Setting Of Hematopoietic Stem Cell Transplantation Research Articles

Engineered Stem Cell Antibody Paired Evasion-2 (ESCAPE-2): Paired HSC Epitope Engineering and Direct Editing of Sickle Allele for Antibody-Mediated Autologous Hematopoietic Stem Cell Therapy Conditioning for the Treatment of Sickle Cell Disease

Introduction of the naturally-occurring Hb G-Makassar variation in the human betaglobin gene (HBB) through base editing to eliminate the polymerizing sickle protein, HbS, the major molecular driver for sickle cell disease (SCD), represents a promising new paradigm for the potential treatment of individuals with this disease. While several ex vivo delivery of gene editing technologies for SCD are advancing in the clinic, several challenges remain for this potentially transformative cell therapy, namely the requirement of myeloablative conditioning necessary for autologous hematopoietic stem cell transplant (HSCT) to be fully effective. Aiming to address this, we have developed a strategy whereby a monoclonal antibody (mAb) that binds to CD117, a critical receptor on HSPCs essential for viability, is coupled with multiplexed engineered HSCs (eHSCs). Our eHSCs are designed to both evade mAb binding and harbor the Makassar therapeutic edit. Our engineered stem cell antibody paired evasion (ESCAPE) strategy is designed to provide a non-genotoxic alternative to current conditioning regimens and a potential curative therapy for the treatment of SCD. In our ESCAPE-1 approach, we demonstrated that we could successfully engineer epitopes of the stem cell marker and receptor, CD117, by introducing missense mutations in the ligand binding domain that preserved normal CD117 function and prevented the binding of a high affinity antibody against wildtype (WT) CD117. We leveraged this selective advantage and screened guides that could install missense mutations that covered the entirety of the CD117 ectodomain and were compatible in a multiplexed edited HSC with a next-generation adenine base editor that could install the therapeutic Hb G-Makassar edit. We generated a library of CD117 variants via highly-efficient base editing of the CD117 gene, in mobilized peripheral blood CD34+ HSPCs and then counter-screened these variants against a library of mAbs that bound to wild-type CD117. We identified an antagonist mAb that interacts in the ligand binding domain of CD117, blocking normal SCF ligand binding to the WT receptor, but was unable to bind eHSCs. In vitro biological de-risking of this engineered epitope showed no significant changes in receptor function in response to SCF, or during in vitro differentiation and colony forming unit (CFU) assays when compared to WT CD117. Furthermore, we could demonstrate that this engineered epitope allowed for evasion of cytotoxicity in vitro when edited HSCs were exposed to increasing concentrations of the mAb. We next optimized the multiplex editing conditions in HSCs and achieved outcomes where all cells harboring a CD117 edit, also included at least one Makassar edit. We previously demonstrated that sickle cells harboring even a single Makassar edit exhibited reduced sickling when exposed to hypoxia in vitro. Subsequent Fc receptor silencing modifications were also optimized to reduce any mast cell degranulation that could be the result of antibody-based binding to Fc-receptor on mast cells. Altogether, our ESCAPE-2 strategy is compatible with the installation of the therapeutic Makassar edit that, when combined with a mAb as a conditioning agent, represents a promising potential alternative to busulfan-based myeloablative regimens in an autologous HSCT setting for the treatment of SCD.

Acute kidney injury after allogeneic hematopoietic stem cell transplantation – Predictors and survival impact: A single center retrospective study

Introduction and objectivesAcute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. Patients and methodsWe performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. ResultsAKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. ConclusionPatients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.

HUMORAL IMMUNITY RESPONSES AFTER VACCINATION FOR HEPATITIS B VIRUS IN AUTOGRAFTED PATIENTS: A SINGLE CENTER EXPERIENCE

The effectiveness of vaccinations post hematopoietic stem cell transplantation (HSCT), is a reliable marker for immune system's functionality assessment. In autologous HSCT (AHSCT) setting, the general aspect is that the immune system recovers quite soon and patients (pts) are considered to be immunocompetent in a period of approximately 3-6 months post AHSCT. We evaluated the hepatitis B virus (HBV) vaccination responses in autografted pts who were in remission and off chemotherapy post AHSCT. 27 autografted pts aged 51,6 (22-67) ys, who had antiHbs titers <10 IU/ml before AHSCT and at the time of vaccination, were studied. After a successful engraftment the median absolute lymphocytes count at +3 months was 1740(450-4090)/mm 3 . In 4,3(0,6–8,5) ys post AHSCT, 3 doses of recombinant HBV vaccine were given monthly. The response rates for pts who completed 3 vaccine doses, compared with an internal group of healthy individuals, vaccinated in the same period with the same product. After the 1 st , 2 nd and 3 rd dose the response rates in the study group were 11%, 81% and 88% respectively. No factor statistically significantly influenced the achievement of protective antiHbs titers. The responses were lower as compared to product's efficacy profile (19%, 86% and 100% after the 1 st , 2 nd and 3 rd dose respectively), while in the comparative analysis with the internal control group, a trend for inferior responses in autografted pts was also noticed (88% vs 100%, p=0,07). This study, in a relatively homogenous group of pts, to our knowledge, is the only one that directly compares the HBV vaccine responses in autografted pts with healthy individuals. Although vaccination was offered late post AHSCT, the responses were lower compared to healthy individuals, indicating a possible long lasting immune impairment post AHSCT highlighting the necessity of prolonged surveillance and intensified vaccination programs for autografted pts.

