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“ Not every patient either qualifies for transplant or should be transplanted , but all patients should be evaluated for transplant .” — JOHN KORETH , MBBS , DPhil
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 reducedintensity 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
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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 costeffectiveness of transplant and nontransplant 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 intermediateor 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 posttransplant outcome for MDS patients . 7 , 8 The exact mutational profile in each study differed slightly , but both research groups
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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 lowrisk 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 .
“ Many of the predictive models for transplant are disease-focused , meaning they don ’ t take patient health into account .” — BART SCOTT , MD
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 decisionmaking model for transplant or nontransplant 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
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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 higherrisk 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 .
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