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Background: Although many patients now survive the short-term complications of bone marrow transplantation for life-threatening hematologic disease, information on the health and activity of long-term survivors is sparse.Objective: To evaluate the morbidity and mortality of patients surviving more than 5 years after allogeneic bone marrow transplantation.Design: Retrospective, multicenter study.Patients: 798 recipients of bone marrow transplants (477 adults, 321 children) from 43 European centers. Patients had received transplants before December 1985 and had survived at least 5 years. Patients had received allogeneic or syngeneic bone marrow for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, and severe aplastic anemia.Measurements: Survival, clinical performance according to Karnofsky score (in increments of 10%), and social reintegration were assessed as outcomes. Patient age and sex, primary disease and status at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, and acute and chronic graft-versus-host disease were evaluated as variables.Results: For the 55 5-year survivors, actuarial mortality was 8% at 10 years and 14% at 15 years. The leading causes of death were disease recurrence (21 patients), chronic graft-versus-host disease with complicating infections and lung disease (11 patients), secondary cancer (8 patients), and the acquired immunodeficiency syndrome (AIDS) (5 patients). When patients with recurrent disease were excluded, late death was associated with chronic graft-versus-host disease (P < 0.001), occurrence of secondary cancer (P < 0.001), male sex of the patient (P = 0.05), and female sex of the donor (P = 0.002). Clinical performance was normal (Karnofsky score, 100%) or minimally reduced (Karnofsky score, 90%) in 93% of patients; 89% of patients resumed full-time work or school. Reduced performance status and incomplete resumption of social activity were associated with chronic graft-versus-host disease, recurrent leukemia, AIDS, secondary cancer, organ dysfunction, and neurologic or psychological problems. Other risk factors for incomplete resumption of social activity were female sex (P = 0.002) and older age at transplantation (P = 0.001).Conclusions: More than 5 years after bone marrow transplantation, most patients were in good health (93%) and had returned to full-time work or school (89%). Recurrence of the primary disease, secondary cancer, and chronic graft-versus-host disease and its sequelae remain problems for some patients. [ABSTRACT FROM AUTHOR]

A 46 year woman with severe long-lasting SLE received an autologous bone marrow transplantation utilising CD34+ haematopoietic progenitors following a 3 log T-lymphocyte depletion. The immunosuppressive regimen (conditioning) consisted of 15mg/kg Thiotepa followed by 100 mg/kg of cyclophosphamide over 2 d. Granulocytic recovery was aided by G- CSF. The post-transplant course was uneventful, and a good clinical and immunologic remission (ANA negativisation) was achieved. This is the first case of SLE having received an autologous progenitor cell transplant for the autoimmune disease by itself, unaccompanied by a haematologic condition requiring transplantation.The potential, advantages and limits of this procedure, which are currently being explored worldwide, are briefly discussed. [ABSTRACT FROM PUBLISHER]

Two children developed papillary thyroid carcinoma after allogeneic bone marrow transplantation (BMT) probably due to radiotherapy during remission and pretransplantation conditioning. Establishing a relationship between the cellular thyroid stimulating hormone (TSH) effect and development of carcinoma in cases with high serum TSH concentrations is difficult. After BMT, patients should be regularly followed up with thyroid ultrasound and, when nodularity is found, fine needle aspiration and/or open biopsy are recommended. [ABSTRACT FROM AUTHOR]

Background: Some patients treated by transplantation of haemopoietic stem cells (peripheral blood or bone marrow) become permanently infertile, but others retain or recover fertility. We assessed the outcome of conception in women, and partners of men previously treated by autologous or allogeneic stem cell transplantation (SCT).Methods: We sent questionnaires to 229 centres of the European Group for Blood and Marrow Transplantation. We sought details about the original disease, transplant procedure, and outcome of conception for both male and female patients.Findings: 199 centres gave information relating to 19412 allogeneic and 17950 autologous transplant patients. 232 (0.6%) patients conceived after SCT. Crude annual birth rate for 4-month survivors of SCT was lower than the national average for England and Wales at 1.7 per 1000 patients. 312 conceptions were reported in 113 patients (74 allograft) and partners of 119 patients (93 allograft). Most pregnancies were uncomplicated and resulted in 271 livebirths. 28 (42%) of 67 allograft recipients had caesarean section compared with 16% in the normal population (difference =26% [95% CI 15-38]), 12 (20%) of 59 had preterm delivery compared with a normal rate of 6% (14% [4-24]), and 12 (23%) of 52 had low birthweight singleton offspring compared with a normal rate of 6% (17% [6-29]).Interpretation: Pregnancy after SCT is likely to have a successful outcome. Pregnancies in allograft patients who have received total body irradiation should be treated as high risk for maternal and fetal complications. [ABSTRACT FROM AUTHOR]

