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Abstract: In patients with myelodysplastic syndrome (MDS), higher revised International Prognostic Scoring System (IPSS-R) scores at transplant are associated with worse transplant outcome and, thus, lowering IPSS-R scores by therapeutic intervention before transplantation may seem beneficial. However, there is no evidence, to date, to support this approach. In a retrospective analysis, a total of 1482 patients with MDS with sufficient data to calculate IPSS-R score at diagnosis and at time of transplantation were selected from the European Society for Blood and Marrow Transplantation transplant registry and analyzed for transplant outcome in a multivariable Cox model including IPSS-R score at diagnosis, treatment intervention, change in IPSS-R score before transplant, and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R score change in untreated patients and moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after hypomethylating agents (HMAs) or other therapies showed no beneficial effect. However, when IPSS-R score progressed after chemotherapy, HMAs, or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R score downstaging or reduction of BM blasts after chemotherapy and no benefit for HMAs or other treatments and thus question the role of prior therapy in patients with MDS scheduled for transplantation. The model-based survival estimates should help inform decision-making for both doctors and patients., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

We retrospectively compared outcomes of 404 MDS patients undergoing 1st matched sibling donor allo-HCT receiving either PTCy-based (n = 66) or other "conventional prophylaxis" (n = 338; mostly calcineurin inhibitor + methotrexate or MMF). Baseline characteristics were balanced, except for higher use of myeloablative regimens in the PTCy group (52.3% vs. 38.2%, p = 0.047). Incidences of neutrophil (Day +28: 89% vs. 97%, p = 0.011) and platelet (Day +100: 89% vs. 97%, p < 0.001) engraftment were lower for PTCy-based. Day +100 cumulative incidences of grade II-IV and III-IV aGVHD, and 5-year CI of extensive cGVHD were 32%, 18% and 18% for PTCy-based and 25% (p = 0.3), 13% (p = 0.4) and 31% (p = 0.09) for the conventional cohort. Five-year OS (51% vs. 52%, p = 0.6) and GRFS (33% vs. 25%, p = 0.6) were similar between groups. Patients receiving PTCy had a trend to a lower cumulative incidence of relapse (20% vs. 33%, p = 0.06), not confirmed on multivariable analysis (p = 0.3). Although higher NRM rates were observed in patients receiving PTCy (32% vs. 21%, p = 0.02) on univariate analysis, this was not confirmed on multivariate analysis (HR 1.46, p = 0.18), and there was no resultant effect on OS (HR 1.20, p = 0.5). Based on these data, PTCy prophylaxis appears to be an attractive option for patients with MDS undergoing MSD allo-HCT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m 2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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.

The aim of this study was to develop and validate a clinical and transplant-specific prognostic score using data from 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 performed 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 × 10 9 /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 group (score of 2-3), 3.49 (95% CI: 2.45-4.97) for the high-risk group (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) versus 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 further 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, compared to existing prognostic systems, this proposed transplant-specific risk score offers improved performance with respect to post-transplant risk stratification in myelodysplastic syndromes., (Copyright© 2019 Ferrata Storti Foundation.)

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The causes and rates of late patient-mortality following alloHCT for myelodysplastic syndromes or secondary acute myeloid leukemia were studied, to assess the contribution of relapse-related, treatment-related, and population factors. Data from EBMT on 6434 adults, who received a first alloHCT from January 2000 to December 2012, were retrospectively studied using combined land-marking, relative-survival methods and multi-state modeling techniques. Median age at alloHCT increased from 49 to 58 years, and the number of patients aged ≥65 years at alloHCT increased from 5 to 17%. Overall survival probability was 53% at 2 years and 35% at 10 years post-alloHCT. Survival probability at 5 years from the 2-year landmark was 88% for patients <45-year old and 63% for patients ≥65-year old at alloHCT. Cumulative incidence of nonrelapse mortality (NRM) for patients <45-year old at transplant was 7% rising to 25% for patients aged ≥65. For older patients, 31% of NRM-deaths could be attributed to population mortality. Favorable post-alloHCT long-term survival was seen; however, excess mortality-risk for all age groups was shown compared to the general population. A substantial part of total NRM for older patients was attributable to population mortality, information which aids the balanced explanation of post-HCT risk and helps improve long-term care.

