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The European society for Blood and Marrow Transplantation (EBMT) has a long-standing interest in the evaluation of hematopoietic cell transplantation. More than three decades ago, its members established a continental registry. Today, more than 700,000 patients have been registered, and information has been gathered on more than 800,000 transplants. This huge amount of information has allowed conducting multiple retrospective studies, evaluating changes in practices over time and for different categories of diseases, benchmarking outcome across EBMT affiliated centers, and increasingly serves to build synthetic comparators to evaluate the introduction of therapeutic innovations in the field of hematology. CAR-T cells therapies draw on human and technical resources that are also used to deliver HCT; they elicit side effects that require the implementation of risk mitigation plans; they are living drugs that persist in the body of the recipient and thus deserve prolonged follow-up; the introduction of CAR-T cells in the pharmacopeia is likely to significantly impact on the practice of BMT; for all these reasons and even before the first approvals of CAR-T Cells in Europe, EBMT engaged in a project aiming at complementing the EBMT Registry with a Cellular Therapy Form, with the objective to register CAR-T cells treated patients and collect information on their short-, middle- and long-term outcome. The goal is to provide EBMT investigators with a tool for primary analyses of the collected information and to support secondary use of data transferred at the individual level to Marketing Authorization Holders and other interested parties, to fulfill their obligations to health authorities and further evaluate the actual medical values of CAR-T Cells in different contexts and indications. The EBMT Registry received a positive opinion from the European Medicines agency in 2019, and five years later contains information on more than 9.000 treated patients. This article describes the journey to start this new activity, lessons to be drawn in view of improving the collection of real-world data, and what existing information tells us in terms of patient access. • Advanced Therapy Medicinal Products deserve peculiar attention in terms of follow-up after market approval. • CAR-T cells are the most widely used advanced therapies, since the first approvals in 2017 in the USA and 2018 in Europe. • Maintenance of clinical benefit in diverse patient populations requires additional demonstration through analyses of real-world data. • The EBMT has built new tools to survey the field of CAR-T Cells. • Establishing a European CAR-T Cells Registry meant addressing internal and external challenges. • Patients have been registered since 2019 in the EBMT Registry, in the year following the approval of the first two products by the European Medicines Agency (EBMT), and are now totaling more than 9.000 individuals. • A formal process is in place through the GoCART coalition to periodically revise the nature and format of data to be reported, and upgrade the quality of the information contained in the Registry, while considering our fast improving knowledge of this emerging field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The European Society for Blood and Marrow Transplant Research data set was used to retrospectively analyze the outcomes of hypomethylating therapy (HMA) compared with those of conventional chemotherapy (CC) before hematopoietic stem cell transplantation (HSCT) in 209 patients with advanced myelodysplastic syndromes. Median follow-up was 22.1 months and the median age of the group was 57.6 years with 37% of the population older than > 60 years. The majority of patients (59%) received reduced-intensity conditioning and 34% and 27% had intermediate-2 and high international prognostic scoring system (IPSS) scores. At time of HSCT, 32% of patients did not achieve complete remission (CR) and 13% had primary refractory disease. On univariate analysis, outcomes at 3 years were not significantly different between HMA and CC for overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM): OS (42% versus 35%), RFS (29% versus 31%), CIR (45% versus 40%), and NRM (26% versus 28%). Comparing characteristics of the groups, there were more patients < 55 years old, more patients in CR (68% versus 32%), and fewer patients with primary refractory disease in the CC group than in the HMA group (10% versus 19%, P < .001). Patients with primary refractory disease had worse outcomes than those in CR with regard to OS (hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.41 to 4.13; P = .001), RFS (HR, 2.27; 95% CI, 1.37 to 3.76; P = .001), and NRM (HR, 2.49; 95% CI, 1.18 to 5.26; P = .016). In addition, an adverse effect of IPSS-R cytogenetic risk group was evident for RFS. In summary, outcomes after HSCT are similar for patients receiving HMA compared with those receiving CC, despite the higher proportion of patients with primary refractory disease in the HMA group. [ABSTRACT FROM AUTHOR]

• Low bone mineral density (BMD) is frequent after hematopoietic cell transplantation (HCT). • There is inconsistency of practice in relation to guidelines on BMD after HCT. • There is a lack of familiarity with BMD guidelines among European HCT centers. Reduced bone mineral density (BMD) is a well-recognized complication of hematopoietic cell transplantation (HCT), with significant drops in BMD occurring within the first 12 months after HCT. Guidance on identifying and managing this complication is available in several published guidelines. In this study, we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation (EBMT). A questionnaire about bone health was sent to all registered centers, and responses were received from 99 centers in 25 countries (52%) currently registered with the EBMT. Our data highlight considerable heterogeneity in practices across European centers in relation to investigations, management, and use of guidelines. Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders. [ABSTRACT FROM AUTHOR]

