Nonmyeloablative Conditioning Research Articles

Non-myeloablative allogeneic blood or marrow transplantation (AlloBMT) with post-transplant cyclophosphamide (PTCy) for peripheral T-cell lymphoma (PTCL): Improved outcomes with peripheral blood (PB) allografts and increased total body irradiation (TBI) to 400 cGV.

7047 Background: The use of PTCy for graft-versus host-disease (GVHD) prophylaxis has revolutionized alloBMT, but there is limited published experience in PTCL. Methods: All patients with PTCL who received a non-myeloablative alloBMT using PTCy-based GVHD prophylaxis between January 2004 and December 2020 at Johns Hopkins Hospital were analyzed. Standard population statistics were used. Results: Sixty-five patients were identified. The median age was 59 years (range, 24-75 years). Lymphoma histology included PTCL-not otherwise specified (n=24), ALK-negative anaplastic large cell lymphoma (n=14), angioimmunoblastic T-cell lymphoma (n=7), enteropathy-associated T-cell lymphoma (n=6), hepatosplenic T-cell lymphoma (n=4), and other (n=10). Eleven patients were in first complete remission (CR1, 17%). The remaining patients were in first partial remission (PR1) or underwent salvage therapy to at least PR prior to transplant. Forty-eight patients received an alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (mMUD, 11%). All patients received non-myeloablative conditioning with fludarabine, cyclophosphamide, and TBI. The graft source was bone marrow (BM) in the first 46 patients (71%). Because of relatively high relapse rates, in 2018 we began using PB and increased TBI from 200 to 400 cGy; the remaining 19 patients (29%) received this regimen. GVHD prophylaxis was PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow up of 2.8 years, the 3-year progression-free survival (PFS) for the entire cohort was 39% (95% confidence interval [CI] 28-54%), and the 3-year overall survival (OS) was 43% (95% CI 31-58%). The cumulative incidence (CuI) of relapse and non-relapse mortality (NRM) at 1 year was 25% (95% CI 14-35%) and 12% (95% CI 4-20%), respectively. Among 29 cases of GVHD (45%), 2 were grade 3-4 acute GVHD (3%) and 3 were severe chronic GVHD (5%). Univariate analysis including age, histology, mMUD, PB/400cGy, and CR1 revealed only PB/400 cGy TBI as a significant predictor of survival, relapse, or NRM. Outcomes by source. Conclusions: AlloBMT with non-myeloablative conditioning and PTCy is safe and well-tolerated in patients with PTCL. Our preliminary data suggest increasing TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings. [Table: see text]

Long-Term Health Effects of Curative Therapies on Heart, Lungs, and Kidneys for Individuals with Sickle Cell Disease Compared to Those with Hematologic Malignancies.

The goal of curing children and adults with sickle cell disease (SCD) is to maximize benefits and minimize intermediate and long-term adverse outcomes so that individuals can live an average life span with a high quality of life. While greater than 2000 individuals with SCD have been treated with curative therapy, systematic studies have not been performed to evaluate the long-term health effects of hematopoietic stem cell transplant (HSCT) in this population. Individuals with SCD suffer progressive heart, lung, and kidney disease prior to curative therapy. In adults, these sequalae are associated with earlier death. In comparison, individuals who undergo HSCT for cancer are heavily pretreated with chemotherapy, resulting in potential acute and chronic heart, lung, and kidney disease. The long-term health effects on the heart, lung, and kidney for children and adults undergoing HSCT for cancer have been extensively investigated. These studies provide the best available data to extrapolate the possible late health effects after curative therapy for SCD. Future research is needed to evaluate whether HSCT abates, stabilizes, or exacerbates heart, lung, kidney, and other diseases in children and adults with SCD receiving myeloablative and non-myeloablative conditioning regimens for curative therapy.

Durable discontinuation of systemic therapy in patients affected by chronic graft-versus-host disease.

