Allogeneic Hematopoietic Stem Cell Transplantation Research Articles

An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA.

X-linked sideroblastic anemia (XLSA) is a congenital anemia caused by mutations in ALAS2, a gene responsible for heme synthesis. Treatments are limited to pyridoxine supplements and blood transfusions, offering no definitive cure except for allogeneic hematopoietic stem cell transplantation, only accessible to a subset of patients. The absence of a suitable animal model has hindered the development of gene therapy research for this disease. We engineered a conditional Alas2-KO mouse model using tamoxifen administration or treatment with lipid nanoparticles (LNP) carrying Cre-mRNA and conjugated to an anti-CD117 antibody. Alas2-KOBM animals displayed a severe anemic phenotype characterized by ineffective erythropoiesis (IE), leading to low numbers of red blood cells (RBC), hemoglobin (Hb), and hematocrit (HCT). In particular, erythropoiesis in these animals showed expansion of polychromatic erythroid cells, characterized by reduced oxidative phosphorylation, mitochondria's function, and activity of key Tricarboxylic Acid (TCA) cycle enzymes. In contrast, glycolysis was increased in the unsuccessful attempt to extend cell survival despite mitochondrial dysfunction. The IE was associated with marked splenomegaly and low hepcidin levels, leading to iron accumulation in the liver, spleen, and bone marrow and the formation of ring sideroblasts. To investigate the potential of a gene therapy approach for XLSA, we developed a lentiviral vector (X-ALAS2-LV) to direct ALAS2 expression in erythroid cells. Infusion of BM cells with 0.6-1.4 copies of the X-ALAS2-LV in Alas2-KOBM mice improved CBC levels, tissue iron accumulation, and survival rates. These findings suggest our vector could be curative in XLSA patients.

Acute myeloid leukemia management and research in 2025.

The first 5 decades of research in acute myeloid leukemia (AML) were dominated by the cytarabine plus anthracyclines backbone, with advances in strategies including allogeneic hematopoietic stem cell transplantation, high-dose cytarabine, supportive care measures, and targeted therapies for the subset of patients with acute promyelocytic leukemia. Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

Splenic Irradiation Preceding Allogeneic Hematopoietic Stem Cell Transplantation as a Possible Risk Factor of Sinusoidal Obstruction Syndrome: A Report of Three Cases

Introduction: Splenomegaly is frequently encountered in patients with myeloproliferative neoplasms. Splenomegaly is associated with an increased incidence of engraftment failure during allogeneic hematopoietic stem cell transplantation (allo-HSCT), and some centers perform prior low-dose splenic irradiation (LDSI) which has been reported to be both safe and effective. However, we report conflicting results by presenting three allo-HSCT patients undergoing LDSI that subsequently developed sinusoidal obstruction syndrome (SOS). Case Presentation: The underlying diseases of the presented cases were atypical chronic myeloid leukemia, secondary myelofibrosis following essential thrombocythemia, and acute myeloid leukemia transforming from myeloproliferative neoplasm, unclassifiable. Endothelial Activation and Stress Index (EASIX) scores of the 3 patients were 0.40, 3.82, and 4.40, respectively. Conclusion: SOS is a potentially fatal complication of allo-HSCT, and the mortality rates of severe cases are reported to be above 80%. LDSI has not been recognized as a risk factor of SOS to date. Alternative management methods of splenomegaly during allo-HSCT such as ruxolitinib administration may be safer compared to LDSI.

Efficacy and safety of hypomethylating agents in the treatment of AML/MDS patients relapsed post allogenetic hematopoietic stem cell transplantation

