantly higher leukemia-free survival (35.8% vs. 20.6%, p=0.003) and overall survival (OS; 47.9% vs. 26.6%, p=0.0001) at three years. The noncompliance rate was 26.3 percent; as-treated analysis showed findings similar to the ITT results. Patient-reported quality of life outcomes were similar in both groups at multiple time points.
Dr. Nicolaus Kröger and colleagues of the German Cooperative Transplant Study Group evaluated 190 patients with de novo or therapy-related MDS and related myeloid malignancies ages 55 to 70 years in a prospective, multicenter trial conducted between June 2011 and November 2016. Distinct from the BMT CTN trial, this one stipulated treatment with four cycles of azacitidine prior to assignment to a treatment arm, with an HLA-compatible donor required to move forward to HCT. Patients without a donor would continue HMA until disease progression or intolerable toxicity. Of the 162 patients who began HMA therapy, only 108 (67%) were eligible for treatment assignment mainly due to progressive disease, adverse events, and death from infectious complications. Event-free survival was superior in the 81 HCT recipients: 34 percent at three years versus 0 percent in the 27 patients receiving continuous azacitidine (p<0.0001). However, the difference in three-year OS was not statistically significant (50% in HCT group vs. 32%; p=0.1236). An as-treated analysis accounting for patients who crossed out of their assigned group (14 received salvage allografts from alternative donors) still found no difference in three-year OS (difference of 0.20 years, 95% CI, −0.11–0.50).
In Brief
These are the first prospective studies studying older patients with higher risk MDS undergoing HCT (or no HCT) based on a biologic factor (presence of a fully matched donor). Both studies examined adults diagnosed with de novo higher risk MDS. Dr. Nakamura and colleagues evaluated a broader age range of patients. The German study was more heterogenous and included patients with therapy-related MDS, dysplastic-type chronic myelomonocytic leukemia, and MDS with intermediate IPSS scores (and high-risk cytogenetics). Both studies were “biologic assignment” in nature, highlighting the ethical quandaries in pursuing a truly randomized controlled study that arbitrarily assigns patients with life-limiting illness to a potentially curative treatment option or not. Both ultimately had patients without a matched donor who subsequently underwent alternative donor HCT, with outcomes among this group appearing favorable.
Importantly, these studies demonstrated that higher risk MDS patients with an available donor have better outcomes than those without, most consistently three-year event/leukemia-free survival. OS at three years was better by 21 percent in HCT recipients per the BMT CTN study; the 18 percent difference found by Dr. Kröger and colleagues was not statically significant, likely due to the study being underpowered. These findings were consistent in as-treated analyses. Subgroup analyses showed benefit to HCT in patients older than 65 years in both studies, and quality of life outcomes were no worse in HCT recipients per the BMT CTN study. Given these results, we hope Medicare beneficiaries will be ensured coverage for HCT.3,4 Interestingly, the increased flexibility afforded in the pre-HCT HMA therapy in the BMT CTN study illustrates how inconsistent responses to HMA can be and the clinical and practical value of earlier referral for consideration of HCT. Consideration of alternative donors can also eliminate the no-donor arm for patients. We hope early referral to a transplant center and broad, equitable, and timely access to HCT for older patients with higher risk MDS can comfortably become the standard.
Competing Interests
Dr. Hochman and Dr. DeZern indicated no relevant conflicts of interest.