Successful treatment of chronic graft-versus-host disease (GvHD) often requires long-term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GvHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from two prospectively followed cohorts from the Chronic GvHD Consortium (n=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half of the patients received non-myeloablative conditioning. The median time from transplantation to chronic GvHD diagnosis was 7.7 months (range, 1.0-141.3) and the median time from chronic GvHD onset to enrollment into the cohorts was 0.9 months (range, 0.0-12.0). The cumulative incidence estimate of durable ST discontinuation was 32% (95% confidence interval: 28%-37%) at 10 years after enrollment into the cohort. Among patients who discontinued ST, the median time from chronic GvHD diagnosis to durable ST discontinuation was 3.6 years (range, 1.2-10.5). In multivariate analysis, patients who received myeloablative conditioning, had chronic GvHD manifested as moderate/severe lower gastrointestinal involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower gastrointestinal involvement and cord blood (vs. peripheral blood) as the graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue ST permanently, most patients require prolonged ST. Viewing chronic GvHD in this way has implications for management approaches.

Fertility after Curative Therapy for Sickle Cell Disease: A Comprehensive Review to Guide Care.

Curative therapy for sickle cell disease (SCD) currently requires gonadotoxic conditioning that can impair future fertility. Fertility outcomes after curative therapy are likely affected by pre-transplant ovarian reserve or semen analysis parameters that may already be abnormal from SCD-related damage or hydroxyurea treatment. Outcomes are also likely affected by the conditioning regimen. Conditioning with myeloablative busulfan and cyclophosphamide causes serious gonadotoxicity particularly among post-pubertal females. Reduced-intensity and non-myeloablative conditioning may be acutely less gonadotoxic, but more short and long-term fertility outcome data after these approaches is needed. Fertility preservation including oocyte/embryo, ovarian tissue, sperm, and experimental testicular tissue cryopreservation should be offered to patients with SCD pursing curative therapy. Regardless of HSCT outcome, longitudinal post-HSCT fertility care is required.

Successful Use of Anti-IL-6R Therapy to Achieve Cardiac Allograft Tolerance in Non-Human Primates

<h3>Purpose</h3> In contrast to kidney allografts, attempts to achieve tolerance of isolated cardiac allografts in non-human primates (NHPs) using a mixed chimerism strategy have been unsuccessful. IL-6 is a pro-inflammatory cytokine known to play an important role in allograft rejection. We investigated whether adding anti-IL-6R therapy to our mixed chimerism protocol would enable the induction of tolerance in NHP recipients of MHC mismatched heart allografts. <h3>Methods</h3> Ten cynomolgous NHPs underwent heart and bone marrow transplantation (BMTx) with non-myeloablative conditioning including total body and thymic irradiation, ATGAM, anti-CD154 mAb, and cyclosporine until post-operative day (POD) 28, with or without anti-IL-6R therapy (tocilizumab, 10 mg/kg IV on POD 0, 7, 14, 21, 28, 56, 84). Group A (n=2) received allogeneic BMTx without anti-IL-6R therapy, Group B (n=6) received allogeneic BMTx with anti-IL-6R therapy, and Group C (n=2) received autologous BMTx with anti-IL-6R therapy. <h3>Results</h3> In Group A, both recipients experienced allograft failure due to rejection on POD 104 and 132 [Table]. In Group B, 3 recipients achieved long-term cardiac allograft survival of >400 days off immunosuppression; one recipient is ongoing at POD 360. Two rejected on POD 169 and 383. For Groups A and B, peak lymphocyte chimerism was 10.1% and 18.1%, respectively and duration of lymphocyte chimerism was 57 and 178 days, respectively. In Group C, one recipient rejected on POD 131 and one is ongoing at POD 120. There was no significant difference in magnitude of peripheral T_reg expansion between groups (p=0.77). Compared to Group A, Groups B and C had lower CRP levels (mean 12.3 vs 54.3 μg/mL) and higher free serum IL-6 (mean 23.0 vs <7.7 pg/mL) while receiving anti-IL-6R therapy. <h3>Conclusion</h3> Tolerance of cardiac allografts has been achieved for the first time in NHPs using a combination of IL-6 signaling blockade and mixed chimerism. This approach represents significant progress towards clinical cardiac allograft tolerance.