We studied the incidence of acute graft versus host disease (GvHD) and its outcome in three consecutive time frames (year <2000; 2000-2010; >2010), in 3,120 patients allografted in two transplant Centers between 1976 and 2020. The median age increased over the three periods from 32 to 42 to 54 years ( p  < 0.00001). The median day of onset of GvHD in the three periods was day +14, day +16, and day +30, respectively ( p  < 0.0001). The cumulative incidence (CI) of GvHD grades II-IV in the three periods was 47, 24, and 16%, respectively ( p  < 0.00001). The CI of GvHD grades III-IV was 13, 5, and 4% ( p  < 0.001). In multivariate analysis, significant predictive factors for GvHD II-IV, on top of year of transplant, were anti-thymocyte globulin (ATG) (RR 0.67, p  > 0.001); post-transplant cyclophosphamide (PTCY) (RR 0.41, p  < 0.001), a family mismatched donor (RR 1.31, p  = 0.03) a matched unrelated donor (RR 2.1, p < 0.001), an unrelated mismatched donor (RR1.8, p  = 0.001), donor age above 40 years (RR 1.27, p  < 0.001), hematological malignancy-as compared to aplastic anemia (RR 2.3, p  < 0.001). When selecting only GvHD grade II, in a multivariate analysis, there was a significant reduction of transplant-related mortality (TRM) for patients grafted in 2001-2010 (RR 0.62, p  < 0.0001) and for patients grafted in 2011-2020 (RR 0.35, p  < 0.0001) as compared to grafts before the year 2000. A similar reduction in time was seen for patients with GvHD grades III-IV. The overall TRM in the three periods was 30, 22, and 16% ( p  < 0.0001) and survival was 47, 51, and 58% ( p  < 0.0001). Relapse risk was unchanged. In conclusion, we showed improved prevention of acute GvHD with time, together with a significant delay in the onset of the disease. Treatment of GvHD has also improved over time, as suggested by both reduced TRM and improved survival in more recent transplant periods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Di Francesco, Raiola, Dominietto, Di Grazia, Gualandi, Van Lint, Bregante, Chiusolo, Laurenti, Sora, Giammarco, Metafuni, Fresa, Sica, Angelucci and Bacigalupo.)

Background: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia., Methods: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months., Results: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome., Conclusions: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.)., (Copyright © 2022 Massachusetts Medical Society.)

Large differences in patient and transplant backgrounds make it difficult to identify consistent prognostic factors of unrelated cord blood transplantation (UCBT) among different populations. Thus, we performed a collaborative study between Eurocord/ALWP-EBMT and JSHCT/JDCHCT. Adults with acute leukaemia who underwent a single UCBT were eligible. In total, 3764 and 1027 patients of the JSHCT/JDCHCT and Eurocord/ALWP-EBMT registries, respectively, were included. The median ages of the Japanese and European cohorts were 51 and 38 years, respectively. Three or more HLA mismatches were more frequently observed in the Japanese cohort. The median total nucleated cell (TNC) counts were 2.58 and 3.51 × 10 7 /kg in the Japanese and European cohorts, respectively. Anti-thymocyte globulin was used in only 2% of the Japanese cohort compared with 65% of the European cohort. The 3-year overall survival (OS) was 41% in JSHCT/JDCHCT and 33% in Eurocord/ALWP-EBMT. In the multivariate analysis, TNC dose and HLA matching had no significant effect on OS in either cohort, whereas year of transplantation, age, and refined disease risk index affected OS in both cohorts. Despite considerable differences in characteristics between the Japanese and European cohorts, we observed similar prognostic factors affecting UCBT outcomes in adult patients with acute leukaemia in both registries.

