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1.
Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT
Shimoni, A., Robin, M., Iacobelli, S., Beelen, D., Mufti, G. J., Ciceri, F., Bethge, W., Volin, L., Blaise, D., Ganser, A., et al
British journal of haematology. 2021
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Editor's Choice
Abstract
Allogeneic haematopoietic-cell transplantation (allo-HCT) is a potentially curative therapy for high-risk myelodysplastic syndrome (MDS). Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM), higher relapse rate and similar overall-survival (OS) as myeloablative-conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced-toxicity regimen with intense anti-leukaemia activity and a favourable toxicity profile. We investigated post-transplant outcomes in 1722 MDS patients following allo-HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow-up was 64 months (1-171). Five-year relapse rates were 25% (21-30), 38% (34-42) and 25% (22-29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25-35), 27% (23-30) and 34% (31-38, P = 0·008), respectively. Five-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo-HCT in MDS.
PICO Summary
Population
Patients reported to the EBMT registry with a diagnosis of myelodysplastic syndrome, receiving allogeneic transplant (n=1722)
Intervention
Fludarabine/treosulfan based conditioning (FT, n=367)
Comparison
Other reduced intensity conditioning regimens (RIC, n=687) or myeloablative conditioning (MAC, n=668)
Outcome
FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively but other disease characteristics were similar. The median follow-up was 64 months (1-171). Five-year relapse rates were 25% (21-30), 38% (34-42) and 25% (22-29), after FT, RIC and MAC, respectively. NRM was 30% (25-35), 27% (23-30) and 34% (31-38), respectively. Five-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), respectively. In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55) and better OS (HR 0·72). MAC was associated with higher NRM (HR 1·44).
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2.
Optimized EBMT transplant-specific risk score in myelodysplastic syndromes after allogeneic stem-cell transplantation
Gagelmann, N., Eikema, D. J., Stelljes, M., Beelen, D., de Wreede, L., Mufti, G., Knelange, N. S., Niederwieser, D., Friis, L. S., Ehnninger, G., et al
Haematologica. 2019
Abstract
Here, we aimed to develop and validate a clinical and transplant-specific prognostic score in a large cohort of patients with myelodysplastic syndromes reported to the European Society for Blood and Marrow Transplantation registry. A Cox model was fitted to detect clinical and transplant-related variables prognostic of outcome. Then, cross-validation was assessed to evaluate the validity and consistency of the model. Seven independent risk factors for survival were identified: age ≥50 years, matched unrelated donor, Karnofsky performance status < 90%, very poor cytogenetics or monosomal karyotype, positive cytomegalovirus status of the recipient, blood blasts >1%, and platelet count ≤50 x 109/L prior to transplantation. Incorporating these factors into a four-level risk score yielded hazard ratios for death (with low-risk [score of 0-1] as reference) of 2.02 (95% CI, 1.41-2.90) for the intermediate-risk (score of 2-3), 3.49 (95% CI, 2.45-4.97) for the high-risk (score of 4-5), and 5.90 (95% CI, 4.01-8.67) for the very high-risk group (score of >5). The score was predictive of survival, relapse-free survival, relapse, and non-relapse mortality (p<0.001, respectively). Cross-validation yielded significant and reproducible improvement in prognostic ability with C-statistics being 0.609 (95% CI, 0.588-0.629) vs. 0.555 for the Gruppo Italiano Trapianto di Midollo Osseo registry and 0.579 for the Center for Blood and Marrow Transplant Research registry. Prediction was even augmented after applying a nomogram using age and platelets as continuous variables showing C-statistics of 0.628 (95% CI, 0.616-0.637). In conclusion, this proposed transplant-specific risk score offers improved performance with respect to posttransplant risk stratification in myelodysplastic syndromes compared with existing prognostic systems.
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A prospective non-interventional study on the impact of transfusion burden and related iron toxicity on outcome in myelodysplastic syndromes undergoing allogeneic hematopoietic cell transplantation()
Cremers, E. M. P., de Witte, T., de Wreede, L., Eikema, D. J., Koster, L., van Biezen, A., Finke, J., Socie, G., Beelen, D., Maertens, J., et al
Leukemia & lymphoma. 2019;:1-10
Abstract
Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p = .02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p = .04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation.