IntroductionAcute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) constitute myeloid malignancies, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as a potentially optimal approach for achieving a long term cure. However, post-allo-HSCT relapse remains a leading cause of mortality and therapeutic failure.MethodsTo evaluate the efficacy and safety of combining hypomethylating agents (HMAs) with Bcl-2 inhibitors in the treatment of AML/MDS relapse following allo-HSCT, we retrospectively collected data from 42 patients who experienced relapse between April 2012 and March 2022 at Peking University First Hospital. Among these patients, 21 underwent intensive chemotherapy (IC) alone, while the other 21 received treatment with HMAs after IC treatment, either alone or in combination with the Bcl-2 inhibitor venetoclax (VEN).ResultsThe median overall survival (OS) was 9 ± 2.153 months, and the one-year OS rate was 41.5%. The overall response rate (ORR) in the chemotherapy group and the IC+HMAs ± VEN group was 52.38% (11/21) and 76.19% (16/21), respectively, with no significant difference found (P=0.107). Kaplan-Meier analysis revealed a significant difference in OS between the chemotherapy group and the IC+HMAs ± VEN group in our retrospective cohort study (P=0.041, χ2= 4.016). Additionally, a significant difference in overall survival (OS) rates was observed between the two groups for patients categorized as intermediate/high risk (P=0.008). The secondary relapse rate was 45.45% (5/11) in the IC cohort and 25% (4/16) in the IC+HMAs ± VEN group, respectively, with no significant difference identified between the two cohorts (P=0.268). Furthermore, upon assessing the risk of graft-versus-host disease (GvHD), infection, and agranulocytosis, no notable differences were observed with the use of HMAs, suggesting that HMAs did not increase the risk. In the IC+HMAs ± VEN group, 7 patients received VEN in addition to HMAs, and no significant statistical difference was found in OS when comparing patients who received HMAs alone and those who received HMA+VEN (P=0.183), also, a statistically significant difference in OS was noted between the two groups whenaccounting for competing risks (P=0.028).ConclusionsThis retrospective study highlights the efficacy of IC+HMAs ± VEN in treating AML/MDS patients experiencing relapse post allo-HSCT, improving survival rates, especially for those classified as intermediate/high risk, with favorable tolerability.

Contributions of Pediatric Hematology/Oncology to the Diagnosis, Treatment, and Cure of Acute Lymphoblastic Leukemia-Part 2b (Numbers 16 to 20).

This offering represents part 2b of a second set of 5 additional contributions of pediatric hematology/oncology to the diagnosis, treatment, and potential cure of precursor B-cell acute lymphoblastic leukemia. It contains numbers 16 to 20 and includes (16) allogeneic hematopoietic stem cell transplantation, newer immunotherapies including (17) blinatumomab, and (18) inotuzumab ozogamicin, (19) ploidy, and (20) creation of the "day hospital" to administer outpatient care to children with acute lymphoblastic leukemia and other cancers. These and the other reviewed contributions have had a significant role in improving the quality and duration of the lives of children, most of whom faced tragic and painful death back in the 1950s and 1960s. Most of our early optimistic goals were achieved and have benefitted substantially our patients, providing those of us who participated in many of these key clinical trials, a profound sense of accomplishment.

Chemo-free salvage treatment outperforms traditional chemotherapy in advanced lines of relapsed/refractory subcutaneous panniculitis-like T-cell lymphoma

IntroductionSubcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of non-Hodgkin lymphoma with a good prognosis, but the optimal treatment for relapsed/refractory (R/R) SPTCL has been rarely discussed.MethodsThis study aims to compare the efficacy of conventional chemotherapy and chemo-free immunomodulatory regimen for R/R SPTCL. We retrospectively reviewed the patients with first relapse or primary refractory SPTCL between September 1997 and October 2020.ResultsA total of 19 patients with R/R SPTCL with a median age of 34 were included. All patient received the first-line chemotherapy-based treatment with a median PFS of 1.8 months. In these patients, 16 received salvage second-line treatment with an ORR of 31.3% and a median TTNT of 3.0 months. 13 of these 16 patients received chemotherapy-based treatment, resulting in a median TTNT of 2.4 months. 2 of these 16 patients received allogeneic hematopoietic stem cell transplantation and achieved long term complete remission (CR). In third-line treatment, 7 patients received chemotherapy-based regimen and 6 received chemo-free regimen such as VRMP (bortezomib, lenadomide and methylprednisolone) regimen and CsA plus IFNα regimen. The median TTNT of chemotherapy and chemo-free group were 3.2 months and not reached, respectively.DiscussionChemo-free group had a better TTNT than chemotherapy group (p=0.007). The use of chemotherapy-free regimens for R/R SPTCL appears promising and warrants further validation.

