Identical Donor Research Articles

Matched pair analysis of the effect of longer hypothermic machine perfusion time on kidney transplant outcomes.

Hypothermic machine perfusion (HMP) has demonstrated benefits in terms of early kidney transplant function compared to static cold storage. While longer preservation times have shown detrimental effects, a previous paired study indicated that longer pump times (the second kidney in a pair) might lead to improved outcomes. To revisit the prior paired study's somewhat unexpected results by reviewing our program's experience. A total of 61 pairs of transplant recipients who received kidneys from the same donor (2012-2021) were analyzed. Patients were divided into two groups depending on whether they were transplanted first (K1) or second (K2). Therefore, the patients in each pair had identical donor characteristics, except for time on the pump. Statistical analyses included Kaplan-Meyer analysis and paired tests, including McNemar's test, student's paired t-test, or Wilcoxon's test, as appropriate. The two groups of recipients had similar demographics (age, body mass index, diabetes, time on dialysis, sensitization and retransplants). Cold ischemic times for K1 and K2 were 8.9 (95%CI: 7.9, 9.8) and 14.7 hours (13.7, 15.8) (P < 0.0001), respectively. Overall, K2 had a higher rate of freedom from biopsy-proven acute rejection at 1 year (P = 0.015). Delayed graft function was less common in K2, 12/61 (20%) than in K1, 20/61 (33%) (P = 0.046). Finally, K2 showed a higher graft survival than K1 (P = 0.023). Our results agree with a previous study that suggested possible advantages to longer pump times. Both studies should encourage further research into HMP's potential anti-inflammatory effect.

Feasibility of co-transplantation of umbilical cord blood and third-party mesenchymal stromal cells after (non)myeloablative conditioning in patients with hematological malignancies

Umbilical cord blood (UCB) is an alternative source of stem cells for patients lacking a 9/10 or 10/10 HLA identical donor. However, after UCB transplantation, time to engraftment and immune recovery are prolonged, increasing the risk of fatal complications. Mesenchymal stromal cells (MSC) can support hematopoietic engraftment and have immunosuppressive effects.The primary objective of this phase I/II multicenter study was to determine the feasibility and safety of UCB transplantation with co-infusion of third party MSC, as assessed by treatment related mortality (TRM) at day 100. Secondary objectives were engraftment, immune recovery, occurrence of graft versus host disease (GVHD), infections, disease free survival, relapse incidence and overall survival.Eleven patients were grafted according to this protocol. Allogeneic transplantation after co-infusion appears feasible with 18 % TRM at day 100. Engraftment data show a median time of 16 days to neutrophil and 27 days to platelet recovery, which is shorter than what is usually reported after UCB transplantation. Only 1 episode of acute GVHD was reported.In conclusion, MSC and UCB co-transplantation is feasible and might help overcome some of the drawbacks of UCB transplantation.

Hematopoietic cell transplantation for older acute myeloid leukemia patients in first complete remission: results of a randomized phase III study.

Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.

Novel Benzothiadiazole-based Donor-Acceptor Systems: Synthesis, Ultrafast Charge Transfer and Separation Dynamics.

Near-infrared (NIR) absorbing electron donor-acceptor (D-A) chromophores have been at the forefront of current energy research owing to their facile charge transfer (CT) characteristics, which are primitive for photovoltaic applications. Herein, we have designed and developed a new set of benzothiadiazole (BTD)-based tetracyanobutadiene (TCBD)/dicyanoquinodimethane (DCNQ)-embedded multimodular D-A systems (BTD1-BTD6) and investigated their inherent photo-electro-chemical responses for the first time having identical and mixed terminal donors of variable donicity. Apart from poor luminescence, the appearance of broad low-lying optical transitions extendable even in the NIR region (>1000 nm), particularly in the presence of the auxiliary acceptors, are indicative of underlying nonradiative excited state processes leading to robust intramolecular CT and subsequent charge separation (CS) processes in these D-A constructs. While electrochemical studies identify the moieties involved in these photo-events, orbital delocalization and consequent evidence for the low-energy CT transitions have been achieved from theoretical calculations. Finally, the spectral and temporal responses of different photoproducts are obtained from femtosecond transient absorption studies, which, coupled with spectroelectrochemical data, identify broad NIR signals as CS states of the compounds. All the systems are found to be susceptible to ultrafast (~ps) CT and CS before carrier recombination to the ground state, which is, however, significantly facilitated after incorporation of the secondary TCBD/DCNQ acceptors, leading to faster and thus efficient CT processes, particularly in polar solvents. These findings, including facile CT/CS and broad and intense panchromatic absorption over a wide window of the electromagnetic spectrum, are likely to expand the horizons of BTD-based multimodular CT systems to revolutionize the realm of solar energy conversion and associated photonic applications.

The Influence of Various Freezing-thawing Methods of Skin on Drug Permeation and Skin Barrier Function.

The selection of skin is crucial for the in vitro permeation test (IVPT). The purpose of this study was to investigate the influence of different freezing-thawing processes on the barrier function of skin and the transdermal permeability of granisetron and lidocaine. Rat and hairless mouse skins were thawed at three different conditions after being frozen at -20℃ for 9days: thawed at 4℃, room temperature (RT), and 32℃. There were no significant differences in the steady-state fluxes of drugs between fresh and thawed samples, but compared with fresh skin there were significant differences in lag time for the permeation of granisetron in rat skins thawed at RT and 32℃. Histological research and scanning electron microscopy images showed no obvious structural damage on frozen/thawed skin, while immunohistochemical staining and enzyme-linked immunosorbent assay for the tight junction (TJ) protein Cldn-1 showed significantly impaired epidermal barrier. It was concluded that the freezing-thawing process increases the diffusion rate of hydrophilic drugs partly due to the functional degradation of TJs. It's recommended that hairless, inbred strains and identical animal donors should be used, and the selected thawing method of skin should be validated prior to IVPT, especially for hydrophilic drugs.

Organocatalytic [3+2] Annulation of β-Tetralones with α,β-Unsaturated Aldehydes

AbstractThe NBS-mediated organocatalytic cascade synthesis of 4,5-dihydronaphtho[2,1-b]furan-1-carbaldehydes from α,β-unsaturated aldehydes and 2-tetralones have been developed. In this synthesis strategy, the C1 of in situ generated brominated 2-tetralone was used as identical twin electron donor–acceptor, and the Cβ and Cα of enals were used as the heterogeneous twin electron acceptor–donors. The process has been realized by a synergistic amine/p-TSA catalyzed one-pot cascade Michael addition–cyclopropanation–ring opening–oxa-Michael addition under mild conditions and without the use of transition metals.

