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BACKGROUND & AIMS: Durable remissions of Crohns Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications. METHODS: DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant. RESULTS: We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications. CONCLUSIONS: The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348).

Background: Hematopoietic cell transplantation (HCT) increases survival for acute leukemia. Outpatient allogeneic HCT reduces costs and increases transplant rates in developing countries. We report outcomes of outpatient HLA-identical and haploidentical HCT in acute leukemia. Methods: This single-center retrospective cohort study analyzed 121 adult patients with acute myeloblastic (AML) and acute lymphoblastic leukemia (ALL) receiving an outpatient allogeneic HCT with peripheral blood allografts after reduced-intensity conditioning (RIC) from 2012-2022. Results: There were 81 (67%) haploidentical and 40 (33%) HLA-identical transplants. Complete chimerism (CC) at day +100 was not different in HLA-identical compared to haploidentical HCT (32.5% and 38.2%, P=0.054). Post-HCT complications, including neutropenic fever (59.3% vs. 40%), acute graft-versus-host-disease (aGVHD) (46.9% vs. 25%), cytokine release syndrome (CRS) (18.5% vs. 2.5%), and hospitalization (71.6% vs 42.5%) were significantly more frequent in haploidentical HCT. Two-year overall survival (OS) was 60.6% vs. 46.9%, (P=0.464) for HLA-identical and haplo-HCT, respectively. There was no difference in the 2-year disease-free-survival (DFS) (33.3% vs. 35%, P=0.924) between transplant types. In multivariate analysis, positive measurable residual disease (MRD) at 30 days (HR 8.8, P=0.018) and 100 days (HR 28.5, P=0.022) was associated with lower OS, but not with non-relapse mortality (NRM) (P=0.252 and P=0.123, univariate). In univariate analysis, both 30-day and 100-day MRD were associated with lower DFS rates (P=0.026 and P=0.006), but only day 30 MRD was significant in multivariate analysis (P=0.050). In the case of relapse, only MRD at day 100 was associated with increased risk in the univariate and multivariate analyses (HR 4.48, P=0.003 and HR 4.67, P=0.008). Chronic graft-versus-host-disease (cGVHD) was protective for NRM (HR 0.38, P=0.015). There was no difference in cumulative incidence of relapse (CIR) between transplant types (P=0.126). Forty-four (36.4%) patients died, with no difference between HCT type (P=0.307). Septic shock was the most frequent cause of death with 17 cases, with no difference between transplant types Conclusions: Outpatient peripheral blood allogenic HCT after RIC is a valid and effective alternative for adult patients suffering acute myeloblastic or lymphoblastic leukemia in low-income populations. [ABSTRACT FROM AUTHOR]

Summary: Reduced‐intensity conditioning regimens are commonly used in allogeneic haematopoietic cell transplantation for non‐Hodgkin lymphoma (NHL); however, the optimal regimen remains unknown. In this study, the outcomes of adult patients with NHL who received fludarabine plus reduced‐dose busulfan (6.4 mg/kg; Flu/Bu2) (n = 286) and fludarabine plus low‐dose melphalan (80 or 100 mg/m2; Flu/Mel80–100) (n = 283) between January 2009 and December 2020 were compared using Japanese registry data. The primary end‐point was the 5‐year overall survival (OS). The 5‐year OS was 53.8% (95% CI, 47.6–59.6) and 42.4% (95% CI, 35.6–49.0) in the Flu/Bu2 and Flu/Mel80–100 groups respectively (p = 0.030). After inverse probability of treatment weighting adjustment, the adjusted HR of Flu/Bu2 compared with Flu/Mel80–100 group for 5‐year OS was 0.77 (95% CI, 0.60–0.99, p = 0.046), 0.97 (95% CI, 0.78–1.21, p = 0.798) for 5‐year progression‐free survival, 0.65 (95% CI, 0.45–0.94, p = 0.022) for 5‐year cumulative risk of non‐relapse mortality and 1.25 (95% CI, 0.95–1.64, p = 0.115) for 5‐year cumulative risk of relapse. In this study, patients with NHL who received Flu/Bu2 were associated with better OS and lower non‐relapse mortality than those who received Flu/Mel80–100. [ABSTRACT FROM AUTHOR]

Immunological dysfunction in multiple lineages of hematopoietic cells and mixed chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with an increased risk of autoimmunity in patients with Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). Here, we report the efficacy of rituximab against autoimmunity in five patients with WAS and XLT. One patient with systemic arthritis and vasculitis, and two patients with immune thrombocytopenia were successfully treated with rituximab before initiating reduced-intensity conditioning. Rituximab was also used in combination with conditioning to prevent autoimmunity by depleting the recipient B cells in the other two patients with XLT. None of the patients developed autoimmunity without delay in donor B cell reconstitution, even though two patients had stable mixed chimerism after HSCT. These results suggest that aberrant B cell-intrinsic mechanisms are a central cause of autoimmunity, and rituximab is an effective therapeutic option for autoimmunity in patients with WAS and XLT.

BackgroundHematopoietic cell transplantation (HCT) increases survival for acute leukemia. Outpatient allogeneic HCT reduces costs and increases transplant rates in developing countries. We report outcomes of outpatient HLA-identical and haploidentical HCT in acute leukemia.MethodsThis single-center retrospective cohort study analyzed 121 adult patients with acute myeloblastic (AML) and acute lymphoblastic leukemia (ALL) receiving an outpatient allogeneic HCT with peripheral blood allografts after reduced-intensity conditioning (RIC) from 2012-2022.ResultsThere were 81 (67%) haploidentical and 40 (33%) HLA-identical transplants. Complete chimerism (CC) at day +100 was not different in HLA-identical compared to haploidentical HCT (32.5% and 38.2%, P=0.054). Post-HCT complications, including neutropenic fever (59.3% vs. 40%), acute graft-versus-host-disease (aGVHD) (46.9% vs. 25%), cytokine release syndrome (CRS) (18.5% vs. 2.5%), and hospitalization (71.6% vs 42.5%) were significantly more frequent in haploidentical HCT. Two-year overall survival (OS) was 60.6% vs. 46.9%, (P=0.464) for HLA-identical and haplo-HCT, respectively. There was no difference in the 2-year disease-free-survival (DFS) (33.3% vs. 35%, P=0.924) between transplant types. In multivariate analysis, positive measurable residual disease (MRD) at 30 days (HR 8.8, P=0.018) and 100 days (HR 28.5, P=0.022) was associated with lower OS, but not with non-relapse mortality (NRM) (P=0.252 and P=0.123, univariate). In univariate analysis, both 30-day and 100-day MRD were associated with lower DFS rates (P=0.026 and P=0.006), but only day 30 MRD was significant in multivariate analysis (P=0.050). In the case of relapse, only MRD at day 100 was associated with increased risk in the univariate and multivariate analyses (HR 4.48, P=0.003 and HR 4.67, P=0.008). Chronic graft-versus-host-disease (cGVHD) was protective for NRM (HR 0.38, P=0.015). There was no difference in cumulative incidence of relapse (CIR) between transplant types (P=0.126). Forty-four (36.4%) patients died, with no difference between HCT type (P=0.307). Septic shock was the most frequent cause of death with 17 cases, with no difference between transplant typesConclusionsOutpatient peripheral blood allogenic HCT after RIC is a valid and effective alternative for adult patients suffering acute myeloblastic or lymphoblastic leukemia in low-income populations.