Survival Outcomes of Pediatric Hematopoietic Stem Cell Transplant Patients Admitted to the Intensive Care Unit

BACKGROUND: Hematopoietic Stem Cell Transplantation (HSCT) increases demand on Paediatric Intensive Care Units (PICU) and survival outcomes has emerged as an area of interest in HSCT research. AIMS AND OBJECTIVES: The aim of this retrospective case-control study is to estimate the incidence and survival outcomes, and identify variables associated with survival amongst HSCT patients: MATERIALS AND METHODS: Patients aged ≤15 years transplanted during January 2016 to December 2019 and requiring PICU admission(s). Statistical analysis involved calculating incidence of PICU admission, 2-year overall survival using Kaplan-Meier method; univariate and multivariate logistic regression analysis performed to identify factors associated with outcomes and P-value of &lt;0.05 considered significant. RESULTS: Total of 130 patients underwent 150 HSCT, 31 (24%) of patients required 50 PICU admissions, discharge following PICU admission was observed in 36 (72%) admission episodes, while 14 (28%) associated with patient demise. Two- year Overall Survival (OS) amongst HSCT patients requiring PICU admission was 58% compared to 96.6% amongst patients not requiring PICU (P&lt;0.001). subgroup analysis of cases with malignant disorders and non-malignant disorders showed similar results (P&lt;0.001). Univariate analysis revealed reduced intensity conditioning, no engraftment at the time of PICU admission, and sepsis associated with decreased survival, however multivariate analysis revealed sepsis as the single independent prognostic factor for decreased survival. Our study reports 24% incidence of PICU admission amongst patients undergoing HSCT with a 28% mortality rate following PICU admission. CONCLUSION: Sepsis identified as the single prognostic factor associated with decreased survival. Therefore, efforts to optimize early identification and management of sepsis in the high-acuity setting of pediatric HSCT is warranted

Physical activity counseling during and following stem cell transplantation – patients' versus advisors' perspectives

ABSTRACT Background People receiving hematopoietic stem cell transplantation (HSCT) endure long phases of therapy and immobility, which diminish their physical activity (PA) level leading to physical deconditioning. One of the reasons is a lack of clarity on the part of those who work in oncology clinical settings of their role in assessing, advising, and referring patients to exercise. Therefore, our study investigates reported physical activity counseling behavior of health care professionals (HCPs) and the patient perspective on this topic. Methods Physicians (N = 52), nurses (N = 52) physical therapists (N = 26), and patients receiving HSCT (N = 62) participated in a nationwide cross-sectional online-survey. Patients‘ preferred source of information concerning PA was determined. We examined HCPs self-assessed PA counseling behavior and patients‘ PA recall by assessing the use of the 5As (Ask, Advice, Agree, Assist, Arrange). Analysis of survey responses was descriptive. Univariate multinomial logistic regression examined whether sociodemographic factors and patient characteristics influence the response behavior. Results Physicians and PA specialists were patients‘ preferred source of information regarding PA. A large discrepancy between HCPs’ perception and the degree to which HSCT patients recall advice became apparent; profound counseling steps like making referrals were less often recalled in our patient sample. Inactive patients reported to receive less basic PA counseling by physicians. Conclusion Future research should identify the requirements to increase patients’ recall concerning PA counseling in the setting of HSCT. Important messages about PA need to be made more salient to those who are less active and less engaged.

Increased incidence of hematologic malignancies in SCD after HCT in adults with graft failure and mixed chimerism

Lawal et al report on a 45-fold increase in secondary hematologic malignancy in 120 patients following hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD), comparable to what has been reported following gene therapy. Notably, the cohort is enriched for older patients and for haploidentical transplant recipients with mixed chimerism following HSCT. These data further support the idea that pre-existing premalignant myeloid clones undergo clonal selection in the setting of nonmyeloablative HSCT and contribute to secondary malignancy.