Oncolytic Tanapoxvirus Recombinants Expressing Flagellin C or Mouse Interleukin-2 Are Capable of Regressing Human Triple-Negative Breast Cancer Xenografts in Immuno-Competent BALB/c Nude Mice.

Triple-negative breast cancer (TNBC) in humans is the most aggressive and deadly form of BC. Although TNBCs are about 15 percent of the total number of BC cases, they are associated with the highest mortalities. Current treatment options are limited, and most modalities are toxic and have not increased the 5-year survival rates of TNBC. Many oncolytic viruses are emerging as potential therapies for TNBC. In this study, two Tanapoxvirus (TPV) recombinants, one expressing FliC and the other expressing mouse interleukin-2 (mIL-2), were assessed for their efficacy in an immuno-competent xenograft mouse model. MDA-MB-231 tumors were planted in BALB/c nude mice, treated, made immuno-competent via adoptive transfer of splenocytes from healthy BALB/c donors, and then monitored for 40 days. TPV/Δ2L/66R/FliC and TPV/Δ66R/mIL-2 demonstrated significant tumor reduction (p = 0.01602 and p = 0.03890, respectively) compared to the reconstituted control (RC), whereas wtTPV did not. Pathological analyses of treated tumors revealed cells consistent with lymphocyte and plasma cell morphology in reconstituted mice treated with TPV recombinants. Anti-viral plaque reduction assays conducted using harvested serum from treated animals indicated the presence of anti-TPV antibodies in mice reconstituted and treated with TPV that were missing from immune-deficient nude mice, including those exposed to TPV and of statistically equivalent serum concentrations to normal BALB/c mice immunized against TPV. The results suggest immuno-deficient BALB/c nude mice can become immuno-competent via adoptive transfer of splenocytes from genetically identical donors and allow for testing of tumor xenografts in a competent model system. The TPV recombinants tested should be further studied for the potential treatment of human TNBC.

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical sibling donors for hematological malignancies in 6064 adults from 2003 to 2020: different impacts on survival according to time period

BackgroundMobilized peripheral blood stem cells (PBSC) have been widely used instead of bone marrow (BM) as the graft source for allogeneic hematopoietic cell transplantation (HCT). Although early studies demonstrated no significant differences in survival between PBSC transplantation (PBSCT) and BM transplantation (BMT) from human leukocyte antigen (HLA)-identical sibling donors to adults with hematological malignancies, recent results have been unclear. ObjectiveThe objective of this retrospective study was to compare overall survival (OS), relapse, non-relapse mortality (NRM), hematopoietic recovery and graft-versus-host disease (GVHD) between PBSCT and BMT according to the time period of HCT (2003–2008, 2009–2014, or 2015–2020). Study designWe retrospectively compared the outcomes after PBSCT versus BMT in 6064 adults with hematological malignancies using a Japanese registry database between 2003 and 2020. ResultsThe adjusted probability of OS was significantly higher in BMT recipients compared to PBSCT recipients during the early period of 2003–2008 (adjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.70–0.91; P < 0.001) and the middle period of 2009–2014 (adjusted HR, 0.80; 95% CI, 0.70–0.91; P < 0.001). However, during the late period of 2015–2020, the adjusted probability of OS was comparable between BMT and PBSCT recipients (adjusted HR, 0.94; 95% CI, 0.79–1.13; P = 0.564), which were mainly due to the reduction of NRM. There was no significant difference in the relapse rate between the groups, irrespective of the time period. Compared to BMT, PBSCT led to faster neutrophil and platelet recovery and the cumulative incidences of grades II–IV and grades III–IV acute and overall and extensive chronic GVHD were significantly higher in PBSCT recipients, irrespective of the time period. ConclusionsPBSCT and BMT had similar survival outcomes and relapse rates in adult patients with hematological malignancies during the late time period of 2015–2020 despite the hematopoietic recovery and acute and chronic GVHD being higher in PBSCT recipients in all time periods.

Abstract 5338: Evaluation of checkpoint inhibitor efficacy in a humanized immune system mouse model lacking murine Fc gamma receptors

Abstract Humanized immune system (HIS) mice are critical immuno-oncology tools for evaluating antibody-based therapeutic target engagement and efficacy in a human-like context. Most antibody-based therapeutics have an IgG backbone and thus engage Fc gamma receptors. Traditional HIS mice retain murine immune cells such as neutrophils and macrophages which can interact with human IgG-based therapeutics and confound preclinical results. To determine whether knockout of murine Fc gamma receptors (FcγRs) in a super-immunodeficient mouse model would alter anti-PD1 efficacy compared to the parent strain, we studied tumor growth kinetics, human reconstitution, and tumor infiltrating leukocytes (TILs) in each strain engrafted with HCC827 lung adenocarcinoma tumor cells treated with pembrolizumab or vehicle. Methods: HIS NOG (huNOG) or HIS FcγR knockout NOG mice (FcResolv™ huNOG) were created using identical protocols with CD34+ cells from three human donors shared across both strains. Baseline reconstitution was evaluated in naïve animals via flow cytometry. HCC827 cells were inoculated in remaining animals. Animals were randomized on day 7 post-tumor implantation into 12 groups. Body weight, clinical observations, and tumor growth were measured. Mice received treatment from D7, dosed twice weekly for four weeks, and were then euthanized for FACS analysis, collecting blood, spleen, and tumor samples. Results: For a given donor, no significant differences were seen between strains in human immune reconstitution and kinetics. Pembrolizumab treatment showed significant tumor growth inhibition in one donor in FcResolv huNOG, but not in donor-matched huNOG mice. Evaluation of human TILs in pembrolizumab-treated animals showed significant differences between the strains across all donors, with FcResolv huNOG mice showing increased CD8+ T cells and decreased tumor-associated macrophages compared to vehicle-treated mice, and no significant differences in huNOG. Evaluation of murine TILs revealed differences in murine macrophage populations, regardless of treatment, with Ly6Clo dominant in FcResolv huNOG and Ly6Chi dominant in huNOG. In the presence of pembrolizumab, the murine myeloid and granulocyte population within the spleen is significantly decreased in FcResolv huNOG mice whereas no change was seen in huNOG. Conclusions: Our study demonstrates when treated with anti-PD1, FcResolv huNOG mice show expected pharmacodynamic changes and donor-dependent efficacy whereas, despite identical donors and creation protocols, pembrolizumab-treated huNOG mice showed neither. These differences are due to the presence or absence of murine FcγRs and their impact on antibody IgG-based therapeutics. Citation Format: Nicholas Smith, Monika Buczek, Megan MacBride, Esther Andino, Emily Sack, Debra Freer, Michelle Vedder, Kathleen Bott, Louise Baskin, Damien France, Francis Bichat, Caroline Mignard, Janell Richardson. Evaluation of checkpoint inhibitor efficacy in a humanized immune system mouse model lacking murine Fc gamma receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5338.