Simple Summary: Allogeneic stem cell transplantation (aHSCT) is the only potentially curative treatment option for patients with high-risk myeloid malignancies. Depending on the underlying genetic risk profile, up to 50% of patients die of relapse even after aHSCT in first remission. Therefore, further improvement of conditioning regimens is an urgent medical need. Current sequential conditioning regimens combine intensive AML-like induction therapy with total body irradiation or alkylators like treosulfan or melphalan. The first and currently widely accepted prototype of this treatment strategy is the fludarabine/amsacrine/ara-C (FLAMSA) protocol, which has been modified multiple times by changing parts or adding additional cytotoxic drugs to improve clinical results. Knowing that venetoclax, an inhibitor of B-cell lymphoma-2 protein (BCL2), has synergistic effects to chemotherapy without increasing the level of non-hematologic toxicity, several German transplant centers have added venetoclax to the FLAMSA protocol as an individualized treatment approach to improve long term outcome in patients with high-risk myeloid malignancies. Up to 50% of patients with high-risk myeloid malignancies die of relapse after allogeneic stem cell transplantation. Current sequential conditioning regimens like the FLAMSA protocol combine intensive induction therapy with TBI or alkylators. Venetoclax has synergistic effects to chemotherapy. In a retrospective survey among German transplant centers, we identified 61 patients with myeloid malignancies that had received FLAMSA-based sequential conditioning with venetoclax between 2018 and 2022 as an individualized treatment approach. Sixty patients (98%) had active disease at transplant and 74% had genetic high-risk features. Patients received allografts from matched unrelated, matched related, or mismatched donors. Tumor lysis syndrome occurred in two patients but no significant non-hematologic toxicity related to venetoclax was observed. On day +30, 55 patients (90%) were in complete remission. Acute GvHD II°–IV° occurred in 17 (28%) and moderate/severe chronic GvHD in 7 patients (12%). Event-free survival and overall survival were 64% and 80% at 1 year as well as 57% and 75% at 2 years, respectively. The off-label combination of sequential FLAMSA-RIC with venetoclax appears to be safe and highly effective. To further validate these insights and enhance the idea of smart conditioning, a controlled prospective clinical trial was initiated in July 2023. [ABSTRACT FROM AUTHOR]

Reduced-intensity conditioning (RIC) regimens have the potential to decrease toxicities related to hematopoietic stem cell transplantation (HCT) in patients with sickle cell disease (SCD). While initial results may have been acceptable in adults and young adults, there are no well-established strategies in children with SCD. Here, it is described the clinical course of two children with symptomatic SCD who have successfully undergone HSCT using Fludarabin-based conditioning. [ABSTRACT FROM AUTHOR]

In response to the widespread COVID-19 pandemic, cryopreservation of allogeneic donor apheresis products was implemented to mitigate the challenges of donor availability and product transport. Although logistically beneficial, the impact of cryopreservation on clinical outcomes and graft composition remains unclear. In this study, we compared outcomes and graft composition with cryopreserved versus fresh allografts in the setting of allogeneic hematopoietic cell transplantation (allo-HCT). We retrospectively analyzed the clinical outcomes of 30 consecutive patients who received cryopreserved allografts between March and August 2020 and 60 consecutive patients who received fresh allografts before the COVID-19 pandemic. Primary endpoints were hematopoietic engraftment and graft failure (GF), and secondary outcomes were overall survival (OS), relapse-free survival (RFS) and nonrelapse mortality (NRM). In addition, extended immunophenotype analysis was performed on cryopreserved and prospectively collected fresh apheresis samples. Compared with recipients of fresh allografts, both neutrophil and platelet recovery were delayed in recipients of cryopreserved reduced-intensity conditioning (RIC) allo-HCT, with a median time to engraftment of 24 days versus 18 days (P = .01) for neutrophils and 27 days versus 18 days (P = .069) for platelets. We observed primary GF in 4 of 30 patients in the cryopreserved cohort (13.3%) versus only 1 of 60 patients (1.7 %) in the fresh cohort (P = .03). Cryopreserved RIC allo-HCT was associated with significantly lower median total, myeloid, and T cell donor chimerism at 1 month. OS and RFS were inferior for cryopreserved graft recipients (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.00 to 4.67) and HR, 1.90; 95% CI, 0.95 to 3.79, respectively. Using an extended immunophenotype analysis, we compared 14 samples from the cryopreserved cohort to 6 prospectively collected fresh apheresis donor samples. These analyses showed both a decrease in total cell viability and a significantly reduced absolute number of natural killer cells (CD3-CD56+) in the cryopreserved apheresis samples. In this single-institution study, we found delayed engraftment and a trend toward clinical inferiority of cryopreserved allografts compared with fresh allografts. Further evaluation of the use of cryopreserved allografts and their impact on clinical and laboratory outcomes is warranted.

Background & aims: Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications. Methods: DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant. Results: We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications. Conclusions: The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348)

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae. [ABSTRACT FROM AUTHOR]

Acute diarrhea is a common and debilitating complication in recipients of allogeneic hematopoietic stem cell transplantation (HCT). In this prospective, observational, and multicenter study we examined all episodes occurring in the first 6 months of 142 consecutive adult patients who underwent a reduced-intensity conditioning HCT in 10 Spanish tertiary university hospitals. Fifty-four patients (38%) developed a total of 75 acute diarrhea episodes. The median time from HCT to the first episode was 38 days (4–157). The main cause of enterocolitis was lower GI-aGVHD (38%), followed by infections (21%) and drug-related toxicity (8%). Causative infectious causes were identified in only 16/75 episodes (21%). C. difficile-related infection was the most common infectious agent with an incidence and recurrence of 13% and 2%, respectively. With a median follow-up for survivors of 32 months, the non-relapse mortality (NRM) and the overall survival (OS) at 1 year, were 20% (95% C.I.: 14–28%) and 69% (95% C.I.: 61–77%), respectively. Development of enterocolitis was not associated with higher NRM (p = 0.37) or worse OS (p = 0.9). This real-life study confirms that the diagnosis and management of acute diarrhea in the early stages after HCT is challenging. Nosocomial infections seem to be relatively uncommon, probably due to more rational use of antibiotics. [ABSTRACT FROM AUTHOR]