Health care professionals’ understanding of contraindications for physical activity advice in the setting of stem cell transplantation

PurposeMost patients receiving a hematopoietic stem cell transplantation (HSCT) are able to tolerate and benefit from physical activity (PA). Therefore, it is important that health care professionals (HCPs) advise patients to perform PA before, during, and after transplantation. By understanding which medical conditions and safety issues are associated with the (non-) promotion of PA, concrete actions and interventions can be planned and implemented.MethodsPhysicians (N = 51), nurses (N = 52), and physical therapists (N = 26) participated in a nationwide cross-sectional online survey. HCPs’ understanding of 15 medical conditions as contraindications for PA was assessed. Significant group differences were determined using chi-square analysis.ResultsAcute infection was the only condition which was considered as contraindication by all HCPs (62.7%). Cachexia (78%), having a stoma (91%), or port (96.2%), psychological problems (88.4%), and leukopenia (83.3%) were not considered as contraindications. Six conditions were rated inconsistently between the groups, whereas physicians had the least concerns regarding PA. Physicians with an additional training in PA perceived a platelet count of ≤ 50,000/μl significantly less often as contraindication (p < 0.05).ConclusionThe large number of potentially-answers especially in nursing staff and physical therapists might reflect caution or uncertainty. There is a clear need for a good multidisciplinary cooperation between all HCPs in order to support patients to confidently engage in PA. Furthermore, education possibilities and evidence-based courses to build knowledge regarding safety concerns should be the standard practice in the setting of HSCT. The investigative nature of the paper indicates that certain trends should be interrogated in a causal-longitudinal design.

Biodiversity screening of gut microbiome during the allogeneic hematopoietic stem cell transplantation: data from the real-life clinical practice

Biodiversity of a gut microbiome has been shown as an important predictor of transplant-related outcomes and infections in allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center real-life clinical study and implemented a routine gut microbiome diversity monitoring across the course of allogeneic HSCT. Twelve patients (with ALL, AML, CML, biphenotypic leukemia and aplastic anemia) were enrolled in a stool samples collection protocol before the start of HSCT and during a 30-day post-transplant period. We have shown the feasibility of a gut microbiome monitoring in a real-life clinical setting and have proven that the alpha-biodiversity of the microbiome is significantly reduced with HSCT in comparison with the individual patient baseline level (Xdc 72.93; p < 0.001; multivariate Dirichlet analysis), what may be related to the antibiotic use and conditioning regimen. Overall, the gut microbiome biodiversity monitoring may be clinically used in a real-life HSCT setting to identify the high-risk groups for developing bloodstream infections and transplant-related negative outcomes.

Febrile Neutropenia Duration Is Associated with the Severity of Gut Microbiota Dysbiosis in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Simple SummaryFebrile neutropenia is a common complication in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation. Its genesis is often attributed to infections; however, a specific cause frequently cannot be defined. We hypothesize that the composition of the intestinal flora may contribute to the genesis of the neutropenic fever. We analyzed the microbial composition of stool samples from pediatric patients from three European centers and assessed the relationship with the duration of the fever during neutropenia. We found that a more stable composition of the microbiota during the transplantation course is associated with a shorter duration of fever. Moreover, patients with a higher duration of fever presented higher levels of Collinsella, Megasphaera, Prevotella, Roseburia, Eggerthella and Akkermansia in the stool.Febrile neutropenia (FN) is a common complication in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Frequently, a precise cause cannot be identified, and many factors can contribute to its genesis. Gut microbiota (GM) has been recently linked to many transplant-related complications, and may also play a role in the pathogenesis of FN. Here, we conducted a longitudinal study in pediatric patients receiving HSCT from three centers in Europe profiling their GM during the transplant course, particularly at FN onset. We found that a more stable GM configuration over time is associated with a shorter duration of fever. Moreover, patients with longer lasting fever exhibited higher pre-HSCT levels of Collinsella, Megasphaera, Prevotella and Roseburia and increased proportions of Eggerthella and Akkermansia at the engraftment. These results suggest a possible association of the GM with the genesis and course of FN. Data seem consistent with previous reports on the relationship of a so-called “healthy” GM and the reduction of transplant complications. To our knowledge, this is the first report in the pediatric HSCT setting. Future studies are warranted to define the underling biological mechanisms and possible clinical implications.