CAR-T cell expansion platforms yield distinct T cell differentiation states

With investigators looking to expand engineered T cell therapies such as CAR-T to new tumor targets and patient populations, a variety of cell manufacturing platforms have been developed to scale manufacturing capacity using closed and/or automated systems. Such platforms are particularly useful for solid tumor targets, which typically require higher CAR-T cell doses. Although T cell phenotype and function are key attributes that often correlate with therapeutic efficacy, how manufacturing platforms influence the final CAR-T cell product is currently unknown. We compared 4 commonly used T cell manufacturing platforms (CliniMACS Prodigy, Xuri W25 rocking platform, G-Rex gas-permeable bioreactor, static bag culture) using identical media, stimulation, culture length, and donor starting material. Selected CD4+CD8+ cells were transduced with lentiviral vector incorporating a CAR targeting FGFR4, a promising target for pediatric sarcoma. We observed significant differences in overall expansion over the 14-day culture; bag cultures had the highest capacity for expansion while the Prodigy had the lowest (481-fold versus 84-fold, respectively). Strikingly, we also observed considerable differences in the phenotype of the final product, with the Prodigy significantly enriched for CCR7+CD45RA+ naïve/stem central memory (Tn/scm)-like cells at 46% compared to bag and G-Rex with 16% and 13%, respectively. Gene expression analysis also showed that Prodigy CAR-Ts are more naïve, less cytotoxic and less exhausted than bag, G-Rex, and Xuri CAR-Ts, and pointed to differences in cell metabolism that were confirmed via metabolic assays. We hypothesized that dissolved oxygen level, which decreased substantially during the final 3 days of the Prodigy culture, may contribute to the observed differences in T cell phenotype. By culturing bag and G-Rex cultures in 1% O2 from day 5 onward, we could generate >60% Tn/scm-like cells, with longer time in hypoxia correlating with a higher percentage of Tn/scm-like cells. Intriguingly, our results suggest that oxygenation is responsible, at least in part, for observed differences in T cell phenotype among bioreactors and suggest hypoxic culture as a potential strategy prevent T cell differentiation during expansion. Ultimately, our study demonstrates that selection of bioreactor system may have profound effects not only on the capacity for expansion, but also on the differentiation state of the resulting CAR-T cells.

Risk factors and predictive model for mortality in patients undergoing allogeneic hematopoietic stem cell transplantation admitted to the intensive care unit.

Hematological malignant tumors represent a group of major diseases carrying a substantial risk to the lives of affected patients. Risk factors for mortality in critically ill patients have garnered substantial attention in recent research endeavors. The present research aimed to identify factors predicting intensive care unit (ICU) mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, the present study analyzed and compared the mortality rate between patients undergoing haploidentical hematopoietic stem cell transplantation (Haplo-SCT) and those undergoing identical sibling donor (ISD) transplantation. A total of 108 patients were included in the present research, 83 (76.9%) of whom underwent Haplo-SCT. ICU mortality was reported in 58 (53.7%) patients, with the values of 55.4 and 48.0% associated with Haplo-SCT and ISD, respectively (P=0.514). The mortality rate of patients undergoing Haplo-SCT was comparable to that of patients undergoing ISD transplantation. The present study found that reduced hemoglobin, elevated total bilirubin, elevated brain natriuretic peptide, elevated fibrinogen degradation products, need for vasoactive drugs at ICU admission, need for invasive mechanical ventilation and elevated APACHE II scores were independent risk factors for ICU mortality. Among patients presenting with 5-7 risk factors, the ICU mortality reached 100%, significantly exceeding that of other patients. The present research revealed that ICU mortality rates remain elevated among patients who underwent allo-HSCT, especially those presenting multiple risk factors. However, the outcome of patients undergoing Haplo-SCT were comparable to those of patients undergoing ISD transplants.

Impact of COVID-19 in Thalassemia Patients Undergoing Hematopoietic Stem Cell Transplant Recipients

Objective: This article primarily examines the clinical attributes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in transplant recipients with thalassemia, offering significant insights into the treatment and care of this patient population. Method: The present study retrospectively analyzed the data of all thalassemia patients who underwent Hematopoietic stem cell transplantation (HSCT) at the First Affiliated Hospital of Guangxi Medical University between December 2019 and December 2022. A total of 280 patients were included, of which 81 had confirmed coronavirus disease 2019 (COVID-19). The study collected information on patient demographics, transplantation type and timing, graft-versus-host disease (GVHD), use of immunosuppressive agents, onset time and severity of COVID-19, and prognosis. Follow-up was conducted until March 31, 2023.Univariate analysis was performed using SPSS v25.0, and GraphPad Prism was used for the cumulative incidence comparisons. Results: The median age was 3.6(2-19) years.The main type of thalassemia was β type (93.9%). Identical sibling donors accounted for 40%, haploidentical donors accounted for 25.4%, and identical unrelated donors accounted for 34.6% (10/10). The main source of hematopoietic stem cells was bone marrow combined with peripheral blood (85%).There were no significant differences in age, gender, diagnosis, donor type, graft type, use of immunosuppressive agents, GVHD, and pneumonia of pro-COVID-19 between infected patients and non-infected patients with SARS-CoV-2. Most of the patients were mild (74 cases, 91.3%) in terms of the severity of COVID-19 infection, only 8.6% of the moderate cases, and none severe and died. 74 cases were cured without drug treatment. Of the seven patients treated with medications, four were azvudine and three were nematasvir. The median number of days (IQR) of treatment for COVID-19 was 5(5) days. The cumulative incidence in the immunosuppressive group was higher than that in the non-immunosuppressive group over the same time frame. There was no significant difference in the final infection rate of COVID-19 among patients receiving transplantation in different years(2020,2021,2022), which was 24.7 26.8 36.5 ( p=0.368), respectively. Conclusion: The low infection rate and no severe cases may be due to scientific protection and timely medication. There are no special risk factors for COVID-19 infection in thalassemia patients after transplantation.