Noninfectious Pulmonary Toxicity after Allogeneic Hematopoietic Cell Transplantation

Noninfectious pulmonary toxicity (NPT), a significant complication of allogeneic hematopoietic cell transplantation (alloHCT), includes idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH), and cryptogenic organizing pneumonia (COP), with an overall incidence ranging from 1% to 15% in different case series and a variable mortality rate. A registry study of the epidemiology and outcomes of NPT after alloHCT has not been conducted to date. The primary objective of the present study was to assess the incidence of and risk factors for IPS, DAH, and COP; the secondary objective was to assess overall survival (OS) in patients developing NPT. This retrospective study included adult patients who underwent alloHCT between 2008 and 2017 and reported to the Center for International Blood and Marrow Transplant Research. Multivariable Cox proportional hazards regression models were developed to identify the risk factors for development of NPT and for OS, by including pretransplantation clinical variables and time-dependent variables of neutrophil and platelet recovery, and acute graft-versus-host disease (GVHD) post-transplantation. This study included 21,574 adult patients, with a median age of 55 years. According to the HCT Comorbidity Index (HCT-CI), 24% of the patients had moderate pulmonary comorbidity and 15% had severe pulmonary comorbidity. The cumulative incidence of NPT at 1 year was 8.1% (95% confidence interval [CI], 7.7% to 8.5%). Individually, the 1-year cumulative incidences of IPS, DAH, and COP were 4.9% (95% CI, 4.7% to 5.2%), 2.1% (95% CI, 1.9% to 2.3%), and .7% (95% CI, .6% to .8%), respectively. Multivariable analysis showed that severe pulmonary comorbidity, grade II-IV acute GVHD, mismatched unrelated donor and cord blood transplantation, and HCT-CI score ≥1 significantly increased the risk of NPT. In contrast, alloHCT performed in 2014 or later, non-total body irradiation (TBI)- and TBI-based nonmyeloablative conditioning and platelet recovery were associated with a decreased risk. In a landmark analysis at day+100 post-transplantation, the risk of DAH was significantly lower in patients who had platelet recovery by day +100. Multivariable analysis for OS demonstrated that NPT significantly increased the mortality risk (hazard ratio, 4.2; P < .0001).

464 - High Resolution KIR in Non-Myeloablative Conditioning Regimen for Hematologic Neoplasms

464 - High Resolution KIR in Non-Myeloablative Conditioning Regimen for Hematologic Neoplasms

The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort.

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort’s experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.

Chimerism-Based Tolerance to Kidney Allografts in Humans: Novel Insights and Future Perspectives

Chronic rejection and immunosuppression-related toxicity severely affect long-term outcomes of kidney transplantation. The induction of transplantation tolerance – the lack of destructive immune responses to a transplanted organ in the absence of immunosuppression – could potentially overcome these limitations. Immune tolerance to kidney allografts from living donors has been successfully achieved in humans through clinical protocols based on chimerism induction with hematopoietic cell transplantation after non-myeloablative conditioning. Notably, two of these protocols have led to immune tolerance in a significant fraction of HLA-mismatched donor-recipient combinations, which represent the large majority of cases in clinical practice. Studies in mice and large animals have been critical in dissecting tolerance mechanisms and in selecting the most promising approaches for human translation. However, there are several key differences in tolerance induction between these models and humans, including the rate of success and stability of donor chimerism, as well as the relative contribution of different mechanisms in inducing donor-specific unresponsiveness. Kidney allograft tolerance achieved through durable full-donor chimerism may be due to central deletion of graft-reactive donor T cells, even though mechanistic data from patient series are lacking. On the other hand, immune tolerance attained with transient mixed chimerism-based protocols initially relies on Treg-mediated suppression, followed by peripheral deletion of donor-reactive recipient T-cell clones under antigenic pressure from the graft. These conclusions were supported by data deriving from novel high-throughput T-cell receptor sequencing approaches that allowed tracking of alloreactive repertoires over time. In this review, we summarize the most important mechanistic studies on tolerance induction with combined kidney-bone marrow transplantation in humans, discussing open issues that still need to be addressed and focusing on techniques developed in recent years to efficiently monitor the alloresponse in tolerance trials. These cutting-edge methods will be instrumental for the development of immune tolerance protocols with improved efficacy and to identify patients amenable to safe immunosuppression withdrawal.