DL-ICE as a bridge to allogeneic transplantation in relapsed/refractory PTCL: survival outcomes and prognostic factors

IntroductionPeripheral T-cell lymphomas (PTCLs) have poor outcomes in the relapsed/refractory (R/R) setting. In this study, we evaluated the efficacy of dexamethasone, L-asparaginase, ifosfamide, carboplatin, and etoposide (DL-ICE) chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with R/R PTCLs.MethodsWe retrospectively analyzed 80 adult patients with R/R PTCLs treated with DL-ICE chemotherapy between September 2009 and March 2023. Patients achieving complete or partial remission were eligible for consolidative allo-HSCT. Overall survival (OS) and progression-free survival (PFS) were evaluated.ResultsThe overall response rate to DL-ICE was 37.5%, with 30% achieving complete remission (CR). With a median follow-up of 96.4 months, the median OS and PFS were 8.9 and 3.8 months, respectively. Seventeen patients (21%) underwent allo-HSCT, including 11 with non-CR status. The 5-year OS was significantly higher in the allo-HSCT group compared to that in the group with chemotherapy alone (64.7% vs 18.3%, p <0.001). Multivariate analysis identified advanced stage, EBV viremia, and non-CR status as poor prognostic factors.DiscussionDL-ICE chemotherapy demonstrated modest activity in R/R PTCLs. Consolidation with allo-HSCT, even in patients who do not achieve CR, resulted in long-term survival in a subset of patients. Early consideration of allo-HSCT may improve outcomes for patients with R/R PTCLs.

Allogeneic hematopoietic stem cell transplantation could overcome the poor prognosis of DNMT3AmutNPM1mutFLT3-ITDmut in acute myeloid leukemia: real-world multicenter analysis in China.

The cooccurrence of NPM1, FLT3-ITD, and DNMT3A mutations (i.e., triple mutation) is related to dismal prognosis in patients with acute myeloid leukemia (AML) receiving chemotherapy alone. In this multicenter retrospective cohort study, we aimed to identify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) could overcome the poor prognosis of DNMT3AmutNPM1mutFLT3-ITDmut AML across four transplant centers in China. Fifty-three patients with triple-mutated AML receiving allo-HSCT in complete remission were enrolled. The 1.5-year probabilities of relapse, leukemia-free survival, and overall survival after allo-HSCT were 11.9%, 80.3%, and 81.8%, respectively. Multivariate analysis revealed that more than one course of induction chemotherapy and allo-HSCT beyond CR1 were associated with poor survival. To our knowledge, this work is the largest study to explore the up-to-date undefined role of allo-HSCT in patients with triple-mutated AML. Our real-world data suggest that allo-HSCT could overcome the poor prognosis of DNMT3AmutNPM1mutFLT3-ITDmut in AML.

A Shared Care Model between community and transplant centers facilitates access to allogeneic and autologous transplantation

Access to allogeneic and autologous hematopoietic stem cell transplantation (SCT) remains inadequate despite its curative potential across hematologic malignancies. In 2015, Hartford HealthCare (HHC) and the Memorial Sloan Kettering Cancer Center (MSK) established the Shared Care Model (SCM) with a primary aim of enhancing SCT access for HHC patients. The SCM comprises several components: an SCT-dedicated nurse-navigator, a health-information exchange for record sharing, telemedicine, and ongoing training of HHC clinicians in transplant patient selection and management. We evaluated the SCM’s impact on SCT access across 126 patients with acute leukemia, myelodysplastic syndrome, and multiple myeloma from 2016-2020. The SCM facilitated 34 referrals. Socio-economic status of HHC referrals by Area Deprivation Index was significantly inferior (38 vs. 14, p < 0.001) when compared to 3,108 non-SCM referrals to MSK during the same period. Allogeneic recipients spent 68-247 days away from home, and autologous recipients 15-48, both requiring few subsequent visits to MSK.

Better pre-transplant treatment options for TP53-mutated MDS: cytoreductive or non-cytoreductive therapy?