Comparison of Outcomes of Hematopoietic Cell Transplantation (HCT) for Asymptomatic Patients with Sickle Cell Disease (SCD) and That of Propensity Matched Symptomatic Patients Undergoing HCT

Introduction Hematopoietic cell transplantation (HCT), a potential curative option for sickle cell disease (SCD) has typically been offered to patients with severe disease manifestations. With improved outcomes, especially in young children receiving HCT from HLA identical donors, some clinicians are performing HCT for patients without severe manifestations. HCT is associated with risk of substantial short-term morbidity, death, and long-term sequelae. Performance of HCT in patients who have not yet suffered from complications of SCD, raises unique issues of cost-benefit tradeoff, ethics, and healthcare equity. Further, it is unknown whether patients who have not suffered complications of SCD would have better outcomes following HCT. The objective of this study was to compare the outcomes for asymptomatic patients in patients undergoing HCT for SCD and propensity matched symptomatic SCD patients undergoing HCT. Methods: We queried the HCT for SCD dataset of patients undergoing HCT between 1990-2022 and reported to the Center for International Bone Marrow Research (CIBMTR) registry. Transplant essential data had been submitted for all patients while a subset of patients was assigned to the comprehensive research form (CRF) track. On these patients HCT centers submitted detailed SCD specific baseline data, as well as outcomes relevant to SCD and organ specific complications. The main reason for HCT is one of the variables collected in the CRF. Thus, we selected patients in the CRF track for further study. We describe demographics, baseline characteristics, transplant essential outcomes including overall survival (OS) and event free survival (EFS), graft failure (GF), Acute graft versus host disease (aGVHD) and chronic GVHD (cGVHD), venocclusive disease of the liver (VOD), post-transplant pneumonia/acute chest syndrome or other pulmonary complications(ACS), nephropathy, stroke, avascular necrosis (AVN), vasocclusive crises (VOC). We created a propensity score model, adding baseline variables. For each categorical outcome variable, frequency tables and tests of difference in proportions were derived. Descriptive statistics and tests of difference in means were derived for the two numeric outcome variables. In addition, survival analysis (Cox regression modeling) was conducted to determine the time until an individual experienced graft failure or death and whether event rates were associated with group classification adjusting for age and donor type. Results: For the entire cohort of 1718 patients undergoing HCT from 1990 to 2022 patients were followed for a median 47.8 months (0.3-312.9), 73.4% of patients with age at HCT &amp;lt;18 years and 74.7% with Karnofsky-Lansky score ≥ 90. The 3-year OS was 91.2%, 3-year EFS 75.5%, and GF rate was 17.9%, aGVHD grades II-IV occurred in 18.3%, and cGVHD developed in 22.3%. A total of 763 patients were assigned to the CRF track. The main reason for HCT was reported for these patients, and 49 patients were reported to be asymptomatic at baseline. In the asymptomatic patients majority of the HCT were performed for patients under the age of 10 years (n = 33) in patients with Hemoglobin SS (n = 45) and most occurred between 2013-2018 (n = 24). Average follow up period was 48 months. The most common graft source and conditioning regimens utilized were bone marrow (n = 35) HLA identical sibling donor type (63.2%, n = 31), and reduced intensity conditioning (n = 25) respectively. Other donor types included HLA mismatched relative (n = 9), mismatched unrelated donor and cord blood (n = 5), and matched unrelated was used in 4 patients. There was one death, at 16.5 months with cGvHD. GF occurred in 14.3%, OS was 97.9%, EFS 83.67%, 20.4% developed aGvHD and 28.5% developed cGvHD and none developed secondary malignancies or post-transplant lymphoproliferative disorders. Propensity matched control group (Figure 1) was constructed based on age at HCT, donor type, graft type, HCT comorbidity index, SCD type. There was good variable balance with a small standardized mean difference for matched observations. There were no statistically significant differences in least mean squares for EFS, death, OS, GF, AGVHD, CGVHD, VOD, VOC, AVN, stroke or ACS between the propensity matched groups ( Figure 1). Discussion: Complications and outcomes of HCT in asymptomatic patients with SCD patients is similar to that in propensity matched symptomatic SCD patients undergoing HCT.

Real World Clinical Characteristics, Treatment Patterns and Outcomes of R/R B-Cell ALL Adult Patients in Latin America

