HSCT significantly improves outcomes among older patients with myelodysplastic syndrome
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Older patients with myelodysplastic syndrome who underwent donor-matched allogeneic hematopoietic stem cell transplant had significantly improved survival outcomes compared with those who did not have a matched donor, study results showed.
The findings, presented at the virtual ASH Annual Meeting and Exposition, showed adjusted 3-year OS rates of 47.6% for those with a suitable HLA-matched donor and 26.6% for those without such a donor. In addition, researchers observed no clinically significant differences in quality-of-life measurements between the donor and no-donor groups.
Previous studies of older patients with myelodysplastic syndrome have shown that allogeneic HSCT leads to superior outcomes compared with hypomethylation alone, according to Corey Cutler, MD, MPH, FRCPC, medical director of the adult stem cell transplantation program at Dana-Farber Cancer Institute.
Two previous studies conducted in Europe also have shown that HSCT improves survival when patients have HLA-matched donors for transplantation. However, the number of control subjects in the two European trials was low and subsequent prospective studies did not indicate a benefit for HSCT in older patients with myelodysplastic syndrome, Cutler said during a presentation.
Cutler told Healio his group was motivated to conduct the multicenter, open-label, biologic assignment study for several reasons. First was the “lack of acceptance of transplantation by many community-based hematologists who do not refer their patients for transplantation.”
Second, Cutler said payers lack a uniform policy on HSCT for patients with myelodysplastic syndrome.
Finally, Cutler cited a lack of understanding regarding the cost-effectiveness of HSCT compared with nontransplant treatment strategies.
“Allogeneic transplant is not offered to a large proportion of older individuals with high-risk myelodysplastic syndrome and is not a covered service by Medicare in the United States,” he said during the presentation.
The study included 384 older patients (median age, 66.7 years; 61.2% age 65 years; 62.8% men) with intermediate- or high-risk myelodysplastic syndrome who were eligible for reduced-intensity conditioning allogeneic HSCT. Researchers enrolled patients at 34 centers before a formal donor search.
The 260 patients for whom an HLA-matched donor was found within 90 days were assigned to undergo reduced-intensity conditioning HSCT within 6 months of study enrollment. The 124 patients for whom a suitable donor could not be found within 90 days received standard supportive care.
The groups were evenly matched with regard to age, gender, myelodysplastic syndrome risk score, disease duration and response to previous hypomethylating therapy.
Three-year OS, determined using adjusted survival estimates to limit potential bias from the biological assessment, served as the study’s primary endpoint. Researchers also assessed leukemia-free survival, changes in quality of life and cost-effectiveness between the study groups.
Median follow-up was 34.2 months (range, 2.3-38) in the donor group and 26.9 months (range, 2.4-37.2) in the no-donor group.
The intent-to-treat analysis showed an adjusted 3-year OS rate of 47.9% (95% CI, 41.3-54.1) in the donor group and 26.6% (95% CI, 18.4-35.6) in the no-donor group, for an absolute difference of 21.3% (95% CI, 10.2-31.8).
The donor group had a higher 3-year leukemia-free survival rate (35.8%; 95% CI, 29.8-41.8) than the no-donor group (20.6%; 95% CI, 13.3-29.1).
A subgroup analysis showed more favorable OS among patients with donors for both those aged 65 years or younger (OR = 2.43; 95% CI, 1.03-5.71) and those aged 66 years and older (OR = 2.96; 95% CI, 1.42-6.14).
The as-treated analysis “demonstrated a strong advantage for HSCT therapy over non-HSCT therapy,” according to Cutler, with a 3-year OS rate of 47.4% (95% CI, 40.1-54.5) in the donor group compared with 16% (95% CI, 8.4-25.9) in the no-donor group (absolute improvement, 31.4%; P < .0001) and superior leukemia-free survival in the donor group (39.3% vs. 10.9%; absolute improvement, 28.4%; P < .0001).
Researchers observed no clinically significant differences in quality life between the study arms, as assessed using the FACT-G, the MOS-SF36 Physical and Mental Component Scores and the EQ-5D utility score.
Results of the ongoing cost-effectiveness analysis will be presented at a later date, Cutler said during the presentation.
He said that HSCT has been underutilized in older patients with myelodysplastic syndrome; therefore, the results of this study should have an impact on clinical practice.
“We are hoping this will lead to greater acceptance of reduced-intensity transplantation by community hematologist-oncologists and will result in earlier referral for transplantation,” he told Healio.
Perspective
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Lisa Hicks, MD
These findings suggest allogeneic hematopoietic stem cell transplantation improves survival for adults aged 50 to 75 years with high-risk myelodysplastic syndrome. Importantly, results were similar among patients [older than age] 65 years when compared with those [younger than age 65 years]. The results offer the most definitive evidence to date that this type of stem cell transplantation significantly improves the outlook for older adults with high-risk myelodysplastic syndrome who would otherwise face a high likelihood of dying.
To know that older patients do well or as well after HSCT is a very important message to take away from this study.
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This practice-changing prospective trial — which I believe should have been a plenary paper —resulted from a substantial grassroots movement by advocacy groups, including The Leukemia & Lymphoma Society, MDS Foundation, National Marrow Donor Program, ASH and American Society for Transplantation and Cellular Therapy (previously the American Society for Blood and Marrow Transplantation).
To appreciate the importance of this study, it’s important to know its history. About 10 years ago, Medicare did not consider transplant for myelodysplastic syndrome a covered benefit. So, patients with myelodysplastic syndrome aged older than 65 years often had to wait until their disease had evolved into an acute leukemia before they could undergo a transplant covered by Medicare. This was absurd, because we know transplant before transformation was associated with better outcomes.
Based on lobbying by the National Marrow Donor Program and American Society for Transplantation and Cellular Therapy, CMS agreed to provide coverage with evidence determination, meaning patients could be transplanted for a set period of time, during which a study would be conducted to provide evidence to CMS showing that transplant is beneficial for Medicare beneficiaries.
The Blood and Marrow Transplant Clinical Trials Network of the Center for International Blood and Marrow Transplant Research designed the trial as a deliverable of that commitment. The study, conducted for more than 5 years, accrued a large number of patients. It was designed in such a way that there wasn’t true randomization, but biological assignment or biological randomization. Patients for whom donors were identified underwent transplant and were compared with a group for whom donors were not identified within a certain time period.
As we expected, the donor group not only had a significant PFS benefit, but also a significant OS benefit, to the order of magnitude of almost 28 percentage points. Now, we expect that CMS will consider transplant a covered benefit, and there will no longer be this coverage with evidence determination issue.
Further, a lot of patients with myelodysplastic syndrome weren’t being referred for transplant based on a lack of data. This provides strong data that should move the referring physicians, particularly those who are not closely linked to transplant centers, to consider their patients for transplant evaluation. Transplant evaluation earlier rather than later is important in order to catch patients earlier and increase access to transplant.
Although this study did not include mismatch-unrelated donors or mismatched-related donors, we believe with post-transplant cyclophosphamide as a platform, everyone has a donor. This study definitely answers the question about the role of transplant, but it doesn’t answer the question of which is the optimal transplant platform, whether it’s reduced intensity or myeloablative, whether we should be doing maintenance, and how we can improve outcomes. We are still trying to answer these questions with prospective trials. But, with the currently available treatments for myelodysplastic syndrome, we should be bridging most people to transplant if they are candidates.
Memorial Sloan Kettering Cancer Center
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Nakamura R, et al. Abstract 75. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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