Refractory or relapsed acute myeloid leukemia (R/R-AML) has poor prognosis. Allogeneic hematopoietic stem-cell transplantation (HSCT) may provide cure in this scenario. We compared outcomes of HSCT from HLA-identical (HLA-id, n = 1654) sibling or haploidentical (Haplo, n = 389) donors in patients with R/R-AML, performed during the period 2007-2015. The Haplo group included patients receiving an unmanipulated graft (post-transplant cyclophosphamide, n = 278; in vivo T-cell depletion, n = 95; or both, n = 16). Median age at HSCT was 52 (range 18-74) years. Median follow-up was 16 and 22 months for HLA-id sibling and Haplo recipients, respectively (p = 0.11). Compared to MSD, Haplo HSCT were performed more recently (2013 vs 2011, p < 0.01), at longer interval from diagnosis (7 vs 5 months, p < 0.01), more frequently using bone marrow as stem cell source (47% vs 8%, p < 0.01) and with a reduced intensity conditioning regimen (50% vs 43%, p = 0.03). Engraftment was higher (93% vs 83%, p < 0.01) in HLA-id sibling. In multivariate analysis, Haplo HSCT was associated with lower GVHD/relapse-free survival, inferior LFS and OS and higher NRM, mainly due to a higher rate of infections (41% vs 25%, p < 0.01). For R/R-AML, HLA-id sibling donors remain the gold standard, when available, due to higher mortality in Haplo without significant gain in disease control.

Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events occur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64% (60-68%) and overall survival was 74% (71-78%) at ten years; results were better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients aged <45 years and 33% (13-53%) in patients aged ≥65 years. The main cause of death was relapse of the primary disease. Graft- versus -host disease (GvHD) before two years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GvHD disease prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at two years. However, the occurrence of late complications, including late relapses, infectious complications and secondary malignancies, highlights the importance of screening and monitoring of long-term survivors., (Copyright© 2019 Ferrata Storti Foundation.)

Background: T cell-replete haploidentical stem cell transplantation (haplo-SCT) is a valid therapeutic option for adult patients with high-risk acute myeloid leukemia (AML) lacking an HLA-matched sibling or unrelated donor., Method: We retrospectively analyzed the outcomes of 912 AML patients ≥45 years of age who had undergone haplo-SCT with either myeloablative conditioning (MAC; n = 373) or reduced intensity conditioning (RIC; n = 539) regimens., Results: The median follow-up was 31.1 and 25.7 months for MAC and RIC, respectively. The incidence of relapse and nonrelapse mortality (NRM) were 25.1% versus 28.7% and 31.0% versus 30.3% for MAC and RIC, respectively; 2-year leukemia-free survival (LFS) was 43.9% for MAC versus 41.0% for RIC. In multivariate analysis, the use of MAC versus RIC was not associated with a difference in the outcomes. Results were confirmed in the propensity score-weighted analysis. Disease status and performance status at transplantation were associated with outcomes. Notably, the use of posttransplantation cyclophosphamide was associated with reduced acute graft-versus-host disease (aGVHD) stage III-IV, and NRM and increased overall survival, LFS, and GVHD-free, relapse-free survival. The use of mobilized peripheral blood stem cells was associated with an increased risk of stage II-IV aGVHD., Conclusion: No differences were found between MAC and RIC regimens for haplo-SCT in adults with AML who were ≥45 years of age. The type of GVHD prophylaxis, disease status, and performance status were the major predictors of transplantation outcome. These results may serve as the background for randomized study comparing RIC versus MAC for haplo-SCT in adults with AML., (© 2019 American Cancer Society.)