Introduction. Acute lymphoblastic leukemia (ALL) frequently affects mainly children and young adults. ALL has seen important progresses in diagnosis techniques and treatment approaches in the last decade. However, in some developing countries, there are inequalities in ALL management, such as heterogeneous access to diagnosis technologies (e.g., cytogenetic and molecular profiling) and access to target therapies treatments. To date, there is scarce data on those impacts in treatment patterns and real-world outcomes of adult relapsed/refractory (R/R) B-cell ALL (R/R ALL) patients in Latin America (LA). Therefore, this study aims to describe treatment patterns, clinical characteristics, and outcomes of R/R ALL adult patients treated in LA. Methods. This was a retrospective multicenter non-interventional study to evaluate treatment patterns, clinical characteristics and outcomes conducted in Argentina, Brazil, and Colombia. The study included patients ≥ 18 years old at diagnosis with confirmed R/R ALL between January 1, 2015, to December 31, 2019 that received at least one line of treatment for R/R ALL. Data collected from medical records was considered for the analysis, which was descriptive in nature, as no hypothesis has been tested. Results: A total of 71 patients diagnosed with R/R ALL were included in the study (23 from Argentina, 27 from Brazil, and 21 from Colombia). Table 1 shows the demographics and clinical characteristics. The median age at diagnosis was 31 years (Q1-Q3: 24.0-46.0), 56.3% were male, and 50% were White/Caucasian patients. At diagnosis, the most common comorbidities were diabetes, hypertension, gastrointestinal disease, and thyroid disease, with 11% each. At diagnosis, most patients presented with poor or intermediate cytogenetic risk prognosis, in 55.1% and 31.6%, respectively. Most of the patients presented with good performance status, 50.9% ECOG 0 and 36.8% ECOG 1. As for treatment patterns, patients received up to six treatment lines (LOT-1 to LOT-6), with a median of 2.0 LOTs (Q1-Q3: 1.5-3.0) within the R/R setting. Fifty-three (74.6%) out of the 71 patients enrolled in the study received two lines of R/R treatment (up to LOT-2), and 27 patients (38%) received 3 lines (up to LOT-3). The median treatment duration of LOTs were 3.4 months (Q1-Q3: 1.14 - 5.7), 1.4 months (Q1-Q3: 0.62 - 2.6) and 0.9 months (Q1-Q3: 0.4 - 2.1) for LOT-1, -2 and -3, respectively. The most frequently used treatment regimens at LOT-1 were the Hyper-CVAD (22.9%), BFM (20.0%) and GRAAL (15.7%). The most reported reasons for patients discontinuing their regimen in LOT-1 were progression of disease (37.5%), followed by adverse events (25%). For LOT-2 discontinuation, adverse events and/or toxicity (33.3%) were most frequently reported, followed by progression of the disease (25%). Of the total number of R/R ALL patients, 26 (36.6%) underwent stem cell transplantation (SCT), with a median time from diagnosis to transplantation of 9.6 months. All those patients (n=26) received allogeneic hematological SCT (100%), and haploidentical donors were most common (42.3%), followed by identical (matched) related (34.6%), mismatched unrelated donor (15.4%), and identical (matched) unrelated donors (7.7%). For R/R ALL patients, the median overall survival (mOS) was 18.96 months, with a probability of survival of 66.6% at 1 year, 32.3% at 3 years, and 16.2% at 5 years. Philadelphia Chromosome (Ph) molecular results were reported in 53 patients: 38 (71.7%) were Ph- and 15 (28.3%) were Ph+. The mOS in Ph+ patients was 31.5 months, numerically longer than the 17.7 months seen in Ph- patients (p = 0.500); however, the Kaplan-Meiers crossed over and separation was not clearly evident within the follow-up period (Figure 1). Conclusions: This study enabled a better understanding of R/R ALL in LA in the real-world. Data from this study demonstrate the high heterogenicity within first salvage (LOT-1) treatment patterns in R/R ALL, likely due to no established single standard of care in the region and highlights that only a fraction of the patients undergo SCT, which should be the treatment goal following induction therapy. In addition, our study reinforces already published data that overall survival on R/R ALL adult patients remain poor. Consistent guidelines and access to new treatments and are needed to remove inequalities in the management of ALL in LA.

Casting Hope, Defying Odds: Unveiling the Impact of Haplo-Identical Stem Cell Transplant in Myeloid Malignancies - a Tertiary Cancer Care Center Experience

Background &amp; Significance: Only 30% to 40% of patients in need of a curative stem cell transplant (SCT) could find a suitable matched sibling donor. For Indian patients, the likelihood of locating a 10/10 HLA identical unrelated donor within limited donor registries is approximately 14%. However, this probability has the potential to rise to 60% if registries with over 1,000,000 registered donors are available. 1,2 Consequently, there is an increasing inclination in India to perform haploidentical transplantations utilizing the post-transplantation cyclophosphamide (PTCY) platform developed by the Johns Hopkins group. 3 The outcomes of haploidentical stem cell transplantation (haplo-SCT) for the treatment of AML were enhanced in the 1990s with the introduction of a T-cell depletion (TCD) strategy followed by a myeloablative conditioning regimen. 4,5 In the last two decades, significant progress in haplo-SCT for hematological malignancies, especially AML, includes donor selection algorithms, improved grafts, GVHD prophylaxis, and enhanced immunologic recovery, benefiting patients. 6 Here, we present our experience of haplo-identical stem cell transplants in myeloid malignancies at our centre. Study design &amp; Methods: We conducted a retrospective study at our site. Patients with myeloid malignancy who underwent haplo-identical stem cell transplant between Jan 2018 - Jan 2023 were included in the study and the follow-up was done till July 2023. Haplo-identical transplants done for diagnosis other than myeloid malignancy were excluded. The objectives of the study were to assess the non-relapse mortality [NRM] rate at day +100, relapse rate, graft-versus-host disease - free relapse-free survival [GRFS] and overall survival [OS] of the study cohort. GRFS was defined as a combined outcome including mortality from any cause, recurrence of malignancy, acute GVHD of grade 3 to 4, or chronic GVHD necessitating systemic immune suppression therapy. 7 Descriptive statistics (including median, mean, and range) were used to describe the central tendency and dispersion of variables. The probability of overall survival [OS] and graft versus host disease relapse free survival [GRFS] was estimated by the method of Kaplan and Meier. Probabilities of relapse or progression of malignancy, RRM, and day-100 NRM were summarized using cumulative incidence estimates All statistical analysis were done using statistical package for social science software (SPSS 21, IBM SPSS Statistics). Results: We have analysed 29 patients with various myeloid malignancies who have underwent haploidentical SCT from Jan 2018 to Jan 2023. There were 28 AML and 1 MDS patients. The median age was 35 (range, 16 - 59) and there were 22 males and 7 females. Conditioning intensity was myeloablative in 19 (65.5%), reduced intensity conditioning (RIC) in 8 (27.6%) and NMA in 2 (6.9%) patients. There were 10 (34.5%) patients in complete remission 1(CR1) and 19 (65.5%) in CR2. Hematopoietic Cell Transplantation-specific Comorbidity Index [HCT-CI] score was as low 11 (37.9%), intermediate 8 (27.6%) and high 10 (34.5%) patients respectively. Median time to neutrophil engraftment was 16 days (range, 12 - 25) and platelet engraftment was 17 days (range, 11 - 32). Median CD34 stem cell dose was 6.25 x 10*6/kg (range, 3.1 - 8.09) x 10*6/kg. Grade II-IV acute GVHD over first +100 days post SCT was observed in 6 (20.7) patients, and grade III-IV acute GVHD and chronic GVHD at follow up of one year was 3 (10.3) respectively. CMV reactivation by +100days was seen in 18 (62.06%) patients. Relapse was seen in 10 (34.5%) patients, out of which 2 patients are alive and 8 expired due to progressive disease. At median follow up of 13 months, OS is 60.3% (CI: 39.7% - 75.9%) and GRFS is at a median follow-up of 6 month was 51.2% (CI: 35.6% - 71%). Fig:1 NRM was 10.3% and 17.24% at +100 days and at last follow-up respectively. Fig:2 Conclusion: In conclusion, our study demonstrates favorable outcomes in terms of NRM (non-relapse mortality) with a low rate of 10.3% at 100 days after haploidentical SCT. The results also show promising overall survival (OS) and GVHD-free, relapse-free survival (GRFS) rates, supporting the potential of haploidentical transplants as an effective treatment option for myeloid malignancies. Further long-term follow-up and research are needed to validate and optimize these findings.