Patients with TP53-mutated myelodysplastic neoplasms (MDS) have unfavorable prognoses; the benefit of cytoreductive treatment before hematopoietic stem cell transplantation (HSCT) is debated. We retrospectively analyzed 284 MDS patients undergoing allogeneic HSCT; among which 49 had TP53 mutation, with 38 receiving cytoreduction and 11 treated exclusively with best supportive care (BSC) before transplantation. Regardless of TP53 allelic state, patients with mutated-TP53 had a lower overall survival rate and higher relapse rate than those with wild-type TP53 (P < 0.001, P = 0.002, respectively). Among the TP53-mutated cohort, the 2-year overall survival rate in the cytoreduction group was comparable to that in the BSC group (34.6% vs. 45.5%, P = 0.53), and no other prognostic benefit was observed as well(all P < 0.05). Moreover, no prognostic difference was found among the chemotherapy subgroup, hypomethylating agent subgroup, and BSC subgroup(all P > 0.05). Patients in the pre-HSCT measurable residual disease (MRD) negative subgroup, pre-HSCT MRD-positive subgroup, and BSC subgroup exhibited similar prognoses (all P > 0.05). Multivariate analyses showed that pre-HSCT cytoreduction was not associated with post-transplant survival (all P > 0.05). In conclusion, TP53-mutated MDS patients have poor post-HSCT outcomes; compared to BSC, pre-HSCT cytoreduction doesn't improve prognosis, even in those with MRD negative before transplantation.

Outcomes of allogeneic hematopoietic stem cell transplantation versus intensive chemotherapy in patients with myeloid sarcoma: a nationwide representative multicenter study.

Myeloid sarcoma (MS) is a rare hematological neoplasm with poor prognosis, posing a significant clinical challenge due to the absence of effective and standardized treatments. We conducted a retrospective analysis of 162 MS patients treated at 12 centers to compare outcomes between intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our analysis revealed that allo-HSCT demonstrated superior overall survival (OS) within the initial 36 months compared to intensive chemotherapy alone (p = 0.037). However, beyond 36 months (36-60 months), a reverse trend was observed (p = 0.056). Subgroup analysis revealed potential benefit for isolated MS patients with allo-HSCT, but not for those with leukemic MS. Additionally, in patients achieving first complete remission (CR1) after induction chemotherapy, allo-HSCT did not significantly improve 5-year OS compared with intensive chemotherapy alone (p = 0.25). Conversely, allo-HSCT significantly improved 5-year OS in non-CR1 patients (p < 0.001). Notably, HLA-matched HSCT and haploidentical HSCT showed comparable outcomes in terms of OS, disease-free survival, and cumulative incidence of relapse. In conclusion, allo-HSCT improved outcomes for MS patients within 36 months of disease onset, and haploidentical HSCT emerged as a viable treatment option for patients without matched donors.

Post-transplant relapse in pediatric acute lymphoblastic leukemia in the era of CAR-T cell therapy. A multicenter analysis of Grupo Español de Trasplante Hematopoyetico y Terapia Celular (GETH-TC) Pediatric Committee.

