Should Patients With Myelodysplastic Syndromes Undergo Transplant?

Associate Professor of Medicine, Harvard Medical School
Senior Physician, Dana-Farber Cancer Institute
Assistant Professor of Medicine, Division of Oncology, University of Washington
Director of Hematology and Hematologic Malignancies, Seattle Cancer Care Alliance

For patients with myelodysplastic syndromes (MDS), hematopoietic cell transplantation (HCT) is the only potentially curative option, but the rates of transplant-related morbidity and mortality preclude some patients from receiving this intervention. In this edition of Drawing First Blood, ASH Clinical News invited John Koreth, MBBS, DPhil, and Bart Scott, MD, to debate the question “Should patients with MDS receive HCT?” Dr. Koreth, of the Dana-Farber Cancer Institute and Harvard Medical School, will argue on the “pro” side, and Dr. Scott, of the Fred Hutchinson Cancer Research Center and the University of Washington, will argue on the “con” side.


John Koreth, MBBS, DPhil: Standard therapies for patients with MDS include hypomethylating agents (HMAs) and a variety of novel agents outside of allogeneic HCT (alloHCT). Although we have seen a substantial survival benefit for patients with higher-risk MDS with non-transplant treatments, in the long term, this disease is fatal. In fact, the survival rates for patients with high-risk MDS and patients with acute myeloid leukemia are not that different. In this setting, the potential benefit of alloHCT should not be taken lightly. Not every patient either qualifies for transplant or should be transplanted, but all patients should be evaluated for transplant.

Bart Scott, MD: Despite the fact that it is the only curative option, I am wary of saying that all patients should be considered for transplant because mortality after alloHCT is high due to relapsed disease and transplant-related complications. So, clearly, transplant doesn’t cure every patient, and some patients die from this intervention. For patients with, for example, many comorbidities, the risk-benefit ratio of transplant is too great to consider it as a viable option: Their survival would likely be relatively short, and likely too short to risk the adverse events associated with transplant.

Dr. Koreth: In the past 15 years, though, the field of transplantation has advanced and transplant-related mortality has declined. Unfortunately, we have not been as effective in addressing relapse, but post-transplant outcomes have improved. This has happened for a few reasons: We have gotten better at matching donors and recipients, treating complications, and overcoming some of the barriers to patients receiving alloHCT.

The issues of patient selection and comorbidity are important, but I also want to emphasize that the barriers to receiving alloHCT should not become barriers to a transplant consultation as early as possible. An early referral does not mean that the transplant itself happens early, simply that the patient is educated about the prospects of transplantation. Our goal is to avoid long gaps between diagnosis and transplant for patients who could be candidates for the procedure.

That determination needs to happen in a transplant center with a transplant specialist. Researchers from Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated the importance of referrals in an analysis presented at the 2016 ASH Annual Meeting.1 They looked at the frequency of alloHCT in patients with MDS who were seen by leukemia physicians at MSKCC and were potentially eligible for transplant, then at the factors associated with transplant referral and barriers to transplant. Of the 362 patients included in the study, 294 were considered potentially eligible for transplant and 244 (67%) were indicated for transplant. Of those patients, 165 were referred to the transplant team. Of that group, only 120 – essentially one-third of the initial, highly selective patient population – underwent alloHCT.

Notably, the patients in that study did not reflect the average U.S. patient with MDS – they had higher incomes and education levels, were mostly white, and were evaluated at a premier transplant and oncology center. Yet, there was still a substantial drop-off.

The major barrier to transplant was death prior to the actual transplant referral. So, even though patients’ MDS did not progress to leukemia, their risk of MDS-related death remained high.

Another factor that precluded referral was the presence of ≥3 comorbidities. Interestingly, the reasons that people did not proceed to transplant were independent of other known risk factors, such as older age and variables included in the International Prognostic Scoring System (IPSS) and Revised IPSS (IPSS-R). So, I would say that comorbidities can exist, but there is a difference between general comorbidities and comorbidities that are barriers to transplantation. What we think of as barriers may not actually be barriers.

Dr. Scott: But I would like to raise an additional point: There are patients who should not be referred for transplant. Age alone is not a barrier to transplant, though there has to be a point at which transplant loses its clinical utility. Do we want to see a 90-year-old patient with MDS being considered for transplant? I suspect the answer would be no.

Dr. Koreth: That’s a great point, and I agree that age is something we can’t ignore. At our institution, our cutoff for transplant consideration is 75 years old, plus or minus a few years, but we need to distinguish age from frailty – a fit 90-year-old differs from a frail 65-year-old.

One way of thinking about the expected utility of alloHCT would be to consider actuarial survival. So, if a 67-year-old patient can anticipate nearly 2 decades of actuarial survival, independent of his or her MDS, then that would justify using transplant.

When we use age as an absolute cutoff, we run the risk of excluding patients who could benefit from a transplant. Some estimates report that approximately 30,000 people >65 years are newly diagnosed with MDS each year in the United States; the total number of alloHCTs performed for MDS is <1,000. Regardless of how you view those data, most patients are older, and most are simply not getting to transplant – likely because of this age bias.

Dr. Scott: This type of ageism is something we see in the clinic, and it’s not only applied to transplant decisions; it can happen with non-transplant therapies and diagnostic work-up.

Expanding on this idea, we need to consider the decision about non-transplant and transplant as part of a continuing therapeutic intervention, rather than as separate entities. And, as you said, the relationship between the transplant center and the treating physician is crucial because the initial treatment affects everything that comes after, including a patient’s eligibility for and outcome with transplant.

We are investigating how to best prepare patients with MDS for alloHCT through approaches such as reduced-intensity preparatory regimens and, though they don’t cure disease, we have multiple, effective options for treating patients with MDS before transplantation.