VOD/SOS and Alkylating Agents in the Hematopoietic Stem Cell Transplant Setting: New Insights and Further Questions

VOD/SOS and Alkylating Agents in the Hematopoietic Stem Cell Transplant Setting: New Insights and Further Questions

Post‐hematopoietic stem cell transplantation relapse: Role of checkpoint inhibitors

Background and AimsDespite the revolutionary effects of hematopoietic stem cell transplantation (HSCT) in treating hematological malignancies, post‐HSCT relapse is considered a critical concern of clinicians. Residual malignant cells employ many mechanisms to evade immune surveillance and survive to cause relapse after transplantation. One of the immune‐frustrating mechanisms through which malignant cells can compromise the antitumor effects is misusing the self‐limiting system of immune response by overexpressing inhibitory molecules to interact with the immune cells, leading them to so‐called “exhausted” and ineffective. Introduction of these molecules, known as immune checkpoints, and blocking them was a prodigious step to decrease the relapses.MethodsUsing keywords nivolumab, pembrolizumab, and ipilimumab, we investigated the literature to figure out the role of the immune checkpoints in the HSCT setting. Studies in which these agents were administrated for relapse after transplantation were reviewed. Factors such as the interval from the transplant to relapse, previous treatment history, adverse events, and the patients’ outcome were extracted.ResultsHere we provided a mini‐review discussing the experiences of three immune checkpoints, including nivolumab, pembrolizumab, and ipilimumab, as well as the pros and cons of using their blockers in relapse control after HSCT. In conclusion, it seems that CI therapy seems effective for this population. Future investigations may provide detailed outlook of this curative options.

512 - We’re in This Together: Health-Related Quality of Life, Self-Preparedness, and Caregiver Burden in Patient/ Primary Caregiver Dyads in the Hematopoietic Stem Cell Transplantation Setting

512 - We’re in This Together: Health-Related Quality of Life, Self-Preparedness, and Caregiver Burden in Patient/ Primary Caregiver Dyads in the Hematopoietic Stem Cell Transplantation Setting

Impact of Donor-to-Recipient ABO Mismatch on Outcomes of Antithymocyte Globulin-Based Peripheral Blood Stem Cell-Derived Myeloablative Conditioning Haploidentical Stem Cell Transplantation

ABO incompatibility is common in hematopoietic stem cell transplantation (HSCT); however, the impact of donor-recipient ABO compatibility on transplantation outcomes in different HSCT settings is controversial. Moreover, haploidentical stem cell transplantation (haplo-SCT) with peripheral blood stem cell (PBSC)-derived grafts has not been well investigated. The present study aimed to investigate the impact of ABO incompatibility on post-transplantation outcomes, engraftment kinetics, blood product requirements, transfusion independence, and the incidence of poor graft function (PGF) in antithymocyte globulin (ATG)-based haplo-SCT with PBSC grafts during long-term follow-up. We prospectively evaluated 510 patients with hematologic malignancies who underwent haplo-SCT after myeloablative conditioning (MAC). The primary endpoint was overall survival (OS), and secondary endpoints were nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, neutrophil and platelet engraftment, blood transfusion requirements, transfusion independence, and the incidence of PGF. There was no significant association between ABO matching and OS, disease-free survival (DFS), relapse, NRM, grade II-IV acute GVHD, grade III-IV acute GVHD, and moderate and severe chronic GVHD. There were also no significant differences in neutrophil and platelet engraftment, blood transfusion independence, and transfusion requirements at 30, 60, 90, 180, and 365 days post-transplantation among patients with ABO matching and those with minor, major, or bidirectional ABO incompatibility. Donor-recipient ABO matching did not differ significantly according to graft function (good versus poor). ABO incompatibility status has no major impact on patient outcomes in patients with hematologic malignancies undergoing ATG-based MAC haplo-SCT with PBSC-derived grafts.

A potential implication of UDP-glucuronosyltransferase 2B10 in the detoxification of drugs used in pediatric hematopoietic stem cell transplantation setting: an in silico investigation