S105: ADDING AZATHIOPRINE/HYDROXYUREA PRECONDITIONING TO ALEMTUZUMAB/TBI CONDITIONING IMPROVES DONOR CHIMERISM IN MATCHED SIBLING DONOR STEM CELL TRANSPLANTATION IN ADULT SICKLE CELL DISEASE PATIENTS

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) has shown promising results in adult SCD patients.1,2 Patients treated with this regimen had their sickle cell phenotype corrected with only mild complications and no reports of graft-versus-host disease (GvHD). However, most of the described patients did not reach complete donor chimerism with graft failure rates of 13%. Furthermore, in almost 10% of patients, immunosuppressives could not be withdrawn because of too low T cell chimerism (<50%).2 We hypothesized that adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism, reduce the risk of graft failure and improve successful withdrawal of immunosuppressives. Aims: In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning on donor chimerism and graft failure in patients receiving non-myeloablative MSD HSCT for SCD. Methods: Adult SCD patients who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day –10, aiming for HbS <30%. Conditioning with alemtuzumab/TBI was started on day –7. Graft versus host disease (GvHD) prophylaxis consisted of sirolimus. Results: As of October 2021, 13 SCD patients (median age 30.6 (range 19–49) years) were transplanted. Twelve patients (92.3%) engrafted successfully. After a median follow-up of 24 months, median donor myeloid and T cell chimerism of engrafted patients were 100% (IQR 84–100%) and 77% (IQR 70.5%-82.5%), respectively. These donor chimerism percentages are higher than previously reported with alemtuzumab/TBI only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Patients reaching 1-year post-transplantation were able to stop sirolimus without decreases in chimerism. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI results in improved donor chimerism, potentially reducing the risk of graft failure after non-myeloablatieve MSD transplantation in SCD patients. Importantly, all engrafted patients reached donor T cell chimerism >50% at 1-year post-transplantation and were able to stop immunosuppressives as scheduled.

BK Polyomavirus Hemorrhagic Cystitis in Hematopoietic Cell Transplant Recipients.

Introduction:BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) is a well-recognized infective complication of hematopoietic cell transplant (HCT) with increased organ dysfunction and mortality. This study was performed to describe the local incidence, risk factors, and outcomes of BKPyV infection.Methods:This retrospective case–control study was conducted between 2007 and 2016 from a tertiary hospital in South India. We identified HCT recipients diagnosed with BKPyV-HC and compared them with recipients over the same period who did not develop BK virus infection matched for age, sex, diagnosis, and donor type. We collected data from central electronic medical records and databases maintained in the departments of hematology and virology.Results:Over the study period, 1276 transplants were performed, of which 262 patients (20.5%) developed HC and 105 (8.2%) were BKPyV-positive. Grade 3 HC was most commonly (57.1%) seen, and the median time to develop BKPyV-HC was 35 (range 0–858) days. Survival was significantly lower in the cases (42.9% vs. 61%, P < 0.05). On univariate analysis, the protective effect of nonmyeloablative conditioning (P = 0.04), residual disease at the time of transplant in malignant conditions (P = 0.001), lower CD34 dose (P = 0.006), presence of acute graft versus host disease (GVHD, P < 0.001), reactivation of cytomegalovirus infection (P < 0.001), and presence of bacterial urinary tract infection (UTI) (P < 0.001) were significant factors. Multivariate logistic regression confirmed the presence of acute GVHD (P = 0.041), bacterial UTI (P < 0.001), and residual disease (P = 0.009) at HCT as significant risk factors for BKPyV-HC.Conclusions:Our study affirms the homogeneity of BKPyV-HC disease in low- and middle-income HCT settings with prior reports and the need for therapeutic strategies to reduce its resultant mortality.