Recently, haploidentical transplantation (haplo) using post-transplant cyclophosphamide (PTCy) has been reported to give very encouraging results in patients with hematological malignancies. Patients who have no HLA-matched donor currently have the choice between a mismatched unrelated donor, an unrelated cord blood (CB) donor, and a haploidentical related donor. The aim of our study is to compare the outcome of patients with myelodysplastic syndrome (MDS) who have been transplanted from a haploidentical donor using PTCy, an HLA-mismatched unrelated donor (marrow or peripheral blood stem cells), or an unrelated mismatched CB donor. A total of 833 MDS patients from the European Group for Blood and Marrow Transplantation (EBMT) registry, transplanted between 2011 and 2016, were identified. The potential benefit of haplo was compared with mismatched unrelated and CB donors in an adjusted and weighted model taking into account potential confounders and other prognostic variables. Haplo was at lower risk of acute graft-versus-host disease (GVHD) than mismatched unrelated donor (P = .010) but at similar risk than CB. Progression-free survival was better after haplo (versus mismatched unrelated, P = .056; versus CB, P = .003) and overall survival tended to be superior after haplo (versus mismatched unrelated, P = .082; versus CB, P = .002). Nonrelapse mortality was not significantly different between haplo and mismatched unrelated donors. Relapse risk was not influenced by the type of donor. In conclusion, patients with MDS from the EBMT registry receiving hematopoietic stem cell transplantation from a haplo donor have significantly better outcome than those receiving hematopoietic stem cell transplantation from a CB donor and at least similar or better outcome than with a mismatched unrelated donor. Prospective studies comparing the type of donors will be needed to confirm this assumption., (Copyright © 2018. Published by Elsevier Inc.)

Increasing donor-recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P < .002) and nonrelapse mortality (HR, .63; P < .001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [P < .02] and HR, 1.57 [P < .001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient-female donor), and cytomegalovirus (CMV) mismatching (positive recipient-negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P = .25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR, .89; P = .46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P = .04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity., (Copyright © 2018. Published by Elsevier Inc.)

The combination of 5-azacytidine (AZA) with donor lymphocyte infusions (DLIs) can induce remissions in patients with relapsed myeloid malignancies after allo-HCT. As decitabine (DAC) is known to be effective also in AML/MDS with leukocytosis, we investigated the combination of DAC with DLIs for relapse after allo-HCT. Between 2006 and 2016, 26 patients (median age 59 years) with AML (n = 18), MDS (n = 6), or MPN (n = 2) and overt hematological relapse after allo-HCT were treated. Median duration from allo-HCT to relapse was 306 days (range, 76-4943). Eighteen patients received DAC + DLIs, 8 DAC-only (median number cycles of DAC: 2, range 1-13, median number of DLIs: 2, range 1-10). The incidence of acute and chronic GvHD in patients receiving DLI was 17% (3/18) and 6% (1/18), respectively. CR/CRi was achieved in 15% (4/26), PR in 4% (1/26), and stable disease in 58% (15/26) of patients. Eight patients received a second allo-HCT. Median overall survival was 4.7 months. Elevated PD-L1 protein expression in bone marrow cells was detected in 4/8 patients with >20% blast infiltration prior to DAC, without a clear association with response. In conclusion, the DAC + DLI regimen proved feasible and effective in relapsed myeloid malignancies after allo-HCT, with efficacy not restricted to patients with low leukemic burden., (Copyright © 2018. Published by Elsevier Ltd.)

Patients with secondary AML (sAML) with antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs) tend to have high-risk disease based on the older age of patients, high-risk cytogenetics, and higher number of prior treatments. Allogeneic hematopoietic cell transplant (HCT) is the only potentially curative therapy available. Eight hundred and two adults with sAML and prior MDS/MPN who received a first HCT between 2000 and 2016 were included in the European Society for Blood and Marrow Transplant (EBMT) Acute Leukemia Working Party (ALWP) study. Median age of the cohort was 59.6 years (range, 18.6-78.6 years). Myeloablative conditioning (MAC) was given to 40% of patients, and 60% received reduced-intensity conditioning (RIC). Overall, the 2-year cumulative incidence of relapse (RI) was 37%, leukemia-free survival (LFS) was 40%, overall survival (OS) was 46%, nonrelapse mortality (NRM) was 23%, and chronic graft-versus-host disease (cGVHD) was 39%. In univariate analysis, a statistical difference between conditioning regimens 6 months after HCT in favor of the MAC group was noted with regard to RI (hazard ratio [HR], 1.47; P = .03), LFS (HR, 1.43; P = .01), and OS (HR, 1.55; P < .05). There was no difference in the cumulative incidence of NRM (HR, 1.38; P = .15). This effect was similarly seen in multivariate analysis (MVA): cumulative incidence of relapse (HR, 1.79; P < .05), LFS (HR, 1.43; P = .02), and OS (HR, 1.53; P = .005) with no difference in NRM (HR, 1; P = .98). This EBMT ALWP analysis suggests that long-term survival can be achieved in patients with sAML with antecedent MDS/MPN and that MAC is a suitable conditioning regimen in patients with sAML., (© 2018 by The American Society of Hematology.)