The role of umbilical cord blood transplantation (CBT) in acute myeloid leukemia (AML) patients with active disease at allogeneic hematopoietic cell transplantation (allo-HCT) remains poorly investigated. In this study, we compared transplantation outcomes of 2963 patients with primary refractory or relapsed AML given CBT, 10/10 HLA-matched UD, or 9/10 HLA-matched UD allo-HCT from 2004 to 2015 at EBMT-affiliated centers. Neutrophil engraftment and complete remission rates in CBT, UD 10/10, and UD 9/10 recipients were 75 and 48%, 93 and 69%, and 93 and 70%, respectively. In multivariate Cox analyses, in comparison with CBT (n = 285), UD 10/10 recipients (n = 2001) had a lower incidence of relapse (HR = 0.7, P = 0.001), a lower incidence of non relapse mortality (HR = 0.6, P < 0.001), better GVHD-free and leukemia-free survival (GRFS, HR = 0.8, P < 0.001) and better survival (HR = 0.6, P < 0.001). Further, in comparison with CBT, 9/10 UD recipients (n = 677) also had a lower incidence of relapse (HR = 0.8, P = 0.02), a lower incidence of nonrelapse mortality (HR = 0.7, P = 0.008), better GRFS (HR = 0.8, P = 0.01) and better survival (HR = 0.7, P < 0.001). In summary, these data suggest that in AML patients with active disease at transplantation, allo-HCT with UD results in better transplantation outcomes than CBT.

Haploidentical stem cell transplantation with T cell-replete grafts and post-transplant cyclophosphamide (PTCy) is increasingly used with encouraging outcome. Natural killer (NK) cell alloreactivity, predicted by missing killer cell immunoglobulin-like receptor (KIR) ligands in the recipient that are present in their donor improves outcome of T cell-depleted haploidentical transplants. We explored the role of KIR ligand mismatching in 444 acute leukemia patients after T cell-replete transplants with PTCy. Thirty-seven percent of all patients had KIR ligand mismatching. Patients were in first remission (CR1) (39%), second remission (CR2) (26%), or active disease (35%). Stem cell source was peripheral blood (PBSC, 46%) or bone marrow (54%). The 2-year relapse, non-relapse mortality (NRM), and survival rates were 36.0% (95% confidence interval (CI), 31.4-40.7), 23.9% (20.0-28.0), and 45.9% (40.8-51.0), respectively. Multivariate analysis identified acute myeloid leukemia compared with acute lymphoblastic leukemia (hazard ratio (HR) 0.55, P = 0.002), female gender (HR 0.72, P = 0.04), and good performance status (HR 0.71, P = 0.04) as factors associated with better survival, while advanced age (HR 1.13, P = 0.04), active disease (HR 3.38, P < 0.0001), and KIR ligand mismatching (HR 1.41, P = 0.03) as associated with worse survival. KIR ligand mismatching was associated with a trend for higher relapse but not with graft-versus-host disease or NRM. The KIR ligand-mismatching effect was more prominent in patients given PBSC. In conclusion, there is no evidence that KIR ligand mismatching results in better outcome in the PTCy setting.

We retrospectively analyzed the outcomes of 1837 adults and children with severe aplastic anemia (SAA) who underwent matched sibling donor (MSD) and matched unrelated donor (MUD) hemopoietic stem cell transplantation (HSCT) between 2000 and 2013. Patients were grouped by transplant conditioning containing either anti-thymocyte globulin (ATG) (n = 1283), alemtuzumab (n = 261), or no serotherapy (NS) (n = 293). The risks of chronic GvHD were significantly reduced when ATG or alemtuzumab were compared with NS (P = .021 and .003, respectively). Acute GVHD was significantly reduced in favor of alemtuzumab compared with ATG (P = .012) and NS (P < .001). By multivariate analysis, when compared with ATG, alemtuzumab was associated with a lower risk of developing acute (OR 0.262; 95% CI 0.14-0.47; P < .001) and chronic GVHD (HR 0.58; 95% CI 0.35-0.94; P = .027). OS was significantly better in ATG and alemtuzumab patients compared with NS (P = .010 and .025). Our data shows inclusion of serotherapy in MSD and MUD HSCT for patients with SAA reduces chronic GVHD and provides a survival advantage over patients not receiving serotherapy. Notably, alemtuzumab reduced the risk of acute and chronic GvHD compared with ATG and indicates that alemtuzumab might be the serotherapy of choice for MSD and MUD transplants for SAA., (© 2018 Wiley Periodicals, Inc.)