Association between haploidentical hematopoietic stem cell transplantation combined with an umbilical cord blood unit and graft-versus-host disease in pediatric patients with acquired severe aplastic anemia.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) based on granulocyte colony-stimulating factor plus anti-thymocyte regimens ('Beijing Protocol') provides a salvage treatment for patients of acquired severe aplastic anemia (SAA) in China. However, graft-versus-host disease (GVHD) is a major impediment of haplo-HSCT due to human leukocyte antigen disparity. Recently, haplo-HSCT combined with umbilical cord blood (UCB) (haplo-cord HSCT) is performed in clinical trials to potentially reduce the risk of severe GVHD. Nevertheless, studies comparing GVHD in pediatric patients receiving haplo and haplo-cord HSCT for SAA are limited. The objective of this study was to investigate the impact of UCB co-infusion on GVHD in pediatric patients receiving haplo-HSCT for SAA. We conducted a retrospective study of 91 consecutive SAA children undergoing haploidentical transplantation based on the 'Beijing Protocol' with or without co-infusion of UCB in our center. All patients received uniform non-myeloablative conditioning and GVHD prophylaxis. We compared baseline characteristics and transplant outcomes between the haplo (n = 35) and haplo-cord (n = 56) recipients. All 91 patients achieved hematopoietic recovery from haploidentical donors, with a higher incidence of peri-engraftment syndrome observed with the haplo-cord group as compared with the haplo group (75.0% versus 48.6%, p = 0.029). Notably, the haplo-cord group showed a lower incidence of II-IV acute GVHD (aGVHD) than the haplo group (16.1% versus 42.9%, p = 0.002). Observed incidences of chronic GVHD (cGVHD) and moderate to severe cGVHD in the haplo-cord group were also lower than that in the haplo group (25.6% versus 51.3%, p = 0.019; 16.2% versus 41.3%, p = 0.016, respectively). Haplo-cord HSCT was identified as the only factor associated with a lower incidence of II-IV aGVHD and cGVHD in multivariate analysis. However, no differences were observed between the two groups for infections and survival outcomes. Our data indicated that co-infusion of UCB in 'Beijing Protocol'-based haplo-HSCT may be effective for reducing the risk of severe GVHD in SAA children.

Oral Mucositis Association with Periodontal Status: A Retrospective Analysis of 496 Patients Undergoing Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation (HSCT) can induce serious oral complications, including oral mucositis (OM). The presence of periodontal inflammation before HSCT is believed to be associated with OM. The aim of our study was to determine the prevalence and severity of OM in patients undergoing HSCT and its relation to periodontal status. Patients and methods: This is a retrospective study of patients who underwent HSCT and a detailed dental examination between 2007 and 2015. The dental and periodontal status of all patients was evaluated by clinical and radiographic examination prior to HSCT. Oral health was assessed with the gingival index, the the community periodontal index, presence of plaque-related gingivitis, and marginal periodontitis. During the HSCT period, patients were examined daily for the presence of OM, which was graded according to World Health Organization (WHO) classification if present. The patients were assigned to the groups according to type of transplantation: autologous HSCT, myeloablative allogeneic HSCT, and non-myeloablative allogeneic HSCT. Results: A total of 496 patients were included in the study. OM was present in 314 of 496 patients (63.3%): 184/251 (73.3%) in the autologous group, 100/151 (66.2%) in the myeloablative allogeneic group, and 30/94 (31.9%) in the nonmyeloablative allogeneic group. Significantly more patients suffered from OM in the autologous and myeloablative groups versus the nonmyeloablative conditioning group (p < 0.001). The presence of periodontal inflammation did not significantly differ among the groups. There was only a borderline trend for the higher prevalence of OM in the non-myeloablative allogeneic nonmyeloablative group when periodontal inflammation was present (0.073939). Conclusions: Oral mucositis prevalence and severity after stem cell transplantation is not widely affected by the oral hygiene and periodontal disease presence before HSCT. We confirmed the wide-known connection of the conditioning regimen intensity to the prevalence of OM.