The understanding and treatment of multiple myeloma (MM) have dramatically improved in recent years. However, accurate assessment of the response of myeloma to therapy and its subsequent relapse remains a difficult task. Criteria have changed over time and new parameters have recently been incorporated to evaluate minimal residual disease status. We present a practical approach to assess response and relapse/progression in myeloma in the context of its treatment. A robust reporting schema is crucial to correctly evaluate any treatment protocol and compare results across trials. MM is a highly heterogeneous disease with multifarious manifestations. To assess the tumor load decline after treatment and its increase during relapse/progression, numerous parameters need to be taken into account. As our ability and the tools to measure low levels of disease have improved over time, so have the accepted definitions of response, most recently in August 2016. The goal of this article is to define, describe, and clarify the practical methodological aspects of disease evaluation in response to therapy and in progression or relapse. We expect this practical manual will help myeloma professionals and research workers in data collection for registries and databases and clinical trial reporting. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic, and 54% hematological) after alloSCT. The overall probabilities of failure- and secondary GVHD–free survival (FGFS) were 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, P < .001). Chronic GVHD before DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS was 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse, independent adverse prognostic factors for FGFS were initial dose of CD3 + cells ≥ 50 × 10 6 /kg, donor-recipient sex mismatch, and chronic GVHD before DLI. FGFS was 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD. [ABSTRACT FROM AUTHOR]

We have recently reported on the outcome of autologous transplantation in the rare myelomas (IgD, IgE, IgM, and nonsecretory [NS]) but there is no real information on the outcome of these conditions after allogeneic transplantation. We used the European Group for Blood and Marrow Transplantation myeloma database to compare the outcomes after allogeneic transplantation of 1354 common myelomas (IgG, IgA, and light chain myeloma) with the outcome in 26 IgD myelomas and 52 NS myelomas. There was little difference between common and the IgD and NS myeloma patients with respect to prognostic factors although the IgD group had a higher beta 2 microglobulin at diagnosis, shorter time to transplantation, and more T cell depletion. IgD and NS patients had a significantly greater achievement of complete remission at conditioning but this did not translate into equivalent progression-free survival and overall survival for the IgD patients although the NS outcome was very similar to that of common myeloma. The PFS and OS of IgD, common, and NS myelomas appear similar after allogeneic transplantation, despite a tendency for higher early relapse rate in IgD myeloma. Allogeneic transplantation may, therefore, be an option to investigate in prospective observational studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate results of high-dose total-body irradiation (TBI) regimens for hematopoietic stem cell transplantation. Methods and Materials: A total of 1,032 patients underwent TBI in one or two fractions before autologous or allogeneic hematologic stem cell transplantation for acute leukemia and non-Hodgkin''s lymphoma. The TBI regimens were normalized by using the biological effective dose (BED) concept. The BED values were divided into three dose groups. Study end points were relapse incidence (RI), non-relapse mortality (NRM), relapse-free survival (RFS), and overall survival (OS). Multivariate analysis was performed, stratified by disease. Results: In the highest TBI dose group, RI was significantly lower and NRM was higher vs. the lower dose groups. However, a significant influence on RFS and OS was not found. Relapses in the eye region were found only after shielding to very low doses. Age was of significant influence on OS, RFS, and NRM in favor of younger patients. The NRM of patients older than 40 years significantly increased, and OS decreased. There was no influence of age on RI. Men had better OS and RFS and lower NRM. Type of transplantation significantly influenced RI and NRM for patients with acute leukemia and non-Hodgkin''s lymphoma. There was no influence on RFS and OS. Conclusions: Both RI and NRM were significantly influenced by the size of the BED of single-dose or two-fraction TBI regimens; OS and RFS were not. Age was of highly significant influence on NRM, but there was no influence of age on RI. Hyperfractionated TBI with a high BED might be useful, assuming NRM can be reduced. [Copyright &y& Elsevier]

One hundred and forty patients who had undergone hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) transformation after treatment of severe aplastic anemia (SAA) were identified in the European Group for Blood and Marrow Transplantation (EBMT) database. The median age at HSCT was 29 years (range, 1 to 66 years). The transplant donor was related in 49% cases and unrelated in 51% cases. The 5-year probability of relapse was 17%, and that of nonrelapse mortality was 41%. The 5-year overall survival was 45% ± 9%, better for patients untreated and patients in remission compared with patients with refractory disease. Our data indicate that allogeneic HSCT leads to prolonged survival in close to one-half of the patients transforming to MDS or AML from SAA. [ABSTRACT FROM AUTHOR]

Abstract: Transformed acute myeloid leukemia in myelofibrosis results in a median survival of less than 5 months. We identified 46 of 1048 myelofibrosis patients in the European Group for Blood and Marrow Transplantation registry who received allogeneic stem cell transplantation for acute leukemia evolving from myelofibrosis. The cumulative incidence of treatment-related mortality at 1 year was 28% (95% confidence interval, 14 to 42) and of relapse at 3 years was 47% (95% confidence interval, 31 to 63). The 3-year progression-free (PFS) and overall survival (OS) rates were 26% and 33%, respectively. The only significant factor for survival was complete remission versus no complete remission before transplantation (69% versus 22%, P = .008); however, complete remission was achieved only in 8 patients. Allogeneic stem cell transplantation can cure myelofibrosis patients transformed to leukemia. [Copyright &y& Elsevier]

