Navigating the Intricacies of alloHCT in Patients With Myelodysplastic Syndromes

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Allogeneic hematopoietic cell transplantation (alloHCT) is the most established and curative treatment for patients who have myelodysplastic syndromes (MDS), said Melvin Berlin Chair in Myeloma Research Sergio Giralt, MD, professor of medicine at Weill Cornell Medical College and deputy head of the division of hematologic malignancies, during a presentation at the Society of Hematologic Oncology (SOHO) 2024 Annual Meeting, held in Houston, Texas. Despite this, he urged that further clinical research and careful patient selection should be to better optimize patient outcomes.

In the session, Giralt begins by describing a patient case. The patient is a male aged 68 years who was diagnosed with immunoglobulin A (IgA) kappa myeloma in 2010 who—following triple induction under transplant—achieves a complete remission (CR) that is minimal residual disease (MRD)-negative. He received maintenance therapy with lenalidomide (Revlimid; Bristol Myers Squibb), but after 5 years, demonstrates progressive thrombocytopenia. Giralt described that it was unknown whether this patient, who should have a life expectancy of another 7 to 10 years, would be a suitable candidate because his disease state reduces his life expectancy to less than a year.

In a phase 1b trial, Giralt described how a combination of venetoclax (Venclexta; AbbVie, Genentech) and azacitidine (Vidaza; Bristol Myers Squibb) demonstrated high response rates in patients with treatment-naïve patients with high-risk MDS. Giralt explained that the clearance of TP53 in MDS can make a difference in transplant outcomes for those who are eligible candidates, such as the described patient. The combination therapy, according to Giralt, may present opportunities for this clearance, therefore, bettering outcomes for transplant patients.

Looking at research, Giralt points to the VidazaAllo (NCT01404741) study, a large, randomized clinical trial which showed significant event-free survival in the 109 studied patients with MDS who received alloHCT up front. He expressed that this finding is more significant than experts may realize. In the trial, compared with those who did not receive alloHCT up front, those who did had a better overall survival (OS) advantage (26.6% [95% CI: 18.4%, 35.6%] vs 47.9% [95% CI: 41.3%, 54.1%], respectively). This finding was present in all age groups, according to Giralt, including those who were over the age of 60 years. Quality of life in patients who received alloHCT was also reported to be stronger than in those who did not receive transplant (35.8% [95% CI: 29.8%, 41.8%] vs 20.6% [95% CI: 13.3%, 29.1%], respectively).

“This was, to me, the biggest game changer [within this space]. And still, after results were reported, in the US today, only 30% of patients who could benefit from alloHCT are referred for alloHCT,” explained Giralt. “There's a huge referral bias, and still, [I have] many colleagues who believe that there's no role for alloHCT [in a patient’s] sixth or seventh decade of life.”

With this information, Giralt returns back to the case patient to assess whether he can be transplanted. Patients over the age of 70 years, according to Giralt, are receiving more transplants with results being more positive than in previous years. One significant point learned is that incorporating comprehensive geriatric assessments is essential in order to give the right patients the correct treatment. Specifically, with MDS, these assessments can bring patients into transplant in “better situations.”

According to Giralt, once a patient with MDS is identified for alloHCT, pretreatment is not necessary, and patients should not have to undergo multiple cycles of pretreatment with hypomethylating agents; however, he emphasized that this finding may change if the combination of venetoclax and azacitidine continues to demonstrate favorable outcomes when reducing tumor burden within this population.

“What we have to do is stop doing the classic ‘triple-P’ transplant, where we push the drugs, pour the cells, and then pray that it all works out, to [instead] do transplants that are precise, personalized, and predictable,” urged Giralt. “The first [part of this] process is early referral to the transplant center. [For example,] one of the things we learned with [acute myeloid leukemia] is that when the transplant physician and the transplant service [are both] involved early in the course of the disease, we can increase pre-transplantation rates from [approximately] 30% to 70% because we can leverage all the resources of the transplant program, social workers, [and] financial counselors to try to be able to reduce the barriers of that patient to undergo transplant.”

Other than geriatric assessment, personalization can be accomplished through donor selection. Retrospective data show that for older patients who are above the age of 40 years, younger, and unrelated donors are associated with stronger results than a donor who is older and related to the patient. Giralt also explained that there is some evidence that suggests class II mismatch donors may reduce relapse incidence in the use of post-transplant cyclophosphamide-based HCT; however, further analysis is required to confirm the finding. Additionally, both drug intensity and dosing can also be utilized to personalized treatment when applicable.

Giralt concluded the session by emphasizing that alloHCT continues to be the most curative and established treatment for patients with MDS. He urged that age should no longer be considered a “barrier” to alloHCT for this patient population, and that comprehensive geriatric assessments and transplant planning are necessary to optimize patients’ outcomes.

“[The] continued development and participation in clinical trials will be essential to improve outcomes further, [and] trials will be essential to determine the best approach in regards to how I take a patient to transplant, how should I transplant them, and whether there are different maintenance strategies for different molecular profiles,” said Giralt. “Today, [the featured patient] remains MRD-negative, [achieved] CR for both his diseases, is off immunosuppressive therapies, and is without graft-versus-host-disease [following his transplant].”

REFERENCE

Giralt, S. Session II—Myelodysplastic Syndromes: Allogeneic HCT for MDS Current State and Future Challenges. Society of Hematologic Oncology Annual Meeting; Houston, Texas. September 4, to September 7, 2024.