BackgroundThe management of relapsed acute lymphoblastic leukemia (ALL) after hematopoietic stem cell transplantation (HSCT) has evolved significantly. Initially, treatment options were limited to palliative care, salvage chemotherapy, and second HSCT. Currently, the focus has shifted to innovative immunotherapies, particularly CAR T-cell therapy. ObjectivesThis study aims to: 1. Analyze outcomes after relapse following HSCT and identify prognostic factors associated with prolonged survival. 2. To evaluate and compare treatment strategies, including immunotherapy (e.g., CAR T-cell therapy) and second HSCT after achieving a new remission, or both treatments in high-risk cases. Study designThis retrospective, multicenter study will evaluate the outcomes of HSCT relapse in pediatric ALL patients. Key endpoints include disease-free survival (DFS), relapse rate, and NRM. We enrolled 73 children with ALL who relapsed after HSCT in 10 hospitals of the Pediatric Committee of the Spanish Group of Transplantation (GETH-TC) between 2013 and 2021. Among them, 56 patients (77%) had B-cell ALL and 17 (23%) had T-cell ALL. ResultsThe median time to relapse was 6 months after the first HSCT. CAR-T cell therapy was administered to 31 patients, all of whom achieved complete remission with negative MRD. However, two patients died prematurely due to cytokine release syndrome (CRS), resulting in a NRM of 7±4%. Sixteen patients relapsed after CAR-T therapy with a cumulative incidence (CI) of 65±11%. Seven of these patients subsequently underwent a second HSCT. The only significant prognostic factor for DFS was the MRD level prior to CAR-T therapy: DFS was 20±8% with MRD ≥3% compared to 100% with MRD <3% (p=0.002). At a median follow-up of 17 months after CAR-T therapy, DFS was 28±10% and overall survival (OS) was 40±10%. Second allogeneic HSCT was performed in 23 patients, including 7 who had previously received CAR-T therapy. Three patients died from NRM (CI: 19±10%). Eight patients relapsed after the second HSCT (CI: 52±13%), of which 2 were successfully treated with CAR-T therapy. At a median follow-up of 33 months after the second HSCT, DFS was 29±11% and OS was 32±10%. Of 17 patients with T-cell ALL, only 2 survived after a second HSCT with a DFS of 12±9%. Of the 73 patients, 20 are alive with a median follow-up of 4 years (DFS: 20±5%). Time to relapse after HSCT was the strongest predictor of outcome; no patient who relapsed within 6 months after the first HSCT survived. There was a trend towards worse DFS in patients who developed chronic GVHD during the first transplant, with 8 out of 9 relapsing despite rescue therapy (p<0.07). ConclusionsChildren with relapsed ALL after HSCT have a substantial chance of long-term survival if relapse occurs more than 6 months after the first transplant and if chronic GVHD was not present. The treatment paradigm has shifted to immunotherapy, including monoclonal antibodies and CAR-T therapy. The role of bridging to a second allogeneic HSCT after CAR-T therapy to improve long-term survival remains a subject of ongoing debate.

CDKN2A/B deletion as an independent negative prognostic factor for allogeneic hematopoietic stem cell transplantation in childhood B cell precursor acute lymphoblastic leukemia.

CDKN2A/B deletion as an independent negative prognostic factor for allogeneic hematopoietic stem cell transplantation in childhood B cell precursor acute lymphoblastic leukemia.

Innovative Personalized Medicine for Immunosuppressive Drugs Based on Novel Control Theory of Pharmacokinetics

Tacrolimus is widely recognized as an anti-rejection agent due to its immunosuppressive characteristics. It binds to the immunophilin FK506-binding protein (FKBP) and thus to calcineurin, and inhibits its activity. Tacrolimus' therapeutic concentration range in blood is narrow, and its pharmacokinetics are highly variable among individuals. First, because tacrolimus primarily distributes to red blood cells (RBCs), anemia and blood transfusions can cause fluctuations in tacrolimus blood concentrations. Variations in blood tacrolimus concentration significantly correlated with variations in RBC count, hemoglobin level, and hematocrit value, but not with variations in white blood cell or platelet counts. Interestingly, FKBP played an important role in tacrolimus distribution to RBCs. The effects of intracellular and extracellular FKBP levels on RBC distribution of tacrolimus in circulating blood were substantial. Secondly, proteins affecting pharmacokinetics can differ at the genetic level in their expression and functional potency. Genetic polymorphisms that influence tacrolimus pharmacokinetics have been reported. A polymorphism in the gene encoding the metabolic enzyme cytochrome P450 (CYP) 3A5 is a particularly influential factor affecting tacrolimus pharmacokinetics in Japanese patients. CYP3A5 polymorphisms correlated with individual differences in tacrolimus blood concentration changes after starting continuous infusion in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In addition, CYP3A5*3 polymorphism also correlated with differences in the frequency of acute graft-versus-host disease (GVHD) development in allogeneic HSCT recipients.

