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In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification., (© 2024 Wiley Periodicals LLC.)

Post-transplantation cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT) and achieves low rates of GVHD in HLA-identical transplantation. To compare the outcomes of haploidentical versus HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. We conducted a retrospective study of 229 patients undergoing first HSCT for AML using PTCY with additional immunosuppression, 99 from matched sibling or unrelated donor (MSD/MUD) performed in 3 hospitals and 130 from haploidentical donors (haplo group) performed in 20 hospitals within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cellular Therapy. Peripheral blood stem cells were used as graft in 89% of patients; myeloablative conditioning was used in 56%. There were significantly more patients with active disease (5% versus 20%, P = .001), high/very high disease risk index (DRI) (32% versus 67%, P = .000) and prior auto-HSCT (2% versus 11%, P = .010) in the haplo group. Median follow-up was 27 and 62.5 months for MSD/MUD and haplo, respectively. At 2 years, no significant differences were observed in overall survival (OS) (72% versus 62%, P = .07), event-free survival (EFS) (70% versus 54%, P = .055), cumulative incidence of relapse (19% versus 25%, P = .13), non-relapse mortality (14% versus 19%, P = .145), and the composite endpoint of GVHD and relapse-free survival (49% versus 42%, P = .249). Multivariate analysis identified only age and active disease as significant risk factors for OS and EFS; reduced-intensity conditioning, high/very high DRI, and haplo donor were nearly statistically significant for these outcomes. Grade II-IV acute GVHD was lower in MSD/MUD (14% versus 47%, P = .000). Cumulative incidences of grade III-IV acute GVHD (4% versus 9%, P = .14) and moderate-severe chronic GVHD (22% versus 19%, P = .28) were similar. Limitations of our study include limited sample size, differences between haplo and MSD/MUD groups and heterogeneous additional immunosuppression and PTCY timing in MSD/MUD. The use of an HLA-identical donor with PTCY in patients with AML showed lower incidence of clinically significant grade II-IV acute GVHD compared to haplo donors. Further studies with larger sample sizes should be performed to establish a possible benefit of HLA-identical donor on survival. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We analysed long-term outcome of patients receiving haematopoietic allogeneic stem cell transplantation (allo-HSCT) as a first transplant for high-risk Hodgkin lymphoma (HL). One hundred and ninety patients were included in this study, 63% of them had previously received brentuximab vedotin and/or checkpoint inhibitors. Seventy patients (37%) received an unrelated donor allo-HSCT, 99 (51%) had myeloablative conditioning (MAC) and 60% had in vivo T-cell/depleted grafts (TCD). The 100-day cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was 25% and the 3-year CI of chronic GVHD was 38%. The 3-year CI of non-relapse mortality (NRM) and relapse rate were 21% and 38% respectively. After a median follow-up of 58 months, 3-year overall survival (OS) and progression-free survival (PFS) were 58% and 41% respectively. Multivariate analysis showed that, in comparison to reduced-intensity conditioning regimens with or without TCD, MAC using TCD had similar NRM and a lower risk of relapse leading to significantly better OS and PFS. MAC without TCD was associated with higher NRM and worse survival outcomes. These results suggest that in patients with high-risk HL and candidates of allo-HSCT, a MAC strategy with TCD might be the best option., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: High-risk acute leukemia (AL) and myelodysplastic syndrome (MDS) remain a therapeutic challenge. Unmanipulated haploidentical-related donor transplantation based on a myeloablative conditioning regimen (HAPLO-MAC) and post-transplant cyclophosphamide (PT-Cy) as prophylaxis against graft vs host disease (GvHD) is now a promising rescue strategy that could become universally available., Objective: To evaluate the results of HAPLO-MAC with PT-Cy in patients with AL and MDS reported to the Haploidentical Transplantation Subcommittee of the Spanish Group for Hematopoietic Transplantation (GETH)., Patients and Methods: We report our multicenter experience using an IV busulfan-based HAPLO-MAC regimen and PT-Cy for treatment of 65 adults with high-risk AL and MDS., Results: Engraftment was recorded in 64 patients (98.5%), with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 28.6% and 27.5%, respectively. After a median follow-up of 31 months for survivors, the cumulative incidence of non-relapse mortality and relapse at 2 years was 18.8% and 25%, respectively. Estimated 30-month event-free survival and overall survival were 56% and 54.5%, respectively., Conclusion: HAPLO-MAC comprising an IV busulfan-based conditioning regimen enabled long-term disease control with acceptable toxicity in high-risk AL and MDS., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34 + cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P < .001) and a higher comorbidity burden (Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI] ≥3: 51% versus 38%; P < .001) in the TCD cohort. Analysis of outcomes at 3 years showed a higher chronic graft-versus-host disease (GVHD)/relapse-free survival (CRFS) (51% versus 7%; P < .001), lower incidences of grade II-IV acute GVHD (18% versus 46% at day +180) and chronic GVHD (6% versus 55% at 3 years; P < .001), and a lower incidence of relapse (19% versus 33% at 3 years; P = .001) in the TCD group compared with the RIC group. Relapse-free survival (RFS), overall survival (OS), and NRM were similar in the 2 groups. Combining transplantation approach (RIC versus TCD) and comorbidity burden (HCT-CI 0-2 versus ≥3), patients with an HCT-CI score of 0-2 seemed to benefit from the TCD approach. In conclusion, in this retrospective study, the use of a CD34 + cell-selected graft and a myeloablative conditioning regimen was associated with higher CRFS and similar RFS and OS compared with unmodified allo-RIC in patients age >50 years with AML and MDS., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Relapsed or refractory Hodgkin lymphoma (advanced HL) still remains a therapeutic challenge. Recently, unmanipulated haploidentical related donor transplant with reduced conditioning regimen (HAPLO-RIC) and post-transplant cyclophosphamide (PT-Cy) as GvHD prophylaxis has became a promising rescue strategy potentially available to almost every patient. This paper reports our multicenter experience using an IV busulfan-based HAPLO-RIC regimen and PT-Cy in the treatment of 43 patients with advanced HL. Engraftment occurred in 42 patients (97.5%), with a median time to neutrophil and platelet recovery of 18 and 26 days. Cumulative incidences of grades II-IV acute GvHD and chronic GvHD were 39% and 19%, respectively. With a median follow-up of 25.5 months for survivors, 27 patients are alive, with 22 of them disease free. Cumulative incidences of 1-year non-relapse mortality and relapse at 2 years were 21% and 24%, respectively. The estimated 2-year event-free survival (EFS) and overall survival (OS) were 48% and 58%, respectively. CR prior to HAPLO-RIC correlated with better EFS (78.5% vs 33.5%; P=0.015) and OS (86% vs 46%; P=0.044). Our findings further confirm prior reports using HAPLO-RIC in advanced HL in a multicenter approach employing an IV busulfan-based conditioning regimen.