BackgroundSinusoidal occlusion syndrome (SOS) is a potentially severe complication following hematopoietic stem cell transplantation (HSCT) in pediatric patients. Treatment related risk factors such as intensity of conditioning, hepatotoxic co-medication and patient related factors such as genetic variants predispose individuals to develop SOS. The variant allele for SNP rs17146905 in UDP-glucuronosyl transferase 2B10 (UGT2B10) gene was correlated with the occurrence of SOS in an exome-wide association study. UGT2B10 is a phase II drug metabolizing enzyme involved in the N-glucuronidation of tertiary amine containing drugs.MethodsTo shed light on the functionality of UGT2B10 enzyme in the metabolism of drugs used in pediatric HSCT setting, we performed in silico screening against custom based library of putative ligands. First, a list of potential substrates for in silico analysis was prepared using a systematic consensus-based strategy. The list comprised of drugs and their metabolites used in pediatric HSCT setting. The three-dimensional structure of UGT2B10 was not available from the Research Collaboratory Structural Bioinformatics - Protein Data Bank (RCSB - PDB) repository and thus we predicted the first human UGT2B10 3D model by using multiple template homology modeling with MODELLER Version 9.2 and molecular docking calculations with AutoDock Vina Version 1.2 were implemented to quantify the estimated binding affinity between selected putative substrates or ligands and UGT2B10. Finally, we performed molecular dynamics simulations using GROMACS Version 5.1.4 to confirm the potential UGT2B10 ligands prioritized after molecular docking (exhibiting negative free binding energy).ResultsFour potential ligands for UGT2B10 namely acetaminophen, lorazepam, mycophenolic acid and voriconazole n-oxide intermediate were identified. Other metabolites of voriconazole satisfied the criteria of being possible ligands of UGT2B10. Except for bilirubin and 4-Hydroxy Voriconazole, all the ligands (particularly voriconazole and hydroxy voriconazole) are oriented in substrate binding site close to the co-factor UDP (mean ± SD; 0.72 ± 0.33 nm). Further in vitro screening of the putative ligands prioritized by in silico pipeline is warranted to understand the nature of the ligands either as inhibitors or substrates of UGT2B10.ConclusionsThese results may indicate the clinical and pharmacological relevance UGT2B10 in pediatric HSCT setting. With this systematic computational methodology, we provide a rational-, time-, and cost-effective way to identify and prioritize the interesting putative substrates or inhibitors of UGT2B10 for further testing in in vitro experiments.

Nurses' Physical and Psychological Symptoms During the first COVID-19 Lockdown in Italy: a Nationwide Cross-Sectional Study in Stem Cell Transplantation Setting.

Background and objectiveNorthern Italy was one of the first European territories to deal with the Coronavirus Disease 2019 (COVID-19) outbreak. Drastic emergency restrictions were introduced to contain the spread and limit pressure on healthcare facilities. However, nurses were at high risk of developing physical, mental, and working issues due to professional exposure. The aim of this cross-sectional study was to investigate these issues among nurses working in Italian hematopoietic stem cell transplant (HSCT) centers during the COVID-19 pandemic.MethodsData were collected online immediately after the first "lockdown" period in order to investigate the prevalence of physical issues, sleep disorders, and burnout symptoms and explore correlations with COVID-19 territorial incidence in Northern Italian regions versus Central and Southern Italian regions.ResultsThree hundred and eight nurses working in 61 Italian HSCT Units responded to the survey. Depression, cough, and fever were more frequently reported by nurses working in geographical areas less affected by the pandemic (p=0.0013, p<0.0001, and p=0.0005 respectively) as well as worst sleep quality (p=0.008). Moderate levels of emotional exhaustion (mean±SD −17.4±13.0), depersonalization (5.3±6.1), and personal accomplishment (33.2±10.7) were reported without significant differences between territories.Conclusionsdifferent COVID-19 incidence among territories did not influence nurses' burden of symptoms in the HSCT setting. However, burnout and insomnia levels should be considered by health care facilities in order to improve preventive strategies.

Investigation of oral and general health status and IL-1β gene polymorphism as risk factors for oral mucositis in hematopoietic stem cell transplantation patients.

The aim of the present study was to analyze the relationship of OM with possible risk factors such as oral health condition, immunological status and IL-1β profile in patients submitted to hematopoietic stem cell transplantation (HSCT). Fifty-four individuals submitted to HSCT were included. All patients received previous dental treatment and photobiomodulation (PBM) as the institutional OM preventive protocol. OM scores, immune status, and IL-1β levels were determined during the conditioning period and at D+3 and D+8 after HSC infusion. IL-1β gene polymorphism was also analyzed during conditioning. Possible associations of OM with risk factors were analyzed using conditional Fisher's exact test. OM was observed in 34 patients (62.9%) classified as Grade 1 (13 patients/24.1%), Grade 2 (14 patients/25.9%), Grade 3 (3 patients/5.5%), and Grade 4 (4 patients/7.4%). Allogeneic HSCT individuals exhibited a higher OM grade than autologous subjects. Moreover, an association was observed between severe OM and severe gingivitis (p = 0.01), neutropenia (p = 0.03), and leukopenia (p = 0.04). A significant association between OM and lower IL-1β levels was detected at three time points, i.e., conditioning (p = 0.048), D+3 (p = 0.01), and D+8 (p = 0.005). The results showed that IL-1β gene polymorphism was not associated with OM. Our study provided important insights into the scope of OM risk factors in the setting of HSCT. Patients submitted to HSCT with severe gingivitis prior to chemotherapy and with severe neutropenia and leukopenia exhibited a higher OM grade. Further investigation will be necessary to better understand the exact role of IL-1β in the context of OM pathobiology and to validate cytokine analysis in larger cohorts.

