Should lower-risk myelodysplastic syndrome patients be transplanted upfront? YES Ibrahim Yakoub-Agha France

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1 Should lower-risk myelodysplastic syndrome patients be transplanted upfront? YES Ibrahim Yakoub-Agha France Myelodysplastic syndromes (MDS) are heterogeneous disorders that range from conditions with a near-normal life expectancy to forms approaching acute myeloid leukemia (AML). A risk-adapted treatment strategy is mandatory, and the definition of individual risk requires the use of prognostic systems. In 1997, the International Prognostic Scoring System (IPSS) has been developed and become a benchmark for clinical trials and decision-making. 1 Nonetheless, a not negligible heterogeneity was observed in IPSS subgroups, in particular in patients classified in low and intermediate-1 risk categories. Recently, the International Working Group for Prognosis in MDS revised the IPSS. On the basis of a large data set that allowed the prognostic value of even less frequent cytogenetic abnormalities to be estimated, five cytogenetic risk groups were determined representing the basis for the revised IPSS (IPSS-R), together with refined categories for bone marrow blasts and peripheral blood cytopenias. 2 IPSS-R improved the capability to capture prognostic information in untreated MDS as well as in patients receiving disease-modifying treatments. Despite improved understanding of the molecular pathogenesis of myelodysplastic syndromes (MDS), currently available therapeutic agents lead to prolongation of life and no cure. Therefore, allogeneic hematopoietic cell transplantation (allo-hct) is still considered as a conventional therapeutic option until the age of in eligible patients. Its efficacy, however, is considerably limited by morbidity and mortality, resulting in a long-term survival rate of less than 50%. 3,4 Decision making flow chart: The ELN and the National Comprehensive Cancer Network (NCCN) formulated the general recommendation for allo-hct at diagnosis based on IPSS. 5,6 More recently, an international expert panel from of the EBMT, ELN, BBT Clinical Trial Group and the International MDS Foundation adjusted this general recommendation to the IPSS-R risk score. 7 Therefore, in this controversy, we are going to refer lower risk patients as those having very-low, low and intermediate risk on the ground of IPSS- R.

2 Figure 1: Decision making flowchart is based on disease risks according to IPSS-R and presence of comorbidity according to the HCT Comorbidity Index (HCT-CI) that are currently recognized as relevant clinical variables for allo-sct eligibility. 8 Abbreviations: FIT refers to patients who are candidate for allo-hct in terms of age and comorbidities (i.e. age-adjusted HCT-CI 5). * nontransplant strategies are offered to patients with intermediate except those with risk factors (i.e. profound cytopenias, poor risk cytogenetic, marrow blasts 5% and/or severe myelofibrosis) 9 Up-front allogeneic transplantation In patients who are fit for allo-hct in terms of age and comorbidities, IPSS-R has to be the base of decision making. Higher-risk patients: While up-front allo-hct is the best option for patients with highrisk IPSS-R, 10 this approach is still controversial for those with very high-risk IPSS-R because they have very poor survival even after all-hct. 11 Lower risk patients: Patients with low and very low IPSS-R score are not candidate for up-front allo-hct. However, allo-hct has to be considered in case of progression to a more advanced disease. Median overall survival in patients with Intermediate-risk patient is approximately three years without allo-hct. 2 Given the potential toxicity of the allo-hct procedure, many hematologists are reluctant to refer patients with intermediate-risk IPSS-R to allo-hct right after the diagnosis. They postpone transplantation until the patients develop profound cytopenias, acquire additional cytogenetic abnormalities, increase their marrow blast percentage or evolve to a higher risk disease. 7 However, allo-hct is still the only curative option for those patients and the timing of transplantation is a

3 key point in its success. Delaying allo-hct, lead to the development of several complications (i.e. infections, iron overload, hemorrhages, transformation into AML ) that can jeopardize the transplantation and even prevent some of those patients to undergo allo-hct. In a multicenter prospective study that compared allo-hct with no transplant approaches in patients with MDS, Robin et al, observed more than 20% of patients who did not undergo transplantation for complications related to prior therapy. 12 In addition, post-transplant survival of patients who failed to a first-line treatment is shorter than survival of those who did not Survival can be shorter in patients with IPSS-R intermediate-risk MDS if they present some risk factors at diagnosis such as, Marrow blasts 5%, profound cytopenias (Hb < 8 g/dl, ANC < 0.8 G/L or platelets < 50 G/L), Severe myelofibrosis or poor cytogenetics. 7,16 The impact of genetic mutations is being investigated in patients with MDS. Although, there is no international consensus regarding their strict impact on patient s outcome so far, some of them are highly predictive for outcome and have to be taken into account for the decision making. The 2017 COSTEM is going to be a great opportunity to debate the best indication of up-front allo-hct in patients with lower risk MDS.

4 References: 1. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: , Greenberg PL, Tuechler H, Schanz J, et al: Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120: , Damaj G, Duhamel A, Robin M, et al: Impact of Azacitidine Before Allogeneic Stem-Cell Transplantation for Myelodysplastic Syndromes: A Study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe- Francophone des Myelodysplasies. J Clin Oncol, Damaj G, Mohty M, Robin M, et al: Up-front Allogeneic stem Cell Transplantation following reduced intensity/nonmyeloablative For Patients With Myelodysplastic Syndrome. A Study By the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Biol Blood Marrow Transplant, Malcovati L, Hellstrom-Lindberg E, Bowen D, et al: Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 122: , Greenberg PL, Attar E, Bennett JM, et al: Myelodysplastic syndromes: clinical practice guidelines in oncology. J Natl Compr Canc Netw 11:838-74, de Witte T, Bowen D, Robin M, et al: Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood 129: , Sorror ML, Storb RF, Sandmaier BM, et al: Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 32: , Della Porta MG, Alessandrino EP, Bacigalupo A, et al: Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R. Blood 123: , Yakoub-Agha I, Deeg J: Are hypomethylating agents replacing induction-type chemotherapy before allogeneic stem cell transplantation in patients with myelodysplastic syndrome? Biol Blood Marrow Transplant 20: , Gauthier J, Damaj G, Langlois C, et al: Contribution of Revised International Prognostic Scoring System Cytogenetics to Predict Outcome After Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes: A Study From the French Society of Bone Marrow Transplantation and Cellular Therapy. Transplantation 99: , 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 29: , Yakoub-Agha I, de La Salmoniere P, Ribaud P, et al: Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation. J Clin Oncol 18:963-71, Prebet T, Gore SD, Esterni B, et al: Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 29:3322-7, Estey E: Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 25: , 2007

5 16. Della Porta MG, Malcovati L, Boveri E, et al: Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J Clin Oncol 27:754-62, 2009