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m2) and FM140 (melphalan dose: 140 mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of UCB recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (n = 5) and class 3 (n = 1) died of GVHD (n = 3), viral pneumonitis (n = 2) and pulmonary hemorrhage (n = 1). Outcomes after this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with relapsed and refractory classic Hodgkin lymphoma (rrHL). However, the optimal conditioning regimen and GVHD prophylaxis for rrHL remain undetermined. The aim of this study was to investigate outcomes of allo-HSCT with a fludarabine plus bendamustine (FluBe) conditioning regimen and GVHD prophylaxis with posttransplantation cyclophosphamide (PTCY) in patients with rrHL. Methods: Allo-HSCT results in 58 adult patients with rrHL were analyzed retrospectively. Results: Three-year overall survival and event-free survival were 81% (95% CI 65–91) and 55% (95% CI 38–72), respectively. The cumulative incidence of relapse (CIR) at 3 years was 33% (95% CI 13–51). The cumulative incidence of aGVHD grade II–IV and severe aGVHD grade III–IV was 36% (95% CI 22–48) and 22% (95% CI 9–33), respectively. The cumulative incidence of cGVHD was 32% (95% CI 17–45), including moderate or severe cGVHD in 17% (95% CI 4–28). Patients who developed aGVHD after allo-HSCT had significantly lower CIR (24% vs 49%, p = 0.004). The use of PBSC as a graft source also significantly reduced CIR (4% vs 61%, p = 0.002). Conclusions: FluBe-PTCY allo-HSCT facilitates favorable outcomes, low toxicity, and mortality in rrHL. [ABSTRACT FROM AUTHOR]

Background: Dyskeratosis congenita/telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field., Objectives/study Design: We report prospectively collected standard alloHCT outcomes from a single-center, single-arm, open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC), including alemtuzumab 1 mg/kg, fludarabine 200 mg/m 2 , and cyclophosphamide 50 mg/kg. A previous single-arm, open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 cGy of total body irradiation (TBI), served as a control cohort., Results: The non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared with the control TBI cohort, which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (non-TBI) compared with 2.6 (TBI) x 10 6 /kg (P = .02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0% and 10% (non-TBI) and 8% and 17% (TBI), respectively (acute, P = .36; chronic, P = .72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (non-TBI cohort). The non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (non-TBI) and 75% (TBI; P = .78). MDS as an indication for alloHCT was uncommon but overall associated with poor outcomes. There were 3 MDS patients in the non-TBI cohort: 1 relapsed and died at day +387; 1 relapsed at day +500 and is alive 5.5 years later following salvage with a second alloHCT; 1 relapsed at day +1093 and is alive at day +100 after a second alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day +827 from a bacterial infection in the setting of immune-mediated cytopenia., Conclusion: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Severe combined immunodeficiency (SCID) is a heterogenous disorder with profound deficiency of T/B-cell functions. The best SCID therapy requires hematopoietic stem cell transplantation (HSCT) early in life. HSCT with conditioning is necessary to achieve a long-term reconstitution of B-cell functions. However, conditioning may aggravate pre-existing infection and cause transplant-related toxicity, especially in very young infants. Hence, the intensity of conditioning should be reduced to allow the reconstitution of immunity including B cells to the extent that prevents transplant-related toxicity and delayed complications., Methods: An infant with a family history of X-linked SCID (X-SCID) was diagnosed with X-SCID disorder soon after birth. The infant exhibited cytomegalovirus (CMV) infection despite being strictly isolated. At 1.5 months of age, we performed an unrelated cord blood transplantation (CBT) with a less intensity conditioning regimen: fludarabine (125 mg/m 2 ) + melphalan (80 mg/m 2 ). We evaluated the efficacy of reconstitution by assessing B-cell function and growth and psychomotor development at 5 years and 7 months after CBT., Results: The clinical course after CBT was uneventful after CBT. The CMV infection was fully controlled by ganciclovir or foscavir therapy, which was discontinued at day 55 after CBT. Furthermore, immunoglobulin (Ig) replacement therapy was also discontinued at 6 months after CBT. A sufficient proportion of CD27 + memory B cells was developed, which was essential for an effective vaccination and prevention of infections. While the B-cell chimerism became recipient-dominant, the Ig replacement therapy was substituted by very successful post-vaccine immunity acquisition after CBT. The analysis of the general developmental parameters showed that chemotherapy did not cause any delay in growth and psychomotor development., Conclusions: The CBT therapy with this conditioning regimen was well tolerated and induced an effective reconstitution of B-cell functions in an X-SCID infant under the 3 months of age., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Conditioning regimens play a crucial role in preventing relapse of acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (HCT). In early times, myeloablative conditioning was used exclusively, but it was associated with significant toxicity. However, the advent of reduced-intensity conditioning has allowed allogeneic HCT to be performed more safely, leading to an expansion of our choices for conditioning regimens. As the transplantation methods have become highly diversified, it is reasonable to determine an optimal conditioning regimen in consideration of patient-, disease-, and transplantation-related factors. In this context, large-scale registry-based studies provide real-world data to allow for a detailed evaluation of the utility of individual conditioning regimens in specific clinical settings. The Japanese Society for Transplantation and Cellular Therapy has been conducting a nationwide survey for HCT since 1993 that currently covers >99% of all the transplantation centers nationwide, and >1,000 allogeneic HCTs performed for adults with AML are registered per year. We have been using the registry data to implement a number of studies focusing on adults with AML, and the large number of patients registered consecutively from nearly all transplantation centers nationwide represent real-world practice in Japan. This article reviews and discusses the results obtained from our registry-based studies pertaining to various conditioning regimens.

Inherited bone marrow failure syndromes (IBMFSs) are a group of rare genetic disorders characterized by bone marrow failure with unique phenotypes and predisposition to cancer. Classical IBMFSs primarily include Fanconi anemia with impaired DNA damage repair, dyskeratosis congenita with telomere maintenance dysfunction, and Diamond–Blackfan anemia with aberrant ribosomal protein biosynthesis. Recently, comprehensive genetic analyses have been implemented for the definitive diagnosis of classic IBMFSs, and advances in molecular genetics have led to the identification of novel disorders such as AMeD and MIRAGE syndromes. Allogeneic hematopoietic cell transplantation (HCT), a promising option to overcome impaired hematopoiesis in patients with IBMFSs, does not correct nonhematological defects and may enhance the risk of secondary malignancies. Disease-specific management is necessary because IBMFSs differ in underlying defects and are associated with varying degrees of risk for clonal evolution and early or late complications after HCT. In addition, long-term follow-up is essential to detect complications related to the IBMFS or HCT. This review provides a summary of current clinical practices along with the latest data on HCT in IBMFSs. [ABSTRACT FROM AUTHOR]