The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil (group 3). Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors., (Copyright© Ferrata Storti Foundation.)

We evaluated the feasibility, safety, and efficacy of the administration of 4 sequential doses (intravenously administered on days 1, 4, 11, and 18) of cryopreserved bone marrow-derived mesenchymal stromal cells (MSC) expanded with platelet lysate and obtained from third-party donors as a second-line treatment for steroid-refractory acute graft-versus-host (aGVHD) disease in a series of 25 patients. All patients received at least 2 doses of MSC, whereas 21 received 3 doses and 18 received the initially planned 4 doses. Because of the achievement of partial response, 4 patients received additional doses of MSC. Median single cell dose administered was 1.1 × 10(6) MSC/kg of recipient body weight. There were no adverse events related to the MSC infusion in the 99 procedures performed, with the exception of a cardiac ischemic event that occurred twice in a patient with prior history of cardiac ischemia. Response to MSC at 60 days after the first dose was evaluable in 24 patients. Seventeen patients (71%) responded (11 complete and 6 partial responses), with a median time to response of 28 days after the first MSC dose, whereas 7 patients did not respond. In summary, we can conclude that sequential cryopreserved third-party MSC therapy administered on days 1, 4, 11, and 18 is a safe procedure for patients with steroid-refractory aGVHD. This strategy may provide a high rate of overall responses of aGVHD with a low toxicity profile., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma., (© 2013 John Wiley & Sons Ltd.)