The HMA azacitidine has been shown to improve survival by >9 months, compared with conventional regimens (including supportive care, low-dose cytarabine, and intensive chemotherapy).2 A randomized trial found that azacitidine delayed disease progression and improved quality of life, compared with supportive care alone, in patients with MDS.3

Dr. Koreth: We may never have a definitive answer about the optimal treatment option for all subgroups of MDS patients until we have large, prospective, randomized, controlled trials comparing transplant and standard therapies. Unfortunately, conducting these trials would be extremely challenging. They would raise ethical concerns because the non-transplant option is non-curative and the number of patients necessary to answer questions about the variety of factors we know are important to outcomes – even beyond IPSS and IPSS-R stratification – would make conducting such a trial unfeasible.

Nevertheless, the preponderance of clinical data does support looking seriously at transplant as an option for most – if not every – patient with MDS.

Dr. Scott: The only trial design that matches the design you described is the ongoing BMT CTN 1102 trial, which is assigning patients to receive either alloHCT with reduced-intensity conditioning (if they have a matched sibling donor or a matched unrelated donor) or non-transplant therapy (if they do not have a matched donor).4 The study’s primary endpoint is survival, and researchers also are looking at the cost-effectiveness of transplant and non-transplant options. The information that comes from this trial will be important in helping to guide treatment decisions. A prospective trial from the French Groupe Francophone des Myelodysplasies showed a survival benefit in patients with MDS who had a matched donor, compared with those who did not; however, this benefit was only seen after two years, likely due to early transplant-related mortality.5 I think this risk-benefit profile is important to keep in mind when selecting the appropriate patient for transplant

Dr. Koreth, in a retrospective comparison of transplant and non-transplant therapies, you and your co-authors showed that patients with intermediate- or high-risk disease (classified by the old IPSS system) benefitted from transplant.6 The selection criteria for patients to undergo transplant were very strict, though, and probably led to a sample more likely to benefit from transplant. So, I think it is important to look at these data in context.

Dr. Koreth: This all comes back to the need for better diagnostic evaluations. MDS models are just starting to move beyond the IPSS and variants that rely on routine clinical data, such as blast count, presence of cytopenias, and peripheral blood counts, to include information from genetic sequencing.

Recently research has uncovered prognostic mutations that can predict a post-transplant outcome for MDS patients.7,8 The exact mutational profile in each study differed slightly, but both research groups found that the presence of TP53 mutations carried a particularly negative prognosis – to the point where it overrode most of the other variables, including age and high IPSS score. This illustrates a situation in which a patient could have relatively low-risk disease based on clinical parameters but could have mutations associated with high-risk disease; such a patient should be referred for a transplant consultation early.

A recent article reported a 20 percent survival even for patients with adverse TP53 mutations, regardless of age or other factors.7 That rate is low, but it may be higher than the outcome for patients with those mutations who receive non-transplant therapies.

The prognostic significance of those mutations will need to be teased out in the coming years; nonetheless, it is becoming apparent that the IPSS and the IPSS-R need to be revised further.

Dr. Scott: Patients with these mutations are likely to experience a poor outcome, regardless of the type of intervention used. They are not likely to be cured without some additional type of intervention – either a novel conditioning regimen or HMAs post-transplant.

On the other hand, research has identified mutations associated with a positive outcome. Patients with the SF3B1 mutation, for instance, have a relatively good prognosis with a low risk of progression to leukemia with non-transplant therapies.9 It can go both ways: These mutational studies may identify patients for whom transplantation should be considered earlier, or they could identify patients who will have good outcomes with non-transplant modalities.

Patients’ underlying social situations should also be included in any decision-making model for transplant or non-transplant therapies. Transplantation is a major, life-changing intervention. Having a solid social support structure is necessary to undergo this intervention. If patients don’t have that, transplantation could cause them harm.

Many of the predictive models for transplant are disease-focused, meaning they don’t take patient health into account. Ultimately, the best models are going to address both.

Dr. Koreth: I completely endorse that and would add that distance from the transplant center is a concern for many patients. Patients require close follow-up to monitor any transplant-related toxicities and ensure that any complications are proactively identified and addressed.

Transplant is a major undertaking, but the only way patients are going to have a chance for a cure is if they are referred for a transplant evaluation. If we can get to the point at which even the patients who are most likely to benefit from transplant are being referred to transplant centers, it would be a vast improvement on the current state of affairs.


References

  1. Getta B, Kishtagari A, Hilden P, et al. Allogeneic hematopoietic stem cell transplantation is underutilized in patients with myelodysplastic syndromes. Abstract #3188. Presented at the 2016 ASH Annual Meeting, December 4, 2016; San Diego, California.
  2. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223-32.
  3. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;10:2429-40.
  4. ClinicalTrials.gov. Allo versus hypomethylating/best supportive care in MDS (BMT CTN 1102). Accessed April 7, 2017, from https://clinicaltrials.gov/ct2/show/NCT02016781.
  5. Robin M, Porcher R, Ades L, et al. HLA-matched allogeneic stem cell transplantation improves outcome of higher risk myelodysplastic syndrome: a prospective study on behalf of SFGM-TC and GFM. Leukemia. 2015;29:1496-501.
  6. Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol. 2013;21:2662-70.
  7. Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536-47.
  8. Yoshizato T, Nannya Y, Atsuta Y, et al. Impact of genetic alterations in stem-cell transplantation for myelodysplasia and secondary acute myeloid leukemia. Blood. 2017 February 8. [Epub ahead of print]
  9. de Witte T, Bowen D, Robin M, et al. Use of hematopoietic cell transplantation for patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2017;129:1753-62.

Disclaimer: Positions were assigned to the participants and do not necessarily reflect ASH’s opinion, the participants’ opinions, or what they do in daily practice.

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