We previously showed the safety of using cord blood (CB) expanded ex vivo in cocultures with allogeneic mesenchymal precursor cells (MPC) after myeloablative conditioning with faster recovery of neutrophils and platelets compared with historical controls. Herein, we report the transplantation outcomes of 27 patients with hematologic cancers who received 1 CB unit expanded ex vivo with MPCs in addition to an unmanipulated CB (MPC group) after reduced-intensity conditioning (RIC). The results in this group were compared with 51 historical controls who received 2 unmanipulated CB units (control group). The analyses were stratified for 2 RIC treatment groups: (1) total body irradiation 200 cGy + cyclophosphamide + fludarabine) (TCF), and (2) fludarabine + melphalan  (FM). Coculture of CB with MPCs led to an expansion of total nucleated cells by a median factor of 12 and of CD34+ cells by a median factor of 49. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 12 days in the MPC group, as compared with 16 days in controls (P = .02). The faster neutrophil engraftment was observed in both RIC groups. The cumulative incidence of neutrophil engraftment on day 26 was 75% with expansion versus 50% without expansion in patients who received FM as the RIC regimen (P = .03). Incidence of neutrophil engraftment was comparable in MPC and control groups if treated with TCF (82% versus 79%, P = .40). Transplantation of CB units expanded with MPCs is safe and effective with faster neutrophil engraftment even after RIC regimens.

Aggressive NK cell leukemia (ANKL) is an exceedingly rare form of leukemia and carries a poor prognosis, with a median survival of only 2 months. Using the Center for International Blood and Marrow Transplant Research database, we evaluated outcomes of allogeneic hematopoietic cell transplantation (alloHCT) in patients with ANKL. Twenty-one patients with a centrally confirmed diagnosis of ANKL were included. Median patient age was 42 years and 15 patients (71%) were Caucasian. Fourteen patients (67%) were in complete remission (CR) at the time of alloHCT, and 5 patients had active disease. Median follow-up of survivors was 25 months (range, 12 to 116). The 2-year estimates of nonrelapse mortality, relapse/progression, progression-free (PFS), and overall survival (OS) were 21%, 59%, 20%, and 24%, respectively. The 2-year PFS of patients in CR at the time of alloHCT was significantly better than that of patients with active disease at transplantation (30% versus 0%; P = .001). The 2-year OS in similar order was 38% versus 0% (P

Summary: There have been no large studies comparing reduced‐intensity/non‐myeloablative conditioning (RIC/NMA) to myeloablative conditioning (MAC) regimens in T‐cell non‐Hodgkin lymphoma (T‐NHL) patients undergoing allogeneic transplant (allo‐HCT). A total of 803 adults with peripheral T‐cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T‐cell lymphoma (age 18–65 years), undergoing allo‐HCT between 2008–2019 and reported to the Center for International Blood and Marrow Transplant Research with either MAC (n = 258) or RIC/NMA regimens (n = 545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race and performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts, haematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort compared to the MAC cohort (hazard ratio (HR) = 1.01, 95% confidence interval (CI) = 0.79–1.29; p = 0.95). Similarly, non‐relapse mortality (NRM) (HR = 0.85, 95% CI = 0.61–1.19; p = 0.34), risk of progression/relapse (HR = 1.29; 95% CI = 0.98–1.70; p = 0.07) and therapy failure (HR = 1.14; 95% CI = 0.92–1.41, p = 0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with a significantly lower risk of grade 3–4 acute graft‐versus‐host disease (HR = 0.67; 95% CI = 0.46–0.99, p = 0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after allo‐HCT for T‐cell NHL. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem-cell transplantation is a well-known curative treatment for patients with chronic granulomatous disease. We present our experiment regarding ten patients with chronic granulomatous disease who underwent a reduced intensity conditioning regimen consisting of melfalan, fludarabine, and antithymocyte globulin. Donor lymphocyte infusion was used in three representative patients who developed mixed donor chimerism. After at least 2 years of median follow-up, 8 of the 10 patients are alive and well.

The article presents a case study of a three year old with Diamond–Blackfan anemia (DBA) who underwent allogeneic hematopoietic cell transplantation (HCT). It is reported that the patient received reduced-intensity conditioning with targeted busulfan. It is further reported that the patient achieved successful engraftment, became transfusion-independent, and showed no severe adverse events during the 12-month follow-up.

Fludarabine with intravenous busulfan (6.4 mg/kg; FB2) and fludarabine with intermediate-dose melphalan (140 mg/m2; FM140) are the most widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation. FM140 generally has a lower relapse rate and higher non-relapse mortality (NRM), resulting in overall survival (OS) comparable to that seen with FB2. To evaluate the effect of reducing the melphalan dose, we retrospectively compared transplant outcomes in 156 patients who received FB2 (n = 103) or FM80 (n = 53) at our center (median age: 63 years; range 27–72 years). All patients received 4-Gy total body irradiation. Three-year OS, the cumulative incidence of relapse, and NRM were comparable between groups (FB2 vs. FM80, 58% vs. 47%, p = 0.24; 30% vs. 36%, p = 0.57; 17% vs. 21%, p = 0.44, respectively). There was no significant difference in the cumulative incidence of graft-versus-host disease (GVHD) at day 100, chronic GVHD at 3 years, or the 3-year GVHD-free/relapse-free survival rate. In the high-risk disease group, patients receiving FM80 tended to have lower 3-year OS (FB2 vs. FM80, 48% vs. 17%, p = 0.06). In summary, transplant outcomes following FB2 or FM80 were comparable except in patients with high-risk disease. [ABSTRACT FROM AUTHOR]

X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II–IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55–86%) and 64% (CI 46–77%), respectively. Recipient and donor HLA mismatch and grade II–IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5–23.3, p = 0.01) and 8.2 (CI 2.1–32.7, p < 0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT. [ABSTRACT FROM AUTHOR]

Summary: Allogeneic haematopoietic‐cell transplantation (allo‐HCT) is a potentially curative therapy for high‐risk myelodysplastic syndrome (MDS). Reduced‐intensity conditioning (RIC) is usually associated with lower non‐relapse mortality (NRM), higher relapse rate and similar overall‐survival (OS) as myeloablative‐conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced‐toxicity regimen with intense anti‐leukaemia activity and a favourable toxicity profile. We investigated post‐transplant outcomes in 1722 MDS patients following allo‐HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow‐up was 64 months (1–171). Five‐year relapse rates were 25% (21–30), 38% (34–42) and 25% (22–29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25–35), 27% (23–30) and 34% (31–38, P = 0·008), respectively. Five‐year OS was 50% (44–55), 43% (38–47), and 43% (39–47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo‐HCT in MDS. [ABSTRACT FROM AUTHOR]