927. Clinical Characteristics and Outcomes of Norovirus Infection in Patients with Hematologic Malignancies: A Retrospective, Single Center Study

BackgroundNorovirus (NV) gastroenteritis has been identified as a cause of significant morbidity among hematopoietic stem cell transplant (HSCT) recipients, often with associated complications. Current guidelines recommend symptomatic relief with antimotility agents, rehydration, and reduction in immune suppression. Nitazoxanide (NTZ) is an anti-parasitic agent but some literature suggests a benefit of nitazoxanide therapy for NV. MethodsWe conducted a single center, retrospective chart review study and evaluated adult patients (age >18 years) who had NV infection and either: 1) underwent stem cell transplantation; or 2) received myeloablative chemotherapy within 4 weeks of NV diagnosis by positive test on gastrointestinal pathogen panel during the time period from January 2015 through March 2020. Results26 patients were reviewed. 14 patients (54%) had a history of HCST prior to infection. Three patients (12%) received both myeloablative chemotherapy and HSCT within four weeks of NV infection. Six patients (46%) had autologous, six (46%) had matched unrelated donor, and one (8%) had haploidentical allogeneic transplants. Nine (69%), three (23%), and one (8%) underwent myeloablative, reduced intensity and non-myeloablative conditioning, respectively. Median duration of diarrhea was 4.5 days (IQR = 2.25-7 days). Three (12%) patients received NTZ or intravenous immune globulin. The 6 month mortality was 42% (11/26), however, none of the deaths were directly attributable to NV infection.ConclusionNV infection led to severe diarrheal disease in our cohort. Overall mortality was high, and a trend toward increased mortality was seen among patients receiving NV-directed therapy; these patients likely received NV-directed therapy due to the severity of their illness. Clinicians must have a high suspicion for this illness and obtain PCR testing for timely diagnosis and management.Table 1. Characteristics of patients with hematologic malignancies and norovirus infection Disclosures All Authors: No reported disclosures

High Failure-Free Survival after Unrelated Donor Peripheral Blood Stem Cell Transplantation in Pediatric Severe Aplastic Anemia

The use of alternative donor peripheral blood stem cell transplantation (PBSCT) has increased in recent years. In this study, we analyzed the effect of stem cell source and HLA disparity on outcomes in pediatric patients with severe aplastic anemia (SAA). A total of 134 patients who underwent HSCT with nonmyeloablative conditioning between 2006 and 2020 were enrolled and classified into 3 groups: HLA-matched bone marrow transplantation (M-BMT; n = 24), HLA-matched PBSCT (M-PBSCT; n = 66), and HLA-mismatched PBSCT (MM-PBSCT; n = 44). Significantly higher stem cell doses were obtained for PBSCT than for BMT. A total of 13 patients experienced secondary graft failure (GF), with a cumulative incidence (CI) of 10.0%. HLA-mismatched PBSCT and a very severe degree of disease significantly decreased the incidence of secondary GF. The CI of grade II-IV acute graft-versus-host disease (GVHD) was significantly higher in PBSCT than in BMT, but the CI of grade III-IV acute GVHD and CI of chronic GVHD requiring systemic treatment did not increase in PBSCT. The estimated 5-year overall survival (OS), failure-free survival (FFS), and GVHD-free failure-free survival (GFFS) of the total cohort were 93.0%, 89.5%, and 77.5%, respectively. The most favorable FFS was observed in the MM-PBSCT group (97.6%; P = .03), whereas OS and GFFS were similar across the 3 groups. In multivariate analysis, HLA mismatch and short time from diagnosis to transplantation were associated with superior FFS. Unrelated donor PBSCT with low-intensity SAA conditioning showed favorable outcomes in terms of low rate of secondary GF, higher FFS, and manageable GVHD regardless of HLA compatibility. Our findings suggest the feasibility of PBSCT from unrelated donors, resulting in the possible expansion of the donor pool in transplantation for pediatric SAA. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