A Parallel Comparison of the Safety and Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation for Refractory and Relapsed T-ALL/Lbl Patients Who Achieved Complete Remission with CD7 CAR-T Versus Patients Who Achieved First Complete Remission with Chemotherapy before Transplantation

Introduction We have developed a fratricide-resistant CD7 CAR-T cells from bulk T cells transduced with CD7 CAR without gene editing or additional gene transfer, named naturally selected CD7 CAR-T (NS7CAR-T). NS7 CAR-T therapy has shown a robust complete remission (CR) rate in patients with refractory or relapsed (R/R) T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma (T-ALL/LBL). Nonetheless, the risk of relapse remains a challenge post-CD7 CAR-T therapy alone, suggesting the potential benefits of consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT). The question remains whether CD7 CAR-T therapy could increase the incidence of post-transplant complications. Here we conduct a parallel study to compare the safety and efficacy of allo-HSCT in R/R T-ALL/LBL patients who achieved CR with NS7 CAR-T therapy vs those who reached first CR (CR1) using chemotherapy prior to transplantation. Methods Between November 2020 and January 2023, a total of 223 consecutive patients with T-ALL/LBL who underwent allo-HSCT at our center were retrospectively analyzed. Patients who met the following criteria were included in this parallel study: 1) underwent the first allo-HSCT in our hospital, 2) achieved CR before transplantation either from NS7CAR-T therapy or CR1 from chemotherapy (Fig. 1). A total of 139 patients met the criteria for analysis and underwent allo-HSCT after achieving CR either from NS7CAR-T therapy (n=43) or chemotherapy (CR1=96). The median patient age at the time of transplantation was 15 years (range: 1-51 years). The median follow-up time was 370 days (2-941 days). CD7 CAR-T patients were from two clinical trials registered at www.clinicaltrials.gov NCT04572308, NCT04916860. Transplant donor types included sibling identical (n=12), haploidentical (n=110), and unrelated donors (n=17). We used total body irradiation (TBI)-based conditioning regimens (n=128) or Busulfan/Melphalan-based regimens (n=11). To prevent graft-versus-host disease (GVHD), we used ATG along with a short-term regimen combining methotrexate, cyclosporine/tacrolimus, and mycophenolate mofetil. Results The characteristics of patients from both groups are detailed in Table 1. The median interval between CD7 CAR-T treatment and transplantation was 59 (39-131) days. Within the CAR-T group, 16 patients had primary refractory disease, 18 had relapsed disease and 9 in minimal residual disease (MRD)-positive status in bone marrow before CD7 CAR-T therapy. Prior to CAR-T therapy, 55.8% (24 patients) had extramedullary lesions. In comparing the CAR-T and chemotherapy CR1 groups, we observed no significant differences in long-term efficacy post-allo-HSCT. The 2-year leukemia-free survival (LFS) rates were 64.9 (95% CI, 49.1-79.2)% and 69.8 (95% CI, 59.0-79.6)% (p=0.340); the 2-year overall survival (OS) rates were 64.1 (95%CI, 48.0-78.6)% and 71.8 (95%CI, 60.5-81.9)% (p=0.107); the 2-year relapse incidence (RI) rates were 9.3 (95%CI, 3.7-23.7)% and 11.5 (95%CI, 6.4-20.7)% (p=0.873); and the 2-year non-relapsed mortality (NRM) rates were 28.3 (95% CI, 16.9-47.4)% and 21.6 (95% CI, 13.9-33.4)% (p=0.244), for the CD7 CAR-T and non-CAR-T groups, respectively. The incidence of all grades of acute GVHD (aGVHD) 37.2 (95%CI, 25.2-54.9)% vs. 42.1 (95%CI, 33.3-53.3)% did not significantly differ between the CAR-T and non-CAR-T groups. A trend toward an increased rate but no P significance was observed in Grade 3-4 aGVHD incidence of 20.93 (95%CI, 11.7-37.4)% vs. 9.5 (95%CI, 5.1-17.6)% (p=0.139). One-year incidences of moderate to severe chronic GVHD (cGVHD) were 12.2 (95%CI, 5.4-28.0)% and 18.0 (95%CI, 11.5-28.0)% (p=0.357) in the CD7CAR-T and non-CAR-T groups, respectively (Table 2). No statistically significant differences were detected in the occurrences of transplant-associated thrombotic microangiopathy (TA-TMA), CMV, EBV, and HHV-6 infections between the two groups. Upon analyzing, we found that r/r patients who received allo-HSCT after achieving remission with NS7 CAR-T had a similar OS to CR1 patients (Fig. 2). Conclusions Our parallel study showed that T-ALL/LBL patients, who achieved CR via CD7 CAR-T therapy followed by a consolidation allo-HSCT, had similar favorable OS and LFS compared to patients who underwent allo-HSCT in the CR1 state induced by chemotherapy. This was achieved without increasing the incidence of GVHD, infections, or TA-TMA.

One-Stop No-Edited Allogenic CAR-T Therapy Bridging HSCT to Treat Children with Relapse and Refractory Acute Lymphoblastic Leukemia: A Prospective Clinical Study from a Single Center