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., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation ( P <0.001), advanced disease ( P =0.001), older age ( P =0.007), unrelated donor ( P =0.008) and acute graft- versus -host disease before relapse ( P <0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation ( P <0.001) and younger age ( P =0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation ( P <0.001), complete remission at second transplant ( P =0.008), no prior chronic graft- versus -host disease ( P <0.001) and change to a new donor ( P =0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials., (Copyright© 2018 Ferrata Storti Foundation.)

An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT., (© 2017 by The American Society of Hematology.)

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.)

The aim of this study was to determine the impact of the revised 5-group International Prognostic Scoring System cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. A total of 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse-free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14), and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5-group classification. The revised International Prognostic Scoring System cytogenetic classification allows patients with myelodysplastic syndromes to be separated into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value to prediction of patient outcome compared to prediction models using only traditional risk factors or the 3-group International Prognostic Scoring System cytogenetic classification., (Copyright© Ferrata Storti Foundation.)

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in patients with higher risk myelodysplastic syndrome (MDS), but the choice of the optimal alternative stem cell source is still a subject of debate in patients lacking an HLA-matched sibling donor. Here, we report on a large series of patients with MDS (N = 631) transplanted either with mobilized peripheral stem cells (PBs) from unrelated donors (n = 502) or with umbilical cord blood transplant (UCB, n = 129) as alternative grafts after reduced-intensity conditioning. Neutrophil engraftment was higher after PB (98% versus 78%, P < .0001). Acute graft-versus-host disease (GVHD) was similar after PB (31%) and UCB (29%), and chronic GVHD incidence was higher after PB (41% versus 23%). Two-year nonrelapse mortality was lower after PB (31% versus 42% P = .03). There was a better overall survival (OS) and disease-free survival (DFS) after PB (49% ± 2% versus 30% ± 4%, P < .0001 and 44% ± 2% versus 28% ± 4%, P < .0001). Multivariate analysis confirmed the advantage of PB for treatment-related mortality, OS, and DFS, whereas relative risk of chronic GVHD was similar. A multivariate analysis comparing PB from a 10/10 HLA-matched donor, PB from a 9/10 HLA-matched donor, and UCB showed an advantage on treatment-related mortality, DFS, and OS only in 10/10 PB. We conclude that in MDS patients lacking an HLA-matched sibling donor, PB from a 10/10 HLA-matched unrelated donor is the preferred source of hematopoietic stem cells. HLA-mismatched unrelated donor or cord blood seem to give similar inferior results except for neutrophil engraftment, which is delayed after UCB., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Acquired chromosomal abnormalities are important prognostic factors in patients with myelodysplastic syndromes treated with supportive care and with disease-modifying therapeutic interventions, including allogeneic hematopoietic stem cell transplantation. To assess the prognostic impact of cytogenetic characteristics after hematopoietic stem cell transplantation accurately, we investigated a homogeneous group of 523 patients with primary myelodysplastic syndromes who have received stem cells from human leukocyte antigen-identical siblings. Overall survival at five years from transplantation in good, intermediate, and poor cytogenetic risk groups according to the International Prognostic Scoring System was 48%, 45% and 30%, respectively (P<0.01). Both the disease status (complete remission vs. not in complete remission) and the morphological classification at transplant in the untreated patients were significantly associated with probability of overall survival and relapse-free survival (P<0.01). The cytogenetic risk groups have no prognostic impact in untreated patients with refractory anemia ± ringed sideroblasts (P=0.90). However, combining the good and intermediate cytogenetic risk groups and comparing them to the poor-risk group showed within the other three disease-status-at-transplant groups a hazard ratio of 1.86 (95%CI: 1.41-2.45). In conclusion, this study shows that, in a large series of patients with primary myelodysplastic syndromes, poor-risk cytogenetics as defined by the standard International Prognostic Scoring System is associated with a relatively poor survival after allogeneic stem cell transplantation from human leukocyte antigen-identical siblings except in patients who are transplanted in refractory anemia/refractory anemia with ringed sideroblasts stage before progression to higher myelodysplastic syndrome stages., (Copyright© Ferrata Storti Foundation.)

Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non -transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of "comparison", the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an "average" hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.

Allogeneic hematopoietic cell transplantation (HCT) is a curative approach for several diseases predominantly affecting elderly patients. Overall survival is compromised by treatment-related mortality (TRM), GvHD, and relapse. Pretransplant clinical risk indicators in elderly patients qualifying for HCT are highly desirable. Pro-BNP is known as a predictor of death in patients with an increasing variety of clinical conditions and frequently used as a routine parameter for organ complications in the allogeneic transplant setting without well-established scientific evidence. Our hypothesis was that pre-HCT NT-pro-BNP could aid in identifying elderly patients at risk for early mortality. We retrospectively evaluated NT-pro-BNP values in 177 consecutive patients of ≥60 years HCT (2005-2010). In 29.4 % of cases, NT-pro-BNP values were within our institute's normal range (<125 pg/ml). Analysis of different NT-pro-BNP cutoff points by receiver operating characteristics curve for mortality at day +100 revealed no single cutoff value with satisfying specificity and sensitivity. The individual outcome of patients with extremely high NT-pro-BNP values was not associated with an increase in mortality or cardiovascular morbidity. NT-pro-BNP values of patients succumbing to TRM did not differ significantly from those alive or having died of relapse-median 276 vs. 217 pg/ml. In conclusion, pre-HCT NT-pro-BNP was of no convincing prognostic relevance for day 100 mortality.

Standard first-line therapy for older patients with high-risk myelodysplastic syndrome (MDS) includes hypomethylating agents, such as azacitidine (AZA). However, the only approach with curative potential remains allogeneic hematopoietic cell transplantation (HCT). To date, no direct comparison of both strategies has been reported. The outcomes of 2 well-balanced cohorts of patients with high-risk MDS defined by age (60-70 years), performance status (Eastern Cooperative Oncology Group score ≤2), and donor availability (yes/no) were compared, including 103 patients undergoing HCT and 75 patients without this option who received AZA. The estimated 2-year overall survival after the start of treatment was 39% (95% confidence interval, 30%-50%) for the patients undergoing HCT and 23% (95% confidence interval, 14%-40%) for the patients receiving AZA therapy. In a multivariate Cox regression analysis of all patients (n = 178), Eastern Cooperative Oncology Group score (0 versus 1 versus 2; hazard ratio [HR], 2.9/3.9; P <  .001), cytogenetics (good versus intermediate versus poor; HR, 1.2/1.7; P = .026), and treatment (HCT versus AZA; HR, 0.3; P = .007) were associated with overall survival. This retrospective cohort analysis suggests a survival advantage for allogeneic HCT compared with AZA therapy in medically fit patients with high-risk MDS age 60-70 years. Prospective controlled studies are warranted., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Peripheral blood stem cells (PBSCs) are increasingly used as the graft source in allogeneic hematopoietic cell transplantation. We compared long-term outcome after unrelated donor transplantation of 85 consecutive patients with acute myelogenous leukemia or myelodysplastic syndrome regarding disease status (early disease [CR1, refractory anemia); n = 25 and advanced/active disease [>CR1, >refractory anemia]; n = 60) who were treated with conventional conditioning regimens followed by bone marrow (BM) or PBSC grafts. Graft-versus-host disease prophylaxis consisted mainly of cyclosporine A, short-course methotrexate, and anti-T-lymphocyte globulin. After a median follow-up of 118 months (68-174), the 10-year event-free survival rate after peripheral blood stem cell transplantation (PBSCT) was 54.8% (95% confidence interval [CI], 39.7%-69.8%), and after bone marrow transplantation (BMT), it was 27.9% (14.5%-41.3%; P < .004). In the advanced/active disease group, the 10-year event-free survival rate after PBSCT was 50% (30.8%-69.2%), and after BMT, it was 23.5% (9.3%-37.8%; P < .007). Non relapse mortality was less after PBSCT than BMT (14.3% vs 30.2%), respectively. In multivariate Cox regression analysis, PBSCT showed a better overall survival (OS; hazard ratio [HR], 0.43; 95% CI, 0.23-0.79; P = .007) compared to BMT; unfavorable/unknown prognostic impact cytogenetic abnormalities were an adverse factor for all patients (HR, 2.202; 95% CI, 1.19-4.06; P = .011). In patients with advanced disease, the use of PBSCs showed a significant favorable outcome via multivariate analysis (HR, 0.49; 95% CI, 0.24-0.99; P = .046). Outcome of acute myelogenous leukemia/myelodysplastic syndrome after unrelated hematopoietic cell transplantation is adversely affected by cytogenetic abnormalities and state of remission at hematopoietic cell transplantation. PBSC as a graft source has a significant favorable influence on survival., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose: This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients., Patients and Methods: We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC)., Results: The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival., Conclusion: Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.