Impact of donor-specific anti-human leukocyte antigen antibodies in haploidentical hematopoietic stem-cell transplantation: A single-center retrospective study

Introduction: While donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have been implicated in graft rejection in solid organ transplantation, their role in hematopoietic stem-cell transplantation (HSCT) remains unclear. Aim: The aim of this study is to study the role of DSA for proper donor selection and its effect in the setting of allogeneic HSCT. Methodology: HLA A, B, C, DRB1, and DQB1 high-resolution typing, and DSA cross match (XM) of patients (n = 73) and their prospective donors (n = 74) were assessed. A case–control study was designed retrospectively to evaluate the effect of pre- existing DSAs on engraftment. Thirty-five cases with 5/10 HLA alleles mismatches and 38 cases with full HLA matched, these two controls were selected for comparison. These were matched for disease, graft type, conditioning regimen, age, gender, blood group, and sensitizing events. DSAs were tested with solid-phase assay (Luminex 100/200 platform). Results: DSAs were detected in six of 35 patients (17%); however, donors selected for transplantation were all negative for DSA crossmatch. These six patients who underwent haploidentical (HI) transplants had antibodies against Class I and II. One patient carried antibodies against both classes. A patient who experienced primary graft failure had a second HI transplant. No other known factors that could negatively influence engraftment were associated with the development of graft failure in this patient. Conclusions: DSAs are not associated with graft rejection in patients undergoing HI stem-cell transplantation. Anti-HLA sensitization should be evaluated routinely in HSCT with HLA mismatched donors for a better outcome.

Incidence of Post-Transplant Lymphoproliferative Disease: A Systematic Literature Review

Introduction: Post-transplant lymphoproliferative disease (PTLD) is an ultra-rare lymphoma following allogeneic hematopoietic stem cell transplant (HCT) or solid organ transplant (SOT). Incidence of PTLD varies over time after transplant with majority of cases occurring within the first year (yr) after HCT (Garcia-Cadenas, Eur J Haematol. 2019). In the SOT setting, PTLD can occur up to 30 yrs post-transplant and is largely dependent on the transplanted organ, the type and degree of immunosuppression, and transplant recipient characteristics (Dierickx, N Eng J Med. 2018; Trappe, J Clin Oncol. 2017). Published literature reports wide ranges of epidemiological estimates due to variation in the follow-up time, transplant type and sample size. We conducted a systematic literature review (SLR) to summarize the incidence of PTLD to better understand the reasons for such variation.Methods: A SLR on the burden of PTLD was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes and Study design (PICOS) criteria. Pertinent literature on epidemiology of PTLD published between January 2010 to February 2020 and relevant conference abstracts published between January 2018 to February 2020 were identified. Comprehensive literature searches were performed using the Ovid platform to identify articles indexed in PubMed, Embase, PsycINFO, and the National Health Service Economic Evaluation Database. Study designs were limited to population/registry-based studies, observational cohort studies (prospective/retrospective), and cross-sectional studies. Studies reporting incidence of PTLD were limited to those with at least 1000 total transplant recipients. All titles and abstracts were reviewed by two independent researchers with any discrepancies resolved by a third researcher. Incidence estimates were calculated by data extractors when it was not directly reported in the literature.Results: A total of 177 studies reporting epidemiological data on PTLD were identified using pre-specified SLR criteria. Most of the studies (n=150) were retrospective in design. Incidence was reported in 114 studies. Majority of the studies reported cumulative incidence (CI) over specified times such as 5-yr or 10-yr incidence or proportion of patients (pts) with PTLD out of a sample of transplanted pts. In the HCT setting, only CI was reported; twelve studies reported CI ranging from 0.1% among 15094 pts receiving autologous HCT over a 19-yr period to 4% in a cohort of 1021 pts receiving allogeneic HCT over a 16-yr period. A total of 100 studies reported incidence of PTLD in SOT pts which was highly influenced by the study population, EBV status at the time of transplant and follow-up time. Of these, 12 reported incidence rates ranging from 24 EBV negative PTLD cases per 100,000 person-years (PY) within 1-5 yrs post-transplant to 3460 PTLD cases per 100,000 PY at 20 yrs post-transplant. Eighty studies reported CI, 19 of which reported CI for various timepoints. In a group of 23171 heart transplant pts CI was 1% during a median follow-up of 4.3 yrs, while in a subgroup of four pediatric multi-organ transplant recipients followed from 2003 to 2011 CI was 25%. Across studies, CI at 1-yr post-transplant ranged from 0.1% to 4.9% and 5-yr CI ranged from 0.7% to 12.1% in select group of transplant pts. Twenty-four studies reported CI by transplant organ type ranging from 0.2% in kidney transplant pts within the first year to 12.1% in lung transplant pts over 7.5 yrs, with higher estimates reported in studies with smaller sample sizes.Conclusions: Our SLR shows large variation in the reported incidence of PTLD due to heterogeneity in the methodology and the study populations in both HCT and SOT settings. Published literature lacks the granularity to correctly interpret the incidence of PTLD in the general transplant population. Thus, additional methods and data considerations such as population type (HCT/SOT transplants, adult/pediatric pts, etc.), representativeness (single institutional data/multi-center/country level registry), unit of measurement of risk (CI/incidence rate, etc.), type of study (retrospective/prospective), length of follow-up, sample size, trends in transplant and treatment landscape over time are needed to ensure accuracy in the estimation of incidence of PTLD. DisclosuresThirumalai: Atara Biotherapeutics: Current Employment. Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Xun: Atara Biotherapeutics: Current Employment. Sadetsky: Atara Biotherapeutics: Current Employment. Schaible: Evidera: Current Employment. Barlev: Atara Biotherapeutics: Current Employment.