Hyperferritinemia has been associated with adverse outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning. However, its characteristics and impact on the outcome in the reduced-intensity conditioning (RIC) and in the lymphoid malignancy settings are far from clear. The study includes 201 adult patients undergoing allo-HCT with RIC (allo-RIC) for lymphoid malignancies with a median follow-up for survivors of 52 months (range, 3 to 123). Median serum ferritin level at allo-RIC was 379 ng/mL (range, 4 to 10,790). In the multivariate analysis, patients with hyperferritinemia at transplantation (>399 ng/mL) showed lower 4-year overall survival (hazard ratio [HR], 1.8 [95% confidence interval {CI}, 1.2 to 2.8]; P = .008), higher nonrelapse mortality (NRM) (HR, 1.8 [95% CI, 1.1 to 3.2]; P = .03), and higher infection-related mortality (HR, 2.3 [95% CI, 1.1 to 4.8]; P = .02) than patients without hyperferritinemia. Neutrophil and platelet engraftment and 100-day NRM were similar between both groups. The adverse outcome associated with hyperferritinemia seemed higher in patients without major comorbidities and was not influenced by the elevation of acute phase reactants. Our results indicate that high ferritin levels at HCT are associated with an adverse outcome after allo-RIC in patients with lymphoid malignancies., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Although Hodgkin's lymphoma is a highly curable disease with modern chemotherapy protocols, some patients are primary refractory or relapse after first-line chemotherapy or even after high-dose therapy and autologous stem cell transplantation. We investigated the potential role of allogeneic stem cell transplantation in this setting., Design and Methods: In this phase II study 92 patients with relapsed Hodgkin's lymphoma and an HLA-identical sibling, a matched unrelated donor or a one antigen mismatched, unrelated donor were treated with salvage chemotherapy followed by reduced intensity allogeneic transplantation. Fourteen patients showed refractory disease and died from progressive lymphoma with a median overall survival after trial entry of 10 months (range, 6-17). Seventy-eight patients proceeded to allograft (unrelated donors, n=23). Fifty were allografted in complete or partial remission and 28 in stable disease. Fludarabine (150 mg/m(2) iv) and melphalan (140 mg/m(2) iv) were used as the conditioning regimen. Anti-thymocyte globulin was additionally used as graft-versus-host-disease prophylaxis for recipients of grafts from unrelated donors., Results: The non-relapse mortality rate was 8% at 100 days and 15% at 1 year. Relapse was the major cause of failure. The progression-free survival rate was 47% at 1 year and 18% at 4 years from trial entry. For the allografted population, the progression-free survival rate was 48% at 1 year and 24% at 4 years. Chronic graft-versus-host disease was associated with a lower incidence of relapse. Patients allografted in complete remission had a significantly better outcome. The overall survival rate was 71% at 1 year and 43% at 4 years., Conclusions: Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. The reduced intensity conditioning approach significantly reduced non-relapse mortality; the high relapse rate represents the major remaining challenge in this setting. The HDR-Allo trial was registered in the European Clinical Trials Database (EUDRACT, https://eudract.ema.europa.eu/) with number 02-0036.

Liver dysfunction is frequent before allogeneic stem cell transplantation (allo-SCT). However, its characteristics and impact on transplantation outcomes are uncertain, especially in the reduced-intensity conditioning (RIC) setting. We analyzed 455 patients receiving an allo-SCT in 3 Spanish centers. Pretransplantation aspartate aminotransferase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), total bilirubin, and international normalized ratio were analyzed. Pretransplantation liver function test abnormalities were found in 94 (22%) patients. The most frequent cause of pretransplantation liver dysfunction was isolated elevation of GGT/AP (n = 49, 53%). Patients with high bilirubin levels before allo-SCT showed higher 4-year nonrelapse mortality (4y-NRM) (hazard ratio [HR] 2 [95% confidence interval [CI] 1.1-3.8] P = .02) and patients with high GGT levels showed higher 100-day NRM and lower 4-year overall survival (OS) (HR 3.4 [95% CI 1.8-6.7] P < .001, and HR 2 [95% CI 1.4-3], P = .001), respectively. High levels of transaminases did not influence on survival or mortality. In conclusion, hepatic dysfunction before allo-SCT is frequent and has an impact on transplantation outcomes. The best indicator of liver dysfunction still has to be determined., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)