In this multicenter retrospective study, the outcomes of 836 patients with myelodysplastic syndrome (MDS) who underwent transplantation with a human leukocyte antigen (HLA)-identical sibling donor were analyzed according to 2 types of conditioning: reduced-intensity conditioning (RIC) in 215 patients, and standard myeloablative (or high-dose) conditioning (SMC) in 621 patients. In multivariate analysis, the 3-year relapse rate was significantly increased after RIC (hazard ratio [HR], 1.64; 95% confidence interval [95% CI], 1.2-2.2; P = .001), but the 3-year nonrelapse mortality (NRM) rate was decreased in the RIC group (HR, 0.61; 95% CI, 0.41-0.91; P = .015). The 3-year probabilities of progression-free and overall survivals were similar in both groups (39% after SMC vs 33% in RIC; multivariate P = .9; and 45% vs 41%, respectively; P = .8). In conclusion, the lower 3-year NRM after RIC is encouraging, since these patients were older (age > 50 years in 73% RIC vs 28% in SMC, P < .001) and had more adverse pretransplantation variables. However, based on the higher risk of relapse, patients with no contraindications for SMC should not receive RIC outside of prospective randomized trials, which are needed to establish the position of RIC-based transplantation in the treatment of patients with MDS.

In this multicenter retrospective study, the outcomes of 234 patients with myelodysplastic syndrome (MDS) who underwent transplantation between 1995 and 1999 from HLA-identical siblings were analyzed according to the hematopoietic stem cell source used, that is, bone marrow (BM, n = 132) or granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells (PBPCs, n = 102). There were 69 cases of refractory anemia (RA), 86 RA with excess blasts (RAEB), 75 RAEB in transformation (RAEB-t), and 4 unclassified MDS at diagnosis. The International Prognostic Scoring System was intermediate-2 or high in 104 of the 158 available scores. Multivariate analyses focused on transplantation-related mortality (TRM), 2-year treatment failure incidence, and survival. Use of PBPCs reduced the median duration of neutropenia and thrombocytopenia by 4 and 12 days, respectively. The incidence of acute GVHD was similar whatever the graft type used. Chronic GVHD was more likely to have occurred with PBPCs (odds ratio [OR], 1.62; 95% confidence interval [CI], 0.87-3.02). Two-year TRM was significantly reduced with PBPCs (relative risk [RR], 0.33; 95% CI, 0.15-0.73; P <.007), except for patients who had either RA or high-risk cytogenetics. The 2-year treatment failure incidence was significantly decreased with PBPCs, from 38% to 13% (RR, 0.22; 95% CI, 0.10-0.48; P <.001). Estimate of the 2-year event-free survival was 50% with PBPCs versus 39% with BM. In multivariate analysis, the outcome was significantly improved with PBPCs (RR, 0.27; 95% CI, 0.13-0.52; P <.001), except for patients with either RA or high-risk cytogenetics. In conclusion, PBPCs might be preferred for allogeneic transplantation in MDS patients at high risk for relapse on the basis of morphologic criteria because the use of this hematopoietic stem cell was associated with lower treatment failure incidence and improved survival.

Summary: Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo‐HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)‐identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46·5 months, the estimated 3‐year progression‐free (PFS) and overall survival (OS) for the entire group was 36% (34–37%) and 41% (40–43%), respectively. The cumulative incidence of relapse and non‐relapse mortality (NRM) was 37% (35–39%) and 27% (26–29%), respectively. In a multivariable analysis for OS, besides age (P < 0·001), unrelated donor (P = 0·011), cytomegalovirus ± constellation (P = 0·007), Karnofsky index ≤ 80 (P < 0·001), remission status (P < 0·001), peripheral blood as stem cell source (P = 0·009), sAML from MPN (P = 0·003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0·06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo‐HSCT. [ABSTRACT FROM AUTHOR]