Background: Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by rapidly progressive deterioration of neurocognitive functions and premature death. In addition to the difficulty in identifying the earliest signs of ALD, treatment-associated exacerbation of neurological symptoms has been an obstacle to achieve successful hematopoietic cell transplantation (HCT) for affected children. Case report: We report a 9-year-boy with ALD. He presented with impairment in social skills compatible to the diagnosis of autism spectrum disorder from 3 years of age. He showed progressive strabismus, slurred speech and dysmetria at 6 years of age. The head MRI showed symmetrical T2-hyperintense lesions in the occipital white matters with a gadolinium enhancement, which extended to the internal capsules. The Loes score was thus calculated as 13. Very-long-chain-fatty-acids were increased to 1.800 (C24:0/C22:0) and 0.077 (C26:0/C22:0) in leukocytes. Sanger sequencing confirmed the pathogenic variant in ABCD1 (NM_000033.4:p.Gly512Ser). After multidisciplinary discussions over the treatment options, we performed a cord blood HCT with a reduced intensity conditioning (fludarabine, melphalan and brain-sparing total body irradiation). He was fully recovered with >90% chimerism of donor leukocytes at 55 days after HCT. He experienced three times of generalized seizures after discharge, that has been well controlled for 2 years without other complications or neurocognitive deteriorations. Conclusion: For patients with ALD on a borderline indication for HCT, brain-sparing irradiation might be an alternative option in reduced intensity conditioning. Careful decision-making process and tailored conditioning are critical for the successful outcome of HCT for children with ALD.

Autologous stem cell transplantation (ASCT) is commonly an in-patient procedure. However, outpatient ASCT grows as a cost-effective and feasible option for patients with lymphoma and reports assessing it after reduced-intensity conditioning (RIC) are sparse. We report the outcome of 102 patients with lymphoma who underwent ASCT on a full outpatient basis in a single-center transplant program between 2010 and 2020. Forty-two percent of the cohort required transfusion support, 36.3% experienced a neutropenic fever episode, 25.5% mucositis, and 9.8% developed severe infection. At a median time of 5 days (range 1–28), only 22.5% of the cohort required admission within the first 100 days after the autograft, median length of hospital stay was 0 days (range 0–14) and neutropenic fever was the most common reason for hospitalization. Non-relapse mortality at 1 year was 5%. ASCT in a completely outpatient setting is feasible, safe, and highly effective to treat lymphoma patients. [ABSTRACT FROM AUTHOR]

Bone marrow transplantation, Diffuse large B-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, PIK3CD, Reduced-intensity conditioning, Rituximab Keywords: Bone marrow transplantation; Diffuse large B-cell lymphoma; Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; PIK3CD; Reduced-intensity conditioning; Rituximab EN Bone marrow transplantation Diffuse large B-cell lymphoma Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue PIK3CD Reduced-intensity conditioning Rituximab 1617 1619 3 06/20/22 20220701 NES 220701 Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00277-022-04809-8. Several studies have reported that 10-19% of patients with APDS1 develop malignant lymphoma; however, no standard therapy has been determined for such patients [[2]-[6]]. [Extracted from the article]

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

Reduced-intensity conditioning (RIC) improves the outcomes of hematopoietic cell transplantation (HCT) in patients with hemophagocytic lymphohistiocytosis (HLH). Proximal (ie, close to graft infusion) dosing of alemtuzumab is associated with a high incidence of mixed chimerism, whereas distal (ie, distant from graft infusion) dosing is associated with less mixed chimerism but more acute graft-versus-host disease (GVHD). The alemtuzumab dose per kilogram of body weight also influences these outcomes. We hypothesized that an intermediate alemtuzumab dosing schedule would reduce mixed chimerism and maintain a low incidence of acute GVHD. In this study, 24 consecutive HCTs were performed in patients with HLH or a related disorder using a novel intermediate alemtuzumab schedule of 1 mg/kg starting on day -14. The cumulative incidences (CIs) of mixed chimerism, upfront acute GVHD grades II-IV, and receipt of additional hematopoietic cell products after HCT were compared in patients treated with a distal alemtuzumab schedule (n = 15) and those treated with a proximal alemtuzumab schedule (n = 33). All patients received fludarabine and melphalan. The CI of mixed chimerism was 31% in the intermediate group, 72% in the proximal group (P

Relapse and graft failure after autologous (auto) or allogeneic (allo) hematopoietic stem cell transplantation (HSCT) are serious and frequently fatal events. A second HSCT can be a life‐saving alternative, however, information on the results of such intervention in an outpatient setting is limited. Outpatient second hematoprogenitors transplant after reduced‐intensity conditioning (RIC) at a single academic center was analyzed. Twenty‐seven consecutive adults who received an allo‐HSCT after an initial auto‐ or allo‐HSCT from 2006 to 2019 were included. Data were compared using the χ2‐test. Survival analysis using Kaplan–Meier and Cox proportional hazard models was performed; cumulative incidence estimation of transplant‐related mortality (TRM) was assessed. Hodgkin lymphoma was the most frequent diagnosis for the group with a first auto‐HSCT with 5/12 (41.7%) cases, and acute myeloid leukemia for those with a first allo‐HSCT with 6/15 (40%). One‐year overall survival and disease‐free survival (DFS) was 66.7% (95% CI 27.2–88.2) and 59% (95% CI 16–86) for 12 patients with a first auto‐HSCT; and for 15 patients with a first allo‐HSCT, it was 43.3% (95% CI 17.9–66.5) and 36% (95% CI 13.2–59.9), respectively. Eight (29.6%) patients died of TRM and the cumulative incidence of TRM at 1 year was 22% (95% CI 8.6–39.27). Chronic graft‐versus‐host disease and late (>10 months) second transplantation were protective factors for longer survival. Neutropenic fever was more common in the group with a first allo‐HSCT (p = 0.01). In conclusion, outpatient second allo‐HSCT using RIC after auto‐ or allografting failure or relapse is feasible and offers a reasonable alternative for patients with severe life‐threatening hematological diseases. [ABSTRACT FROM AUTHOR]

Despite aggressive multimodal treatment, the outcomes of pediatric patients with high-risk (HR) neuroblastoma (NB) remain poor. The rationale for allogeneic hematopoietic stem cell transplantation (allo-HCT) to treat NB was based on the possible graft-versus-tumor effect; however, toxicity limits its efficacy. We sought to prospectively assess the feasibility and efficacy of allo-HCT using a reduced-intensity conditioning regimen in pediatric patients with HR NB in a multicenter phase II trial. Primary endpoints were the rate of neutrophil and platelet engraftment, 5-year transplantation-related mortality (TRM), and disease-free survival (DFS). Secondary endpoint measures included the incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD. Fifty-one patients were enrolled in the study. The 5-year cumulative incidence (CuI) of TRM was 29.4 ± 6.4%, and that of DFS was 11.8 ± 4.5%. Patients undergoing allo-HCT within 1 year of diagnosis or with bone marrow as their stem cell source had a higher DFS probability. The CuI of neutrophil engraftment, platelet engraftment, and grade II-IV aGVHD was 97.9 ± 2.1%, 93.8 ± 3.5%, and 47.1 ± 7.0%, respectively. The development of new therapeutic strategies could further improve disease control., (Copyright © 2024. Published by Elsevier Inc.)