Object: Chimeric Antigen Receptor T-Cell (CAR-T) therapy has been developed to be the most effective treatment for relapse and refractory(R/R) B-cell acute lymphoblastic leukemia(B-ALL). However, in some patients prolonged chemotherapy and previous autologous-CAR-T(auto-CAR-T) therapy severely impaired lymphocyte function leading to inability in vitro expansion for effective CAR-T therapy. To address this challenge, we designed this clinical trail to use one-stop no-edited allogenic CAR-T（allo-CART）bridging to same donor conditioning free HSCT to treat children with R/R B-ALL. Methods: Myeloablative conditioning was given to reducing the leukemia burden and clearing lymphatic function for these active ALL. After that allo-CART was used to regain the immune killing effect and clear leukemia cells. Same donor seamless conditioning free HSCT were performed to rapid reconstruction of hematopoietic cells to overcome Immune effector cell associated hematologic toxicity post CAR-T therapy. Ex vivo TCRαβ+ T-cell depleted hematopoietic stem cell were transplanted for haplo-identical donor (HID) to minimize allogeneic reactivation and only macophenolate mofetil (MMF) were given for GHVD prophylaxis and to avoid more immunosuppressive to injury CART effect. Results: From October 2020 to April 2023, 16 extremely R/R B-ALL children with the median age of 10y (1.5-17) were recruited in this study, all patients relapsed 2-5 times and failure of 1-3 times auto-CART therapy with mean blast 70.6%±28.8%. Myeloablative conditioning with total body irradiation (12GY，-7d to -5d),Flu (160mg/m2, -5 to -2d) and CTX (120mg/kg，-4d to -3d) were given. After conditioning all patients received no-edited family donor allo-CAR-T therapy with the average cart (5.29±2.92)×10 6/kg, 3 from matched sibling donor (MSD) and 13 from haplo identical donor(HID). 6 patients received CD22-targeted CAR-T therapy due to loss of CD19 after previous auto-CART and another 10 received bispecific CD19/CD22-targeted CAR-T therapy. Immediately after the peak of cytokine release syndrome (CRS), median 11 days (range: 8-34 days), same allo-CART donor hematopoietic stem cell were transplanted with the median CD34+cells(6.88±2.77)×10 6 /kg and TCRαβ+T cells(18.65±16.10)×10 4 /kg for TCRαβ+depleted HSCT. After median follow-up of 8 (range 3 to 34) months for the surviving patients. Out of the 16 patients, 6 (37.5%) achieved CR after conditioning, 13 (81.3%) achieved CR after CAR-T therapy and 15 (93.8%) got CR at one month post HSCT. Among the 16 patients, 15 experienced CRS (above grade 1) and one accompanied by immune effector cell-associated neurotoxicity syndrome (ICANS), but no one died of CRS. 13(81.2%) patients developed acute graft-versus-host disease (aGvHD) before transplant mainly presented with skin GVHD except 3(18.9%) had a grade III GVHD which easily be resolved. Before HSCT, all patients achieved complete chimerism with donor T-cells. Almost every one experienced several episode infection during these therapy. Until the last follow-up, 2 cases relapsed and 5 died (2 died of infections, 1 died of relapse and 2 died of GvHD combined thrombotic microangiopathy and infection). Despite being a cohort of R/R patients with non-CR, the estimated overall survival (OS) at 1 year was 58.7%±16.0%, event-free survival (EFS) was 44.4%±14.2%. Conclusion: For children with repeated relapsed B-ALL failure of previous auto-CART, Allo-CART treat can be considered as long as CART targets still presented. One-stop no-edited same donor allo-CART bridging to conditioning free HSCT provides a chance of survival for these extremely refractory/relapsed B-ALL with manageable CRS and GVHD, but more serious infection.

Clinical Factors but Not Somatic Mutations Predict for Survival in Patients with Myelofibrosis Undergoing Allogeneic Hematopoietic Cell Transplant: Analysis of the North American Myelofibrosis Transplant Outcome (NAMTO) Study

Introduction: Myelofibrosis (MF) is a clonal hematologic malignancy characterized by constitutive JAK-STAT activation and aberrant cytokine signaling. Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative therapy in MF. The contribution of disease-, patient- and donor-related factors to allo-HCT outcomes remains to be fully elucidated, as well as the presence of somatic mutations in genes such as ASXL1, EZH2, SRSF2, U2AF1 and IDH1/2 which are associated with worse prognosis in MF patients (pts). In this large multi- center retrospective analysis, we aimed to study the impact of clinical and molecular mutations on transplant outcomes. Methods: This analysis including 498 pts from 11 centers in North America and Canada. Univariate proportional-hazard Cox regression analysis stratified by center was used to assess the association of patient, transplant, and disease characteristics on overall survival (OS). Baseline patient demographic data and disease characteristics were selected as covariates in the multivariate analysis. Results: Pts transplanted between 2002-2021 were included in this analysis. Baseline and transplant characteristics are summarized in table 1. The 1- and 2-year OS was 77% (95% CI; 73-81) and 70% (95% CI; 66-74) and non-relapse mortality (NRM) 19% (95% CI: 17-21) and 23% (95% CI: 19-27), respectively. The cumulative incidence (CMI) of relapse at 1- and 2-years was 12% (95% CI; 10-14) and 16% (95% CI; 12-20). The CMI of acute graft versus host disease (aGVHD) grade II-IV was 31% (95% CI; 27-35) at 3 months and 42% (95% CI; 38-46) at 1-year post-transplant and grade was III-IV 13% (95% CI; 11-15) and 18% (95% CI; 14-22), respectively. The CMI of neutrophil engraftment at 1 and 3 months was 90% (95% CI: 87-93) and 97% (95% CI: 95-95) and for platelets 55% (95% CI: 50-59) and 80% (95% CI: 76-83). Univariate analysis included pts (age and gender), transplant (donor type and conditioning regimen intensity) and disease characteristics (DIPSS, mutations, cytogenetics (CG), blood counts, and spleen size). Hemoglobin &amp;gt; 10 g/dL (HR .5, 95% CI .34 -.73 p=3 x 10 -4) and platelets &amp;gt;50× 10 9/L (HR .59, 95% CI .42-.81, p=.0013) prior to transplant were associated with improved OS. High risk DIPSS was associated with decreased OS (p=0.0002). Mutations in ASXL1, EZH2, IDH1/2, U2AF1 and SRSF2 were not associated with decreased OS in this analysis (Figure 1). However, mutations in ZRSR2 were associated with inferior OS (HR 2.07, 95% CI 1.08-3.95, p=.0252). Lastly, JAK2 which had the most frequent mutations was not associated with OS (HR .0.93, 95% CI .65-1.31). There was no association between the CG risk groups and OS. Splenomegaly, measured radiographically, had no impact on OS but was strongly associated with engraftment (better engraftment defined as HR&amp;gt;1). For platelets, spleen size of 15.6-18.9 cm HR of 0.69 (95% CI .47-1, p=.0489) and size &amp;gt;18.9-22.5 cm HR of 0.48 ( 95% CI .33-.7, p=1x10^-4). For neutrophils, spleen size &amp;gt;19.9-22.5 cm had a HR of 0.68, (95% CI .48-.96, p=.0268) and size&amp;gt;22.5 cm had a HR of 0.65 (95% CI .46-.91, p=.0114). Mismatched unrelated (MMURD) and haplo identical donors had no impact on survival but were associated with delayed platelet engraftment; MMURD (HR .67, 95% CI .47-.96, p=.0298) and haploidentical donors (HR .56, 95% CI .39-.8, p=.0017). In a multivariate analysis adjusted for age, gender, highest DIPSS, donor type and conditioning regimen, platelets &amp;gt; 50× 10 9/L (HR .61, 95% CI .44-.87, p=.0053) hemoglobin &amp;gt;10 g/dL (HR .6, 95% CI .4-.9, p=.0244) and lower DIPSS at the time of transplant were associated with improved OS. Conclusions: In this large multicenter analysis only clinical variables; hemoglobin and platelets, were found to be associated with OS after allo-HCT in MF patients. Somatic mutations associated with poor prognosis were not associated with OS suggesting that transplant can overcome their negative impact. Splenomegaly was associated with delayed engraftment but not OS. Interestingly, using alternative donors (MMURD and haplo identical) didn't have a negative effect on OS, possibly reflecting the use of post-transplant cyclophosphamide for GVHD prophylaxis in recent years. These results highlight the importance of biologic factors in the prognostication of outcomes in MF pts undergoing allo-HCT independent of somatic mutations. Supported by the American Society of Hematology (ASH) and MPN Research Foundation