Allogeneic stem cell transplantation (SCT) is potentially curative therapy for patients with MDS. Prior studies have shown no overall-survival (OS) advantage of any conditioning regimen over the others. Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM) compared to myeloablative conditioning (MAC), however, relapse rates are higher, resulting in similar OS. Fludarabine and treosulfan (FT) is a reduced-toxicity regimen with intense anti leukemia activity in patients with myeloid malignancies. We explored outcomes following FT conditioning in comparison with other regimens. We retrospectively analyzed SCT outcomes of MDS patients reported to the chronic malignancies working party of EBMT (n=1722). The conditioning regimens were defined according to standard EBMT criteria and included 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). More FT recipients had untreated MDS at SCT, 45%, 26% and 36%, respectively (P < 0.001). Disease status at diagnosis, cytogenetics, secondary origin and prior transformation to AML, were not different between the regimens. With a median follow-up of 20 months (1-171), 807 patients are alive, 328 died of relapse and 587 had NRM. The 5-year rates of relapse, NRM and OS for the entire group were 21% (95%CI, 19-23), 35% (95%CI, 33-38) and 44% (95%CI, 42-437), respectively. Relapse rates were similar after FT and MAC, 16% (13-21) and 19% (16-22), respectively, significantly lower than after RIC, 25% (21-28) (P = 0.003). Multivariate analysis (MVA) identified age >55 years (HR 1.42), advanced histology (RAEB 1/2, HR 2.01/ 1.73), prior transformation to AML (HR 1.87), refractory disease to prior therapies (HR 1.75) secondary origin (HR 1.33) and poor cytogenetics (HR 2.83) as associated with higher relapse risk. FT conditioning was associated with a lower risk (HR 0.63, P = 0.006). NRM was lower after FT and RIC than after MAC, 34% (29-39), 33% (30-37) and 38% (35-40), respectively (P = 0.05). MVA identified age >55 years (HR 1.39) and MAC (HR 1.34) as associated with higher NRM, while SCT from sibling donor (HR 0.81) and in CR (HR 0.80) were associated with a lower risk. In all, 5-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), after FT, RIC and MAC, respectively (Figure 1, P = 0.03). MVA identified age >55 years (HR 1.39), advanced histology (RAEB 1/2, HR 1.35/ 1.10), prior transformation to AML (HR 1.37), and poor cytogenetics (HR 1.58) as associated with lower OS. FT conditioning was associated with better OS (HR 0.79, P = 0.01). FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved outcome over both RIC and MAC. FT might be the preferred regimen for SCT in MDS. These observations merit further study in randomized prospective trials. [ABSTRACT FROM AUTHOR]

In the last decade, the number of older patients undergoing allogeneic Hematopoietic Cell Transplantation (alloHCT) has increased substantially. Analyzing the long-term outcomes of these patients poses new methodological challenges since their population mortality (the risk of mortality that they would have faced in the absence of their disease and treatment) is non-negligible. Interpreting all non-relapse mortality (NRM) as treatment-related mortality cannot be justified in this older population. An additional problem in the analysis of the causes of death is that individual adjudication as to treatment-related complications is often impossible. Although more common in transplant recipients, both cardiac deaths and cancer also occur frequently in the general population in this age group. For these reasons, we propose to extend the analysis of standard outcomes with statistical methods to estimate the size of population- and treatment-related mortality in heterogeneous populations. We analyzed the outcomes of two large cohorts of patients whose data had been collected by the European Society for Blood and Marrow Transplantation: (1) myelodysplastic syndromes or secondary acute myeloid leukemia (n=6434, median age 56 years), and (2) chronic lymphocytic leukemia (n=2589, median age 55 years). We focused on patients who had survived for two years after alloHCT without relapse or progression. We used integrated methods from relative survival and multi-state models to estimate what proportion of mortality can be attributed to disease relapse and what to the expected general population mortality. A key assumption was that the risk of mortality of the patient cohorts, apart from that associated with the disease and its treatment, was similar to that of the age-, sex-, calendar year- and country-matched general population. The remaining mortality, excess non-relapse mortality, can then be interpreted as closely approximating to treatment-related mortality, where 'treatment' refers both to treatment prior to transplantation and to alloHCT and its sequelae. The figures illustrate the probabilities of these events for the MDS cohort. This non-parametric model was then extended to a Cox model where we also assessed the impact of age and other risk factors on the different components of mortality. Combining relative survival and multi-state models gives more insight into the different causes of mortality and the impact of age and other risk factors on them. We show that for older patients, a substantial part of NRM is actually attributable to population mortality, information which should hopefully lead to more informed discussions regarding the risk of alloHCT and improvement of long-term care. [ABSTRACT FROM AUTHOR]