The prophylactic application of low-dose rabbit antithymocyte globulin in matched siblings HSCT with high-risk factors for graft-versus-host disease

Relapse and graft-versus-host disease (GVHD) are currently the predominant causes of mortality post allogeneic hematopoietic stem cell transplantation (allo-HSCT). The contentious use of antithymocyte globulin (ATG) for preventing GVHD in matched sibling HSCT scenarios has been a topic of significant debate. A retrospective analysis was conducted on matched sibling HSCT cases with high-risk factors for GVHD in our center from January 2018 to June 2023. Our assessment revealed that the group administered with ATG exhibited a 30 % incidence of acute GVHD (aGVHD), in contrast to 81.8 % in the non-ATG cohort (P = 0.037) among matched sibling HSCT cases with high GVHD risk factors. Furthermore, chronic GVHD (cGVHD) occurred in 20 % of the ATG group and 72.7 % of the non-ATG group (P = 0.03). Notably, the administration of ATG did not significantly impact disease relapse (p = 0.149), infection rates (p = 0.64), granulocyte recovery time (p = 0.15), platelet recovery time (p = 0.12), overall survival (p = 0.889), or disease-free survival time (p = 0.787). The use of rabbit antithymocyte globulin (r-ATG) at a 5 mg/kg dosage demonstrated a notable reduction in aGVHD and cGVHD incidences within sibling matched HSCT cases with high-risk factors for GVHD, without increasing rates of disease recurrence or infections. These findings highlight the potential benefit of using low-dose r-ATG in high-risk of GVHD sibling matched allogeneic HSCTs, although further validation with a larger cohort is necessary.

Diagnosing recipient- vs. donor-derived posttransplant myelodysplastic neoplasm via targeted single-cell mutational profiling.

Distinguishing donor- vs. recipient-derived myelodysplastic neoplasm (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is challenging and has direct therapeutical implications. Here, we took a translational approach that we used in addition to conventional diagnostic techniques to resolve the origin of MDS in a 38-year-old patient with acquired aplastic anemia and evolving MDS after first allo-HSCT. Specifically, we used single-cell transcriptional profiling to differentiate between donor- and recipient-derived bone marrow cells and established a strategy that additionally allows identification of cells carrying the MDS-associated U2AF1S34Y variant. The patient exhibited mixed donor chimerism combined with severely reduced erythropoiesis and dysplastic morphology within the granulocytic and megakaryocytic lineage along with the MDS-associated U2AF1S34Y mutation in the bone marrow. Single-cell transcriptional profiling together with targeted enrichment of the U2AF1S34Y-specific locus further revealed that, while the immune compartment was mainly populated by donor-derived cells, myelopoiesis was predominantly driven by the recipient. Additionally, concordant with recipient-derived MDS, we found that U2AF1S34Y-mutated cells were exclusively recipient derived with X but not Y chromosome-specific gene expression. Our study highlights the clinical potential of integrating high-resolution single-cell techniques to resolve complex cases for personalized treatment decisions. The study was funded by intramural resources of the Charité- Universitätsmedizin Berlin and the Berlin Institute of Health.

Haematopoietic gene therapy of non-conditioned patients with Fanconi anaemia-A: results from open-label phase 1/2 (FANCOLEN-1) and long-term clinical trials

Allogeneic haematopoietic stem-cell transplantation is the standard treatment for bone marrow failure (BMF) in patients with Fanconi anaemia, but transplantation-associated complications such as an increased incidence of subsequent cancer are frequent. The aim of this study was to evaluate the safety and efficacy of the infusion of autologous gene-corrected haematopoietic stem cells as an alternative therapy for these patients. This was an open-label, investigator-initiated phase 1/2 clinical trial (FANCOLEN-1) and long-term follow-up trial (up to 7 years post-treatment) in Spain. Mobilised peripheral blood (PB) CD34+ cells from nine patients with Fanconi anaemia-A in the early stages of BMF were transduced with a therapeutic FANCA-encoding lentiviral vector and re-infused without any cytotoxic conditioning treatment. The primary efficacy endpoint of FANCOLEN-1 was the engraftment of transduced cells, as defined by the detection of at least 0·1 therapeutic vector copies per nucleated cell of patient bone marrow (BM) or PB at the second year post-infusion, without this percentage having declined substantially over the previous year. The safety coprimary endpoint was adverse events during the 3 years after infusion. The completed open-label phase 1/2 and the ongoing long-term clinical trials are registered with ClinicalTrials.gov, NCT03157804; EudraCT, 2011-006100-12; and NCT04437771, respectively. There were eight evaluable treated patients with Fanconi anaemia-A. Patients were recruited between Jan 7, 2016 and April 3, 2019. The primary endpoint was met in five of the eight evaluable patients (62·50%). The median number of therapeutic vector copies per nucleated cell of patient BM and PB at the second year post-infusion was 0·18 (IQR 0·01-0·20) and 0·06 (0·01-0·19), respectively. No genotoxic events related to the gene therapy were observed. Most treatment-emergent adverse events (TEAEs) were non-serious and assessed as not related to therapeutic FANCA-encoding lentiviral vector. Nine serious adverse events (grade 3-4) were reported in six patients, one was considered related to medicinal product infusion, and all resolved without sequelae. Cytopenias and viral infections (common childhood illnesses) were the most frequently reported TEAEs. These results show for the first time that haematopoietic gene therapy without genotoxic conditioning enables sustained engraftment and reversal of BMF progression in patients with Fanconi anaemia. European Commission, Instituto de Salud Carlos III, and Rocket Pharmaceuticals.