Phase I/II Study of Reduced Dosing of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Identical Peripheral Blood Hematopoietic Stem Cell Transplantation

Introduction Post-transplant cyclophosphamide (PTCy)-based prophylaxis for acute graft versus host disease (aGvHD) has become a standard protocol in HLA haploidentical bone marrow transplantation. Preliminary evidence indicates that compared to the standard dosage (50 mg/kg on days +3 and +4 post-transplantation), a regimen of half the typical cyclophosphamide dosage is both feasible and effective. However, the optimal dosage and timing of PTCy for aGvHD prophylaxis in a HLA identical setting, using peripheral stem cells as the graft, remain unknown. This study aims to investigate the efficacy and safety of a reduced PTCy dosage regimen in patients undergoing peripheral blood stem cell transplants (PBSCT) with HLA indentical donors. Methods This prospective, single-center phase I/II study enrolled patients scheduled for PBSCT with HLA identical donors. The aGVHD prophylaxis regimen comprised PTCy on days +3 and +4, followed by cyclosporine initiation from day 5 post-transplant. In the phase I stage, an initial cohort of five patients received PTCy at a dosage of 50 mg/kg/day on days +3 and +4 (designated as dose level 1, DL1). This was followed by a 3+3 dose de-escalation design with subsequent dose levels as follows: DL2, 50 mg/kg on day +3 and 25 mg/kg on day +4; and DL3, 25 mg/kg on both day +3 and +4. The dose-limiting toxicity for this de-escalation was defined as the occurrence of grade III-IV aGVHD within the first 100 days post-transplantation. The phase II stage comprised an expansion cohort, which was based on the optimal dose identified during phase I. aGvHD classification was established using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, while chronic GvHD (cGvHD) was assessed per the latest National Institutes of Health Consensus on cGvHD. Patients were closely followed-up at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results In the first stage, a total of 11 patients (5 in DL1, 3 in DL2, and 3 in DL3) were included, and no patient developed grade III-IV aGVHD. Based on this, DL3 was selected as the PTCy dose for phase II, which comprised 18 patients. Overall, 29 patients (17 females, 12 males) with a median age of 39 years (range 17-65) were included, and the median follow-up duration was 12.7 months (range 2.2-22.1). Patient and disease characteristics are summarized in Table 1. By day +30 post-ASCT, all patients achieved complete remission (CR) and minimal residual disease (MRD) clearance. No patient developed grade III-IV aGVHD within 100 days post-transplantation. There was no significant difference in the neutrophil and platelet engraftment interval among the three groups (Figure 1A, B). Among the 21 patients who received the DL3 dose of PTCy, the estimated cumulative incidence of grade II to IV aGVHD at day +100 was recorded at 28.6%, and the incidence of aGVHD at day +100 presented no difference among the three DL groups (Figure 1C). In addition, 1 patient in DL3 developed grade IV intestinal aGVHD on day +141 and died one month later. The estimated 1-year cumulative incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) reactivation was 19.3% and 19%, respectively (Figure 1D). Five patients (all in DL3) experienced relapse, with a median interval of 6.7 months and an estimated 1-year cumulative incidence of 10.6%. A total of 5 fatalities occurred during our study (1 in DL1, and 4 in DL3), 1 due to relapse, 2 from COVID-19-associated pulmonary aspergillosis, 1 from severe septicemia and 1 due to grade IV aGVHD as mentioned above. The estimated 6-month cumulative incidence of NRM was 9.5%, presenting no difference among the three DL groups (Figure 1E). Among the 20 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) and moderate cGVHD was 37.3% and 16% (Figure 1F), respectively, with no severe cGVHD observed. No cases of patient relapse were reported. The estimated 1-year progression-free survival (PFS) and overall survival (OS) were 61.2% and 80.4%, respectively (Figure 1G). Conclusion The findings of this study substantiate that a two-day regimen of PTCy at 25 mg/kg/day serves as an effective and safe prophylactic measure against aGVHD, comparable to the standard dosing protocol. However, to definitively establish whether the de-escalated PTCy dosage provides superior outcomes to the standard regimen, longer-term follow-up and comparative studies are warranted.

Seizures in children undergoing stem cell transplantation.

Neurological complications (NCs) are of major concern following hematological stem cell transplantation (HSCT), most of which present with seizures. We performed a retrospective study (2002-2018) of patients undergoing HSCT in order to analyze the incidence and aetiologies related to seizures. Of 155 children undergoing HSCT, 27 (17.4%) developed seizures at some point in 2 years of follow-up. The most frequent etiologies were central nervous system (CNS) infection (n = 10), drug toxicity (n = 8), and vascular disease (n = 5). A statistically significant association was found between seizure and the HSCT type (lower risk for a related identical donor, p = .010), prophylactic or therapeutic mycophenolate use (p = .043 and .046, respectively), steroid use (p = .023), selective CD45RA+ depletion (p = .002), pre-engraftment syndrome (p = .007), and chronic graft-versus-host disease (GVHD) severity (p = .030). Seizures predicted evolution to life-threatening complications and admission to intensive care (p < .001) and higher mortality (p = .023). A statistically significant association was also found between seizures and sequelae in survivors (p = .029). Children who developed seizures had a higher risk of CNS infection and vascular disease (odds ratio 37.25 [95% CI: 7.45-186.05] and 12.95 [95% CI 2.24-74.80], respectively). Neurological complications highly impact survival and outcomes and need to be addressed when facing an HSCT procedure.