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Reduced-intensity, standard conditioning demonstrate comparable transplant outcomes in myelodysplastic syndrome
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A reduced-intensity conditioning regimen yielded comparable RFS and OS as standard myeloablative conditioning among patients with myelodysplastic syndrome, according to results of the phase 3 RICMAC clinical trial.
“Our study shows that [reduced-intensity conditioning regimen] and [myeloablative conditioning regimen] followed by allogeneic stem cell transplantation results in at least an equivalent survival trend for a better 2-year OS, especially in the cytogenetic low-risk group, and can be offered as an alternative to a myeloablative regimen,” Nicolaus Kröger, MD, from the department of stem cell transplantation at University Medical Center Hamburg-Eppendorf in Germany, and colleagues wrote.
The European Leukemia Net recommends a standard myeloablative condition regimen for all patients with myelodysplastic syndrome without comorbidities prior to allogeneic transplantation. However, these recommendations are based solely on retrospective single-center or registry studies in which age groups have not been consistent among patients, which could lead to different outcomes.
To avoid selection bias, Kröger and colleagues conducted a prospective multicenter open-label trial. They randomly assigned 129 patients with myelodysplastic syndrome or acute myeloid leukemia to a busulfan-based standard myeloablative conditioning regimen (n = 64; median age, 50 years; range, 19-64) or busulfan-based reduced-intensity conditioning regimen (n = 65; median age, 51 years; range, 22-63) followed by allogeneic stem cell transplantation.
The researchers matched all patients based on donor, age and blast count at the time of transplantation.
Nonrelapse mortality at 1 year served as the study’s primary endpoint.
Patients assigned the reduced-intensity and myeloablative treatments demonstrated comparable
cumulative incidence of stage II to stage IV acute graft-versus-host disease (GVHD; 32.3% vs. 37.5%) and chronic GVHD (61.6% vs. 64.7%).
Nonrelapse mortality after 1 year occurred in 17% (95% CI, 8-26) after reduced-intensity conditioning compared with 25% (95% CI, 15-36) after myeloablative conditioning.
Relapse at 2 years occurred in 17% (95% CI, 8-26) of the reduced-intensity group and 15% (95% CI, 6-24) of the myeloablative group.
Reduced-intensity conditioning conferred higher 2-year RFS (62% vs. 58%) and OS (76% vs. 63%).
Multivariate analysis showed advanced disease increased risk for relapse (HR = 13.26; 95% CI, 1.77-99.14) but reduced-intensity conditioning had an HR of 1.05 (95% CI, 0.44-2.54).
Advanced disease increased risk for poor RFS (HR = 2.77; 95% CI, 1.3-5.91), whereas reduced-intensity conditioning regimen did not (HR = 1.05; 95% CI, 0.44-2.54). Reduced-intensity conditioning also improved OS (HR = 0.41; 95% CI, 0.19-0.87).
Because the results of the RICMAC trial are based on the standard therapy of busulfan/cyclophosphamide — which is linked to higher transplant-related mortality — more data are needed, Michael A. Pulsipher, MD, section head of blood and marrow transplantation at the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles, wrote in a related editorial.
“More data from the use of the safer myeloablative conditioning regimen approach of higher-dose busulfan/fludarabine compared with busulfan/fludarabine [reduced-intensity conditioning] or compared with fludarabine/melphalan [reduced-intensity conditioning] are needed to make a more compelling argument for use of [reduced-intensity conditioning] for myelodysplastic syndrome, especially for advanced myelodysplastic syndrome,” Pulsipher wrote.
Although a large number of centers participated, the small number of patients left the trial “severely underpowered,” according to Pulsipher.
Despite a trend toward improved OS among patients who received reduced-intensity conditioning, questions remain unanswered and the case for the treatment for myelodysplastic syndrome is even more challenging.
“For patients with myelodysplastic syndrome who are well and who are candidates for [myeloablative conditioning] approaches, is [reduced-intensity conditioning] worth the gamble?” Pulsipher wrote. – by Melinda Stevens
Disclosures: Pierre Fabre provided partial support for the study. Kröger reported honoraria from Gilead Sciences, Neovii and Novartis; consultant/advisory roles with Medac, Neovii and Novartis; and research funding from Celgene, Neovii and Riemser. Please see the full study for a list of all other researchers’ relevant financial disclosures. Pulsipher reports consultant or advisory roles with CSL Limited, Jazz Pharmaceuticals and Novartis; research funding from Adaptive Biotechnologies; and travel, accommodations and expenses from Medac.
Perspective
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This study surely poses an important question: Should patients undergoing hematopoietic cell transplantation for myelodysplastic syndrome (MDS) receive myeloablative or reduced-intensity conditioning? The authors’ conclusion that reduced-intensity regimens result in at least similar RFS and OS, however, appears less certain.
A determination of noninferiority requires an appropriately designed and sufficiently powered trial. This trial was neither designed nor powered to analyze this endpoint. It was designed to detect a lower nonrelapse mortality at 1 year, was underpowered to do so because of lower-than-expected nonrelapse mortality in the myeloablative arm, and was stopped far short of the planned 160 patients because of slow accrual.
Further limiting the conclusion, the “standard” myeloablative arm included many patients — up to 65 years of age — who received 16 mg/kg of orally administered busulfan with no requirement for dose adjustment based on plasma levels, an approach many consider substandard.
Most importantly, it is unlikely that this small sample of patients actually is representative of the larger population of patients with MDS selected to undergo transplantation, undermining its ability to help answer the questions posed. Would a young, high-risk MDS patient with an HLA-identical sibling be entered on this study or simply proceed with a myeloablative transplant? Because the precise criteria for hematopoietic cell transplantation are not defined, might patients at low risk for relapse undergoing transplantation on this trial diminish the potential relapse-lowering advantage of myeloablation?
Important questions regarding transplantation in MDS abound and concern patient selection, timing, conditioning regimens, donor source and approach to GVHD. The answers are harder to come by. The limitations of this study are common and serve as a reminder that prospective randomized studies are not immune from the complexities of determining the best endpoints, eligibility criteria and methods.
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