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Allogeneic Stem Cell Transplantation for Myelodysplastic Syndrome Patients with a 5q Deletion
Garderet, L., Ziagkos, D., van Biezen, A., Iacobelli, S., Finke, J., Maertens, J., Volin, L., Ljungman, P., Chevallier, P., Passweg, J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(3):507-513
Abstract
The deletion (5q) karyotype (del [5q]) in patients with myelodysplastic syndrome (MDS) is the most common karyotypic abnormality in de novo MDS. An increased number of blasts and additional karyotypic abnormalities (del [5q]+) are associated with a poor outcome. We analyzed the outcome of allogeneic hematopoietic cell transplants (HCT) in patients suffering from MDS with only del (5q) or del (5q)+ . A total of 162 patients, of median age 54 years (range, 9 to 73), having MDS and del (5q) abnormalities received HCT from identical siblings (n = 87) or unrelated donors (n = 75). The cumulative incidence of nonrelapse mortality and relapse incidence at 4 years was 29% (95% CI, 22 to 36) and 46% (95% CI, 38 to 54), whereas the estimated 4 year survival, relapse-free and overall, was 25% (95% CI, 18 to 33) and 30% (95% CI, 23 to 38), respectively. In a multivariate analysis patients with del (5q) and a blast excess displayed poorer survival (hazard ratio, 2.38; 95% CI, 1.44 to 3.93; P < .001), whereas female recipient sex resulted in improved survival (hazard ratio, .61; 95% CI, .41 to .90; P = .01). We conclude that allogeneic HCT can cure a subset of patients with MDS and a del (5q) abnormality.
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Allogeneic Stem Cell Transplantation for Patients Age >= 70 Years with Myelodysplastic Syndrome: A Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party of the EBMT
Heidenreich, S., Ziagkos, D., de Wreede, L. C., van Biezen, A., Finke, J., Platzbecker, U., Niederwieser, D., Einsele, H., Bethge, W., Schleuning, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(1):44-52
Abstract
In this retrospective analysis we evaluated the outcome of 313 patients aged >= 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n=221) and secondary acute myeloid leukemia (n=92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n=79) or unrelated (n=234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n=54), reduced intensity (n=207), or standard intensity (n=52). Allogeneic HSCT for MDS patients >= 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% (P=.01) and 46% (P=.002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.[Erratum appears in Bone Marrow Transplant. 2017 Jul;52(7):1081; PMID: 28677682]
Robin, M., Porcher, R., Zinke-Cerwenka, W., van Biezen, A., Volin, L., Mufti, G., Craddock, C., Finke, J., Richard, C., Passweg, J., et al
Bone Marrow Transplantation. 2017;52(2):209-215
Abstract
We report a retrospective analysis of 246 myelodysplastic syndrome (MDS) patients in the EBMT (The European Society for Blood and Marrow Transplantation) database who were transplanted for International Prognostic Scoring System (IPSS) low or intermediate-1 disease. The majority of these patients (76%) were reclassified as intermediate or higher risk according to R-IPSS. The 3-year overall survival (OS) and PFS were 58% and 54%, respectively. In a multivariate analysis, adverse risk factors for PFS were marrow blast percentage (hazard ratio (HR): 1.77, P=0.037), donor/recipient CMV serostatus (donor-/recipient+: HR: 2.02, P=0.011) and source of stem cells (marrow and non-CR: HR: 5.72, P<0.0001, marrow and CR: HR: 3.17, P=0.027). Independent risk factors for OS were disease status at time of transplant and the use of in vivo T-cell depletion (TCD). Patients who did not receive TCD and were transplanted from an unrelated donor had worse OS (HR: 4.08, P<0.0001). In conclusion, 'lower' risk MDS patients have better outcome than those with 'higher risk' after haematopoietic stem cell transplant (HSCT). Selecting the right source of stem cells, a CMV-positive donor for CMV-positive patients and using in vivo TCD results in the best outcome in these patients. More studies are needed to evaluate the role of HSCT in these patients as compared with conventional treatment.
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7.
Prognostic pre-transplant factors in myelodysplastic syndromes primarily treated by high dose allogeneic hematopoietic stem cell transplantation: a retrospective study of the MDS subcommittee of the CMWP of the EBMT
Cremers, E. M., van Biezen, A., de Wreede, L. C., Scholten, M., Vitek, A., Finke, J., Platzbecker, U., Beelen, D., Schwerdtfeger, R., Volin, L., et al
Annals of Hematology. 2016;95(12):1971-1978
Abstract
Many pre-transplant factors are known to influence the outcome of allogeneic stem cell transplantation (SCT) treatment in myelodysplastic syndromes (MDS). However, patient cohorts are often heterogeneous by disease stage and treatment modalities, which complicates interpretation of the results. This study aimed to obtain a homogeneous patient cohort by including only de novo MDS patients who received upfront allogeneic SCT after standard high dose myelo-ablative conditioning. The effect of pre-transplant factors such as age, disease stage, transfusions, iron parameters and comorbidity on overall survival (OS), non-relapse mortality (NRM), and relapse incidence (RI) was evaluated in 201 patients. In this cohort, characterized by low comorbidity and a short interval between diagnosis and transplantation, NRM was the most determinant factor for survival after SCT (47 % after 2-year follow-up). WHO classification and transfusion burden were the only modalities with a significant impact on overall survival after SCT. Estimated hazard ratios (HR) showed a strongly increased risk of death, NRM and RI, in patients with a high transfusion-burden (HR 1.99; P=0.006, HR of 1.89; P=0.03 and HR 2.67; P=0.03). The HR's for ferritin level and comorbidity were not significantly increased.