Post-Transplant Cyclophosphamide in Acute Leukemia Patients Receiving More Than 5/10 HLA-Mismatched Allogeneic Stem Cell Transplantation: A Study on Behalf of the ALWP of the EBMT

BackgroundPost-transplant cyclophosphamide (PTCy) is a powerful strategy to prevent occurrence of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Initially developed in the setting of haploidentical HSCT, PTCy has been increasingly used for fully HLA-matched transplants with favorable results.The purpose of this retrospective multi-center study is to evaluate PTCy-based GvHD prevention for patients with acute leukemia receiving a traditionally prohibitive highly mismatched HSCT and to describe their outcome.MethodsThis is a registry-based study employing the data set of the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT). We retrospectively assessed the outcome of adult patients with acute myeloid or lymphoblastic leukemia (AML/ALL), transplanted between 2010 and 2020 with grafts from HLA-mismatched donors with more than 5/10 mismatches using PTCy-based GvHD prophylaxis.ResultsThe study cohort consisted of 59 patients, with a median time of follow up of 20 (95% CI, 14-39) months. The median age was 47 (range, 18-69) years. Forty-four patients had a diagnosis of AML, 14 of ALL and one case of mixed phenotype acute leukemia. At time of transplant, 39 (66%) were in first or second complete remission, 4 (7%) were in later remission and 16 (27%) had active, relapsed or refractory, disease. Conditioning regimens were myeloablative for 54% of cases and peripheral blood was the preferred source of stem cells (64%). All donors were related. Most patients (85%) received a 4/10 HLA-matched transplant, the most commonly mismatched loci were C and DQB1, often with a double mismatch involving the same locus. Two cases of fully mismatched donors were also recorded.PTCy was always associated with other immunosuppressive treatments, especially with the standard combination of calcineurin inhibitors and mycophenolate mofetil. In only 8 cases in vivo T-cell depletion was realized with anti-thymocyte globulin.A large proportion of patients (86%) attained engraftment with a median time of 19 (range, 11-37) days. Only 8 patients did not reach engraftment and all of them died of infection or disease relapse in the first one-hundred days (range, 6-99) after HSCT.Thirty-three patients (58%) did not present any sign of acute GvHD (aGvHD). Cumulative incidence of grade II-IV and grade III-IV aGvHD at day 180 were 30.3% and 14.3%, respectively. At 2 years, the cumulative incidence of chronic GvHD (cGvHD) was 21%, and 7% for extensive cGvHD.Twenty-four patients died during the study period, mostly because of leukemia progression (n=13, 54%), infectious complications (n=6, 25%) and interstitial pneumonia (n=2, 8%). Other causes of death were hemorrhage, GvHD, and another non HSCT-related that accounted for one case (4%) each. At 2 years, the overall survival (OS), leukemia-free survival (LFS), and a GVHD and relapse free survival (GRFS) were 56%, 54% and 47% respectively. Rates of relapse incidence and non-relapse mortality were 28% and 19%, respectively.ConclusionAccording to this preliminary data overview, transplantation in a highly mismatched framework is possible, without unfavorable OS, LFS and GVHD rates. Despite the important limitation of the retrospective non-controlled nature of this analysis, these findings suggest that PTCy-based strategies could help overcome the barrier of HLA-matching and configure a new setting of transplantation, encouraging more in-depth investigations. [Display omitted] DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Gilead: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Astellas: Honoraria.