HLA-Matched Related Hematopoietic Stem Cell Transplantation in Adolescents and Adults with Sickle Cell Disease: Comparison of Myeloablative Versus Non Myeloablative Approaches. Report from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) allowing a SCD-free survival over 95% among children with matched HLA-identical donor (Gluckman E. Blood, 2017; Bernaudin F. Haematologica, 2020). In adults, myeloablative HSCT is associated with more graft-versus host disease (GVHD) and higher toxicity (Cappelli B. Haematologica, 2019). More recent approaches using non myeloablative (NMA) conditioning regimen (3 gray (Gy) total body irradiation (TBI) plus alemtuzumab) followed by HLA-identical peripheral blood stem cells (PBSC) and post-transplant sirolimus appear safe in adults (Hsieh MM. JAMA, 2014), but incidence of graft failure might be higher than the one reported after myeloablative conditioning (MAC) (Alzahrani M. Br J Haematol, 2021). Here, we compare outcomes after MAC or NMA conditioning regimens in patients over 15 years old transplanted from a matched related donor (MRD).Patients and methodsAll consecutive patients transplanted for SCD from a MRD from January 2015 to October 2020 were eligible if they were over 15 years old and received a busulfan-based MAC conditioning regimen or a NMA conditioning regimen.Chimerism was studied by analyzing various polymorphisms after polymerase chain reaction (PCR) amplification of DNA obtained from whole blood cells. Rejection was defined as donor chimerism <5%. Event-free survival (EFS) was defined as the probability to be alive with blood donor chimerism over 20%.ResultsThirty-four patients were included: 20 in the MAC and 14 in the NMA groups. Median age at transplant was 17 years (range 15-46) without difference between groups. Forty four percent of patients had a history of cerebral vasculopathy, 79% of recurrent vaso-occlusive crises and 76% of acute chest syndrome. ABO major incompatibility was present in 15% of patients. There was no difference in patient characteristics according to the conditioning regimen group except for pre-transplant cerebral vasculopathy, more frequently reported in the MAC group: 70% versus 6% in the NMA group (p<0.001).In the MAC group, conditioning regimen associated busulfan (12.8 mg/kg IV), cyclophosphamide (N=17) or fludarabine (N= 3) and anti-thymoglobulin (ATG, mostly 20mg/kg). Stem cell source was bone marrow and post-transplant immunosuppression combined cyclosporine and mycophenolate or methotrexate. In the NMA group, conditioning regimen associated 3Gy TBI and alemtuzumab (1mg/kg), followed by PBSC and post-transplant sirolimus.All patients engrafted and no secondary graft failure was observed. One MAC group patient died from GVHD. The 2-year overall and EFS were 95% (CI 95%: 85.9-100) in the MAC group (median follow-up of 39 months (range 8-63)) and 100% (CI 95%: 100-100) in the NMA group (median follow-up of 17 months (range 9-39)). Incidence of grade II-IV acute GVHD was 0% in the NMA group versus 20% in the MAC group (p=0.12). Incidence of chronic GVHD was 0% in the NMA group versus 25% in the MAC group (p=0.06). From the 27 patients with follow-up>12 months, 17/17 discontinued immunosuppressive therapy in the MAC group versus 8/10 in the NMA group. Hematopoietic recovery was faster in the NMA group with less platelet and red blood cell units transfused (Table). Throughout the follow-up, median donor chimerism was higher after MAC transplantation than after NMA transplantation: 98% (range 69-100) and 86 % (range 50-97) respectively at 1 year (p=0.017). Donor chimerism remained above 50% throughout the follow-up in all patients except 1 of the NMA group who displayed stable chimerism between 40 and 50%. All patients achieved HbS level close to the one of their donors. There was no difference between the 2 groups regarding occurrence of infections. MAC transplant was more often associated with hypertension, neurological complications, severe mucositis and need of enteral or parenteral nutrition. Moreover, duration of hospitalization was longer in MAC group: 54 days (range 39-192) versus 35 days in the NMA group (range 21-52) (p<0.001) (table).ConclusionIn this series of adolescents and adults transplanted for SCD, the survival without SCD was excellent with a faster hematological recovery and a lower toxicity after NMA HSCT. Longer follow-up is required to confirm stable mixed donor chimerism and the cure of SCD after NMA approach. [Display omitted] DisclosuresJoseph: bluebird bio: Consultancy. Boissel: Servier: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; CELGENE: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Pondarré: ADDMEDICA: Honoraria.