The present study compared lower-dose melphalan (80 mg/m 2 , FM80) and higher-dose melphalan (140 mg/m 2 , FM140) when administering reduced-intensity conditioning with fludarabine in adult patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data (2006 to 2019) and compared transplant outcomes between the 2 groups. Ninety-two patients (median age, 61 [interquartile range, 56 to 65] years) were assigned to the FM80 and FM140 groups by propensity score matching. The 3-year overall survival (OS) rate in the FM140 group (63.9%; 95% confidence interval [CI], 52.9% to 73.0%) was significantly higher than that in the FM80 group (54.2%; 95% CI, 37.1% to 52.1%) (P = .038). The FM140 group had a nonsignificantly (P = .095) lower 3-year cumulative incidence of relapse (15.5%; 95% CI, 8.9% to 23.8% versus 26.0%; 95% CI, 17.3% to 35.5%). The 3-year cumulative incidences of nonrelapse mortality were 22.3% (95% CI, 14.1% to 31.8%) and 23.7% (95% CI, 15.4% to 33.2%) in the FM80 and FM140 groups, respectively (P = .49). The beneficial effect of FM140 was more evident in patients with a poor cytogenetic risk. Our findings suggest the superiority of FM140 in patients with MDS undergoing allo-HSCT, especially in high-risk patients., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Hematologic malignancies disproportionately affect older adults. Hematopoietic cell transplantation (HCT) is potentially curative, but poor overall survival (OS) has limited its use in older adults. Fried's frailty phenotype (FFP) is a geriatric assessment tool that combines objective and subjective performance measures: gait speed, grip strength, activity level, exhaustion, and weight loss. People meeting ≥3 criteria are classified as frail; 1 or 2 criteria, as pre-frail; and 0 criteria, as fit. To evaluate the association of pre-HCT FFP with post-HCT outcomes, we assessed FFP prior to conditioning for 280 HCT recipients age ≥60 years with acute leukemia or a myeloid neoplasm at 3 institutions. When analyzing survival by age group, patients age ≥70 years had inferior OS compared to patients age 60 to 69 years (P = .002), with corresponding OS estimates of 38.9% (95% confidence interval [CI], 27.8% to 49.9%) and 59.3% (95% CI, 51.9% to 65.9%). Nonrelapse mortality (NRM) also was significantly higher in the older patients (P = .0005); the 2-year cumulative incidences of NRM were 38.5% (95% CI, 27.5% to 49.2%) and 17.2% (95% CI, 12.3% to 22.8%), for older and younger recipients, respectively. The cumulative incidences of relapse did not differ by age group (P = .3435). Roughly one-third (35.5%) of the patients were fit, 57.5% were pre-frail, and 7.5% were frail, with corresponding 2-year OS estimates of 68.4% (95% CI, 57.9% to 76.8%), 45.5% (95% CI, 37.4% to 53.2%), and 45.8% (95% CI, 23.4% to 65.8%) (P = .013). FFP was not significantly associated with NRM, but being frail or pre-frail was associated with a higher rate of disease-related deaths (33.3% and 27.3%, respectively, compared with 17.4% for fit patients; P = .043). In univariate modeling of restricted mean survival time with a 3-year horizon (RMST&#95;3y), the factors that were significantly associated were FFP, age, Karnofsky Performance Status (KPS), Disease Risk Index (DRI), and HCT-specific Comorbidity Index (HCT-CI). Of those factors, only FFP (P = .006), age (P = .006), KPS (P = .004), and DRI (P = .005) were significantly associated in multivariate modeling of RMST&#95;3y. Estimates of RMST&#95;3y were computed and 5 risk-groups were created with survival ranging from 31.4 months for those who were age 60 to 69 years, fit, had KPS 90 to 100, and low/intermediate-risk DRI compared to 10.5 months for those who had high-risk features for all the evaluated factors. In univariate and multivariate analyses for restricted mean time to relapse with a 3-year horizon (RMRT&#95;3y), FFP (pre-frail versus fit, P = .007; frail versus fit, P = .061) and DRI (P = .001) were the only significant factors. Predicted RMRT&#95;3y was longest (30.6 months) for those who were fit and had low/intermediate-risk DRI scores and shortest (19.1 months) for those who were frail and had high-risk or very high-risk DRI scores. Both age and FFP impact survival after HCT. Incorporation of FFP into pre-HCT evaluations may improve decision-making and counseling regarding HCT risk for older adults. Our findings support future trials designed to reverse frailty, such as pre-HCT supervised exercise programs, and correlative analyses to unravel the connection of frailty and relapse to generate future targets for intervention. Finally, exploration of novel HCT platforms to reduce relapse in pre-frail and frail patients, as well as reduce NRM in adults age >70 years, are warranted., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Changes in serum cytokines after autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis (MS) patients were documented. Thirty‐six consecutive MS patients who had their Expanded Disability Status Scale (EDSS) scored before AHSCT were prospectively enrolled. Cyclophosphamide (Cy) was infused at 200 mg/kg in two administrations given 10 days apart: the first dose for mobilization, the second as the conditioning regimen. Patients were mobilized with 10 µg/kg/day subcutaneous G‐CSF. Serum was collected 14 days before and 14 after AHSCT. IL‐6, IL‐9, IL‐10, IL 17‐A, IL‐21, IL‐22, IL‐23, TNF‐A, CCL2, CCL3, and CCL4 were measured by magnetic bead‐based immunoassay. t Test and Wilcoxon test were used to compare cytokine levels before and after AHSCT. There were 28 women and 8 men with a median age of 46 (15–62) years, median duration of MS was 9.5 (1–32) years, and EDSS score was 5.7 (1.5–8.0). Patients had a decrement of pro‐inflammatory IL‐21 and IL‐22 (p =.003 and p =.028) and an increment of anti‐inflammatory CCL2 and CCL4 (p <.001 and p =.039) after AHSCT. Decrease of IL‐21 and IL‐22 coupled with an increment of CCL2 and CCL4 could reflect the immunomodulatory effect of auto‐HSCT and be an early indicator of its efficacy. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem-cell transplantation is a well-known curative treatment for patients with chronic granulomatous disease. We present our experiment regarding ten patients with chronic granulomatous disease who underwent a reduced intensity conditioning regimen consisting of melfalan, fludarabine, and antithymocyte globulin. Donor lymphocyte infusion was used in three representative patients who developed mixed donor chimerism. After at least 2 years of median follow-up, 8 of the 10 patients are alive and well. [ABSTRACT FROM AUTHOR]