COVID-19 Infection of HSCT Recipients Is Associated with High Mortality but No Detectable Cytokine Storm at Presentation

IntroductionThe clinical manifestations of COVID-19 infection in recipients of allogeneic hematopoietic stem cell transplantation (HSCT) have been reported in multiple retrospective cohorts of patients, but there have been no prospective studies to date. Previous studies report that HSCT recipients are at higher risk, with cumulative incidence of death between 17-35%. Although an excessive pro-inflammatory viral response has been documented in the general population, its role in the immune incompetent HSCT setting has not been documented.We present a combined prospective and retrospective national study run through the UK IMPACT trial network to characterize the clinical and immunological features of COVID-19 infection in 96 adult and pediatric recipients of HSCT in the United Kingdom.MethodsHSCT recipients of any age and transplanted for any indication, with an RT-PCR-proven COVID-19 infection, were eligible for this study. Patients within 72 hours of COVID-19 diagnosis, who had not received cytokine-targeted treatment, were recruited to a prospective cohort. All other patients were eligible for a retrospective cohort. Prospective patients provided blood samples within 72 hours of COVID-19 diagnosis, and again within 72 hours of clinical deterioration (defined as requirement for oxygen administration) if applicable. Follow-up data were collected on patients 30 and 100 days after COVID-19 diagnosis.Results100 patients were recruited from 16 sites across the UK between May 2020-June 2021, comprising 12 in a prospective cohort and 88 recruited retrospectively. 96 patients were evaluable, as 4 proved ineligible post-registration. Patients were diagnosed with COVID-19 at a median of 11 months after HSCT. Patient/HSCT characteristics are shown Table 1.The most common symptoms associated with the onset of COVID-19 were fever in 8 prospective (73%) and 35 (41%) retrospective patients, followed by cough in 5 (45%) prospective and 35 (41%) retrospective patients and dyspnea in 4 (36%) prospective and 16 (19%) retrospective patients. 8 (73%) prospective and 40 (47%) retrospective patients were actively immunosuppressed at the time of COVID-19 infection. 16% of the patients had moderate/severe disease at baseline.At day 30 (±2 days) after COVID-19 diagnosis, 2 prospective and 8 retrospective patients continued to demonstrate SARS-CoV-2 positivity on respiratory PCR testing. The median time to viral clearance was 40 (IQR 17-78) days for the prospective and 34 (IQR 15-70) days for the retrospective cohort.Prolonged (more than 14 days) neutropenia was reported in 4 (5%) patients in the retrospective cohort, prolonged thrombocytopenia in 2 (18%) prospective and 11 (13%) retrospective patients. 1 retrospective patient developed secondary hemophagocytic lymphohistiocytosis, and graft rejection was reported in 1 (1%) retrospective patient, within 30 days of COVID-19 diagnosis.In the prospective cohort, 3 (27%) patients died, all by day 30, and all due to COVID-19. In the retrospective cohort, 13 (17%) patients died by day 30, rising to 18 (21%) by day 100, 61% of deaths were attributed to COVID-19.Lower baseline platelets (p=0.013, Mann-Whitney U test), lymphocytes (p=0.012), albumin (p=0.028), and higher baseline CRP (p=0.007), were seen in patients who died following COVID-19 diagnosis. Additionally, exploratory univariate logistic regression of the retrospective cohort found mortality at day 100 to be associated with increased age at diagnosis (OR 1.04, 95% CI 1.01-1.08, p=0.04), and no requirement compared with requirement for invasive ventilation (OR 0.02, 95% CI 0.00-0.16, p=0.001).The 11 prospective patients showed normal levels of interleukin (IL)-2, -4, -10, interferon gamma and tumor necrosis factor alpha at COVID-19 presentation. IL-6 was minimally raised (up to 127 pg/ml, nv<50) in 3/11 pts at presentation. Respiratory deterioration was not associated with detectable cytokine storm.ConclusionOur study confirms a significant mortality rate in patients affected by COVID-19 post HSCT and confirms age as well as requirement for invasive ventilation to be independent risk factors associated with death at day 100.Baseline laboratory data at disease presentation can identify patients at higher risk of COVID-19 related death.In the prospective cohort of our study, pathophysiology of the viral disease did not seem related to cytokine storm-mediated inflammation. [Display omitted] DisclosuresProtheroe: Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Kite Gilead: Honoraria. Peggs: Autolus: Consultancy, Current equity holder in publicly-traded company. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicholson: BMS/Celgene: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; Pfizer: Consultancy. Amrolia: ADC Therapeutics: Other: Named inventor on a patent which is being transferred to ADCT.; Autolus: Patents & Royalties.