Some patients with myelodysplastic syndromes (MDS) receive therapy before an allogeneic hematopoietic cell transplant (alloHCT) to improve their Revised International Prognostic Scoring System (IPSS-R) score, as a higher IPSS-R score at transplant is associated with worse transplant outcomes. Now, the results of a retrospective analysis, published in Blood, question this approach. The analysis showed that a worsened IPSS-R score after any downstaging therapy led to a much worse transplant outcome compared to cases when no therapy between diagnosis and transplant was administered to patients with MDS.1
“Our study compared the outcome of alloHCT in patients with MDS. The focus was on IPSS-R risk score at diagnosis and the potential change of this risk score between diagnosis and transplant,” said study author Christof Scheid, MD, of the Department of Medicine at the University of Cologne in Germany. “We investigated the role of therapy between diagnosis and transplant in relation to changed or unchanged IPSS-R risk.”
In a retrospective analysis of 1,482 patients with MDS from the European Society for Blood and Marrow Transplantation (EBMT) registry, the researchers found that if untreated patients had a change in their IPSS-R score, this did not affect their transplant outcomes. The study also found that an improved, IPSS-R score after chemotherapy to downstage the disease led to a moderately improved outcome, but this was not true when hypomethylating agents (HMA) were used for potential downstaging. Additionally, a worsened IPSS-R score after therapy, which reflected resistance to treatment, led to a much worse transplant outcome compared to cases with no therapy between diagnosis and transplant. Between diagnosis and alloHCT, the majority of patients showed an improved IPSS-R score (n=659), while 429 patients had an unchanged score, and 394 had worse risk category at transplant.
“Thus, our results clearly question the benefit of giving any therapy to patients with MDS while awaiting alloHCT,” Dr. Scheid said.
Thus far, no study has found a clear answer to the question of whether and which patients with MDS should receive induction therapy before an alloHCT, although the studies were relatively small and at a single center. Current recommendations suggest induction therapy for patients with greater than 10% blasts and secondary acute myeloid leukemia, in part based on studies from the 1980s and 1990s.2
“Since IPSS-R score at transplant is prognostic for transplant outcome, it feels logical that we should try to lower the IPSS-R score before transplant by applying therapy. This rationale has found broad acceptance; however, there is no empirical evidence for it,” Dr. Scheid said. “Physicians were, in particular, afraid to leave patients with high-risk MDS untreated for fear of disease progression while on the waiting list for transplant.”
The researchers analyzed a cohort of 1,482 patients with sufficient data in the registry to calculate their IPSS-R at diagnosis and at transplant. The median follow-up time for the cohort was 48.1 months, and the median time from diagnosis to an alloHCT was nine months.
There was a significant association between prior treatment and change in IPSS-R between diagnosis and transplant (p=0.008). Among the patients receiving chemotherapy who showed an improved IPSS-R, there was a significant benefit compared to those with an unchanged IPSS-R (hazard ratio [HR] = 0.55; 95% CI 0.41-0.76; p<0.001). In contrast, a progressive IPSS-R after treatment with an HMA had a significant negative effect compared to patients who had an unchanged IPSS-R after HMA induction therapy (HR=1.98; 95% CI 1.27-3.07; p=0.002).
In patients with high-risk IPSS-R at diagnosis and no change until transplant, the predicted five-year overall survival (OS) was 42% (95% CI 33-54%) without prior therapy, 28% (95% CI 19-42%) after chemotherapy, 41% (95% CI 30-56%) after HMA, and 29% (95% CI 17-49%) with other treatments. If IPSS-R improved between diagnosis and transplant, the five-year OS was estimated to be 40% (95% CI 29-56%) without prior therapy, 50% (95% CI 42-58%) with chemotherapy, 41% (95% CI 32-52%) with HMA, and 39% (95% CI 29-52%) with other treatments. In case of a worsening IPSS-R, OS was predicted to be 44% (95% CI 34-56%) with no prior therapy, 25% (95% CI 15-41%) after chemotherapy, 17% (95% CI 9-33%) after HMA, and 17% (95% CI 8-35%) with other treatments.
“The fact that untreated patients with progressive IPSS-R had no deterioration in transplant outcome was a surprise and should be reassuring both for patients and doctors to spare therapy to patients with MDS planned for transplant,” Dr. Scheid said. “The limited benefit of chemotherapy and no benefit after HMA induction therapy among patients with successful downstaging of IPSS-R was also unexpected.”
A limitation of the study was the inability of the authors to include “intent to transplant” patients, including those who died while awaiting transplantation. “While we have no data on these patients, we suspect that more patients will make it to transplant if they are spared the toxicity, morbidity, and mortality of prior therapy,” Dr. Scheid said.
The question of whether induction therapy is beneficial for patients with less than 10% blasts is being assessed in an ongoing prospective trial in Italy (ACROBAT [NCT04184505]) in which patients are randomized to upfront transplantation or HMA followed by transplantation.
For patients with more than 10% blasts, the authors also plan to perform a retrospective oligocentric analysis of patients being transplanted without prior therapy to validate the findings with a more contemporary cohort of patients.
“This EBMT study underlines the importance of collecting registry data of large numbers of patients to provide clinically relevant outcome analyses for questions that are not covered by current evidence,” Dr. Scheid said. “Especially when it comes to treatment sequences, prospective studies are scarce and difficult to perform.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Scheid C, Eikema D, Gelder M, et al. Does IPSS-R down staging before transplantation improve the prognosis of patients with myelodysplastic neoplasms? [published online ahead of print, 2024 May 10]. Blood. doi 10.1182/blood.2023022273.
- Runde V, de Witte T, Arnold R, et al. Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Bone Marrow Transplantation. 1998;21(3):255-261.