• FLAMSA (fludarabine, Ara-C, and amsacrine) sequential chemotherapy followed by total body irradiation (TBI)-based reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) led to similar transplantation outcomes in relapsed/refractory active acute myeloid leukemia. • FLAMSA sequential chemotherapy followed by TBI-free RIC was associated with lower nonrelapse mortality resulting in increased overall survival. • There were no significant differences in relapse incidence between FLAMSA sequential chemotherapy followed by RIC and MAC. The use of myeloablative conditioning (MAC) in the setting of active relapsed/refractory (R/R) acute myeloid leukemia (AML) has been hindered by high historical rates of nonrelapse mortality (NRM). FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) has been proposed as an effective and potentially safer alternative in this scenario. As improvements in supportive care have contributed to decreasing NRM rates after MAC, a comparative reassessment of these two strategies was performed. This was a registry-based analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Eligibility criteria included age 18 to 50 years, primary refractory, first or second relapsed active AML, first allogeneic stem cell transplantation from a matched sibling donor (MSD) or an unrelated donor (UD) performed between 2005 and 2018, MAC or FLAMSA-RIC. A total of 1018 patients were included. The median patient age was 39 years (range, 18 to 50). Two hundred and fifty-eight patients received busulfan (Bu)/cyclophosphamide (Cy), 314 received Cy/total body irradiation (TBI), 318 received FLAMSA-TBI, and 128 received FLAMSA-CT. The median duration of follow-up was 50 months. In univariate analysis, the 2-year relapse incidence (RI) (54%; 95% confidence interval (CI), 50%-57%), leukemia-free survival (LFS) (30%; 95% CI, 27%-33%), and refined graft-versus-host disease-free, relapse-free survival (GRFS) (21%; 95% CI, 18%-24%) were not significantly different between cohorts. Lower 2-year NRM was observed in the FLAMSA-CT group (7% versus 16% in Bu/Cy, 19% in Cy/TBI, and 18% in FLAMSA-TBI; P =.04), as well as increased 2-year overall survival (OS) (50% versus 33% in Bu/Cy, 34% in Cy/TBI, and 36% in FLAMSA-TBI; P =.03). These results were maintained in the multivariate analysis (hazard ratio [HR] for NRM:.40, P =.01; HR for OS:.65, P =.01; Bu/Cy as reference). These data suggest that FLAMSA-CT may be a preferred conditioning regimen in patients with active R/R AML due to lower NRM. Yet, the high relapse rates observed in our analyses emphasize the need for novel therapeutic strategies in this clinical setting. [ABSTRACT FROM AUTHOR]

• Allogeneic stem cell transplantation (SCT) in patients with lower-risk myelodysplastic syndrome (MDS) resulted in very good outcomes. • Transplantation from a matched donor was a significant factor in survival. • The risk of relapse risk is <10% in patients with lower-risk MDS after allogeneic SCT. The indication for allogeneic stem cell transplantation (SCT) in patients with lower-risk myelodysplastic syndrome (MDS) is controversial. Here we report 60 patients with a low risk (n = 32) or intermediate risk (n = 28) classification according to the revised International Prognostic Scoring System (IPSS-R) who underwent allogeneic SCT with a reduced-intensity conditioning (n = 45) or myeloablative conditioning (n = 15) regimen from an HLA-identical sibling (n = 9), a matched unrelated donor (n = 36), or a mismatched unrelated donor (n = 15). The rates of grade II-IV and grade III-IV acute graft-versus-host disease were 32% and 7%, respectively, resulting in a transplantation-related mortality (TRM) of 17% at 3 years. The cumulative incidence of relapse at 5 years was only 7%, resulting in a 5-year disease-free survival of 72% and overall survival (OS) of 79%. Transplantation from a fully matched donor resulted in significantly improved OS at 5 years (91% versus 70%). Allogeneic SCT in lower-risk MDS (IPSS-R low or intermediate risk) from an HLA-matched donor resulted in excellent OS with a low risk of relapse. [ABSTRACT FROM AUTHOR]

• Reduced-intensity conditioning increased the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to older patients with acute myeloid leukemia (AML) and those with comorbid conditions. • Haploidentical donors expanded the availability of allo-HSCT for patients with AML. • Improved graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide may further reduce nonrelapse mortality for patients with HLA-matched donors. • Relapse post-transplant is the main cause of treatment failure; ongoing research will clarify if it can be decreased, especially for high-risk AML. • Integrated, comprehensive, and more precise prognostic tools can better assess risk prediction for patients with AML. Allogeneic hematopoietic stem cell transplantation remains an important treatment modality for patients with acute myeloid leukemia (AML). Recent advances have extended donor availability for patients without matched donors. Transplantation is now increasingly offered to older patients, including those above 70 years and less fit individuals. Better prognostic models are being developed. Proceeding faster to transplantation with haploidentical donors if an urgent transplant is needed, such as in patients with detectable minimal residual disease, may allow more patients to get to transplant, and it is hoped more will be cured from their disease. With continuous improvements in treatment-related toxicity and mortality, relapse has become the most important cause of treatment failure, and novel approaches are needed to make the next big leap in the treatment of this disease with transplantation. In this review we aim to summarize recent advances and provide future research directions in the transplantation for patients with AML. [ABSTRACT FROM AUTHOR]

Summary: Reduced‐intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo‐HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)‐matched sibling or unrelated donor allo‐HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0·01. There were no significant differences between regimens in risk for non‐relapse mortality (NRM) (P = 0·54), relapse/progression (P = 0·02) or progression‐free survival (PFS) (P = 0·14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo‐HCT (HR = 0·28; 95% CI = 0·10–0·73; P = 0·009), but beyond 11 months post allo‐HCT it was associated with a significantly higher risk of mortality, (HR = 2·46; 95% CI = 0·1.32–4·61; P = 0·005). Four‐year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0·64), respectively. These data confirm the choice of RIC for allo‐HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo‐HCT (possibly due to late NRM events). [ABSTRACT FROM AUTHOR]

• CALGB (Alliance) 100001 evaluated tandem autologous/allogeneic transplant for myeloma. • A fludarabine/cyclophosphamide conditioning regimen was associated with a very low treatment-related mortality rate. • Long-term follow-up demonstrates a subset of patients who derived benefit from this approach. CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by nonmyeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m2). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m2/d i.v. on days -7 through -3) and cyclophosphamide (1 g/m2/d i.v. on days -4 through -3). The primary objective was to determine the 6-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host disease (GVHD), disease-free survival, and overall survival (OS). Sixty patients were enrolled, of whom 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49; 90% confidence interval, 0.10% to 9.3%). Moderate to severe (grades 2 to 3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of nonprotocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate. [ABSTRACT FROM AUTHOR]