Cord Blood Transplantation Using Myeloablative Conditioning for Pediatric Advanced Myelodysplastic Syndrome in AMeD Syndrome With a Novel ADH5 Variant.

Aplastic anemia, mental retardation, and dwarfism syndrome (AMeDS) is a rare inherited bone marrow failure syndrome. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only possible treatment option for hematological complications in AMeDS; however, there are no reports addressing allo-HSCT for AMeDS. A 6-year-old female diagnosed with AMeDS accompanying myelodysplastic syndrome with increased blast was successfully treated with cord blood transplantation followed by myeloablative conditioning (MAC). A novel ADH5 c.1101-3C>G variant detected in this patient was demonstrated to be a null variant causing several patterns of alternative splicing in ADH5 gene. MAC might be feasible and effective in AMeDS.

Prospective phase II study of allogeneic hematopoietic stem cell transplantation with targeted busulfan, fludarabine, and etoposide conditioning in pediatric acute lymphoblastic leukemia.

Prospective phase II study of allogeneic hematopoietic stem cell transplantation with targeted busulfan, fludarabine, and etoposide conditioning in pediatric acute lymphoblastic leukemia.

Evaluation of the Clinical Outcomes of Cyclosporine Short Infusion Versus Continuous Infusion Postallogenic Stem Cell Transplantation.

Cyclosporin A (CsA) exhibits a narrow therapeutic index and large inter-individual variation in pharmacokinetics. Two intermittent and 24-h continuous infusions (CI) are both commonly used regimens in hematopoietic stem cell transplantation (HSCT), with no universal consensus. The objective of this study was to assess whether CsA as a 2-h, twice-daily intravenous infusion (2 h/12 h) is non-inferior to 22h CI every 24 h (22h-CI/24 h) in terms of acute graft-versus-host disease (aGVHD) incidence and adverse events in allogeneic HSCT adult patients. An open-label randomized trial recruited 31 allogeneic HSCT patients to receive the 2 h/12 h or 22 h-CI/24 h regimen. The primary outcomes were the incidence of aGVHD and CsA-related adverse events. The secondary outcomes included the correlation between the time concentration and area under the concentration-time curve (AUC) of 2 h/12 h versus 22 h-CI/24 h regimens. Six (19.4%) patients developed aGVHD. There was no statistically significant difference between the two groups concerning the incidence of aGVHD (13.3% in 2 h/12 h vs. 25% in 22 h-CI/24 h; p = 0.359). The distribution of different aGVHD types (p = 0.20) and mortality (p = 0.9) were not significantly different between the two groups. The two groups did not differ at any time with respect to AUCs, nephrotoxicity, hepatotoxicity, or electrolyte disturbance. The study suggested that the 2 h/12 h regimen is non-inferior to the conventional regimen (22 h CI/24 h) in terms of aGVHD incidence and adverse events. Further research is necessary to validate these findings and to guide practice, considering the small sample size of this study. ClinicalTrials.gov identifier NCT04575779 with initial release on 19 September 2020-Retrospectively registered, https://clinicaltrials.gov/study/NCT04575779 .