• Graft failure was associated with alemtuzumab, reduced-intensity conditioning, and unrelated donor grafts. • Intermediate scheduling of alemtuzumab had the highest incidence of graft failure. • Costs and outcomes of graft failure have improved over time but remain a significant burden. Allogeneic hematopoietic cell transplantation (HCT) has the capacity to cure numerous malignant and nonmalignant disorders. A dreaded complication is graft failure (GF), as it puts patients at high risk of infection and disease relapse. There are few contemporary data on the risks, outcomes, and economic burden of GF in pediatric patients. In this study, we address this gap by focusing on 14 years of transplant at our single center, for which data are compared in 2 time periods: 2005 to 2010 (n = 146) and 2011 to 2018 (n = 144). In the 290 patients studied, the median age was 9.33 years, and 50.3% had malignant versus nonmalignant disease. Cell source included bone marrow (51%), cord blood (19.7%), unmanipulated peripheral blood stem cells (PBSCs; 12.1%), and CD34-selected PBSCs (17.2%). Twenty-one percent of patients had reduced-intensity conditioning (RIC), and 54.8% of transplants were fully HLA matched. Most patients received serotherapy with rabbit anti-thymocyte globulin (39.3%) or alemtuzumab (42.8%). The incidence of neutropenic and non-neutropenic GF (NGF and NNGF) was 6.6% and 3.8%, respectively. Multivariate analysis demonstrated alemtuzumab (odds ratio [OR], 6.256, P <.001) was the main variable associated with a higher rate of GF in both time periods, whereas RIC (OR, 11.8, P <.001) and cell source (CD34-selected PBSCs; OR, 4.22, P =.04) showed period-specific effects. Specifically, from time periods 1 to 2, cord blood transplants were discontinued at our center, with a concomitant increase in CD34-selected grafts and a shift from more episodes of NGF to NNGF. Overall survival was 69% in the entire HCT cohort and 50% among patients with GF. Survival among GF patients improved from time periods 1 to 2 (20% versus 80%, P =.001), potentially due to a higher incidence of NNGF and increased ability to perform stem cell boosts from the same donor once cord blood transplants were phased out. Inpatient length of stay was consistently higher for patients with GF. Similar trends were seen for inpatient costs, although improvements were seen in our entire HCT population over time. In summary, GF remains a significant challenge in pediatric HCT and poses an economic burden on the health care system. [ABSTRACT FROM AUTHOR]

• Augmentation of total body irradiation (TBI) dose from 2 to 4 Gy for patients with non-Hodgkin lymphoma undergoing reduced-intensity conditioning allogeneic hematopoietic cell transplantation is associated with higher nonrelapse mortality and inferior overall survival. • Higher dose of TBI does not result in improved disease control. Disease relapse is the most common cause of therapy failure in patients with non-Hodgkin lymphoma (NHL) undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2 to 4 Gy in a RIC platform can provide improved disease control without increasing nonrelapse mortality (NRM). Using the Center for International Blood & Marrow Transplant Research (CIBMTR) database, we evaluated the outcomes of patients with NHL receiving RIC allo-HCT with either fludarabine (Flu)/2-Gy TBI versus Flu/4-Gy TBI. In the CIBMTR registry, 413 adult patients with NHL underwent a first allo-HCT using either a matched related or unrelated donor between 2008 and 2017, using a RIC regimen with either Flu/2-Gy TBI (n = 349) or Flu/4-Gy TBI (n = 64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression, and progression-free survival (PFS). At baseline, the Flu/2-Gy TBI cohort had significantly fewer patients with Karnofsky performance status ≥90 and significantly more patients had a higher HCT-comorbidity index. On multivariate analysis, the 2 conditioning cohorts were not significantly different in terms of risk of grade 3 to 4 aGVHD or cGVHD. Compared to Flu/2-Gy TBI, the Flu/4-Gy TBI conditioning was associated with a significantly higher risk of NRM (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.11 to 2.89; P =.02) and inferior OS (HR, 1.51; 95% CI, 1.03 to 2.23, P =.03). No significant differences were seen in the risk of relapse/progression (HR, 0.78; 95% CI, 0.47 to 1.29, P =.33) or PFS (HR, 1.09; 95% CI, 0.78 to 1.54, P =.61) between the 2 regimens. Comparing Flu/2-Gy TBI versus Flu/4-Gy TBI cohorts, the 5-year adjusted outcomes were NRM (28% versus 47%; P =.005), relapse/progression (35% versus 29%; P =.28), PFS (37% versus 24%; P =.03), and OS (51% versus 31%; P =.001), respectively. Relapse was the most common cause of death in both cohorts. In patients with NHL undergoing Flu/TB I-based conditioning, augmenting TBI dose from 2 to 4 Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. The optimal dose is 2-Gy in the RIC Flu/TBI platform for lymphomas. [ABSTRACT FROM AUTHOR]

• In comparison with reduced-intensity conditioning, myeloablative conditioning (MAC) reduced leukemia-related mortality and improved overall survival for patients with cytogenetically poor-risk acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation (HCT) during first complete remission. • In the subgroup analysis, these results applied to patients aged 16 to 59 years, with HCT-comorbidity index scores ≥3 and with cytogenetic remission. • Among MAC regimens, there was a trend for worse survival and nonrelapse mortality with the busulfan/fludarabine-based regimen compared with the total body irradiation-based regimen. The optimal intensity of conditioning regimen may be dependent on not only age and comorbidities but also disease characteristics and risk of relapse after allogeneic hematopoietic cell transplantation (HCT). We, therefore, analyzed the transplant outcomes of 840 adult patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who received first allogeneic HCT with either myeloablative conditioning (MAC; n = 652) or reduced-intensity conditioning (RIC; n = 188) between 2006 and 2017. The median age at HCT was 50.5 years (range: 16 to 77 years). The multivariate analysis showed that patients receiving MAC had a significantly higher overall survival and lower leukemia-related mortality than those receiving RIC (P =.011 and P =.025, respectively). In the subgroup analysis, these results applied to patients aged 16 to 59 years, with HCT-comorbidity index scores ≥3, and with cytogenetic remission. Among MAC regimens, there was a trend for worse survival and nonrelapse mortality with the busulfan/fludarabine-based regimen compared with the total body irradiation (TBI) ≥8 Gy-based regimen (P =.082 and P =.062, respectively), whereas the busulfan/cyclophosphamide-based regimen and the fludarabine/melphalan-based regimen had similar outcomes with the TBI-based regimen. These data suggest that MAC is preferable to RIC for patients with cytogenetically poor-risk AML undergoing allogeneic HCT in CR1. Image, graphical abstract [ABSTRACT FROM AUTHOR]