Haploidentical Allogeneic Stem Cell Transplantation in Sickle Cell Disease: A Systematic Review and Meta-Analysis

▪BackgroundAllogeneic hematopoietic stem cell transplantation (SCT) is the only established curative treatment option for patients with sickle cell disease (SCD). Transplantations with an HLA-identical matched sibling donor (MSD) have resulted in excellent disease-free survival of >90% and overall survival (OS) of >95%. However, lack of HLA-identical siblings is a limiting factor. The chance of finding a potential matched unrelated donor is low for patients with a non-Western ethnic background (< 20%). Haploidentical related donors are a promising pool of donors potentially extending SCT as a curative treatment to a larger group of SCD patients with no other meaningful treatment options. Myeloablative conditioning regimens (MAC) are not recommended for adult SCD patients, as cumulative SCD-related organ damage renders these patients susceptible to increased toxicity and higher risk of transplant-related mortality. Using reduced-intensity conditioning (RIC) or non-myeloablative conditioning (NMC) in both adult and pediatric patients has resulted in decreased transplant-related toxicity and mortality. However, while successful in hematologic malignancies, NMC has been associated with significant risk of graft failure in hemoglobinopathies. In the present study, we aimed to systematically review (1) the outcomes of haploidentical SCT (Haplo-SCT), (2) the effects of conditioning intensity and modes of T-cell depletion on Haplo-SCT outcomes and (3) comparative outcomes between matched sibling donor SCT (MSD-SCT) and Haplo-SCT in selected studies.MethodsA comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data was extracted by two reviewers independently and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Only studies reporting at least one of the outcomes: graft failure, OS, transplant-related mortality, and acute/chronic graft-versus-host disease (GvHD) were included. Fourteen studies met the inclusion criteria. To have an overview of the results of Haplo-SCT, we divided the included studies in four groups according to the conditioning intensity (MAC versus NMC/RIC) and the T-cell depletion method (in vivo (post-transplant cyclophosphamide (PTCy)) vs. in vitro).ResultsAll included studies were observational cohort studies. A subgroup meta-analysis of the results of Haplo-SCT showed relatively low overall pooled proportions of graft failure (7%, 95% CI: 2 - 20), acute (4%, 95% CI: 2 - 12) and chronic (11%, 95% CI: 7 - 16) GvHD. Overall survival was high (91%, 95% CI: 85 - 94). Graft failure in MAC-in vitro, MAC-in vivo, NMC/RIC-in vitro and NMC/RIC-in vivo groups was 4% (95% CI: 1 - 14), 0% (95% CI: 0 - 100), 25% (95% CI: 10 - 51) and 11% (95% CI: 3 - 36) respectively (Figure 1). OS was 100% and 93% for MAC and NMC/RIC groups with PTCy (in vivo T-cell depletion) respectively. In patients with in vitro T-cell depletion, OS was 87% and 81% in MAC and NMC/RIC groups respectively (Figure 2). Based on a comparative meta-analysis of the three studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio 5.3, 95% CI: 1.0 - 27.6). Overall survival, transplant-related mortality and acute/chronic GvHD were not significantly different between the groups.ConclusionsThis systematic review shows that modifications in the intensity of the conditioning regimen and improved T-cell depletion approaches in Haplo-SCT in SCD have led to reduced transplantation-related toxicity while keeping graft failure rates low. Both in vitro and in vivo (PTCy) T-cell depletions result in very low transplantation-related mortality, though in vitro T-cell depletion is associated with a higher incidence of viral reactivations and other infectious complications.Haploidentical stem cell transplantation is becoming a viable alternative curative option for SCD, extending the availability of allogeneic SCT as a treatment option to many more transplant eligible SCD patients. Novel immunosuppression (immunoablation) and improvement in supportive care have allowed the use of RIC or NMC regimens, resulting in low risk of transplantation-related complications and improvement in engraftment rates. [Display omitted] DisclosuresBiemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria; Sanquin: Research Funding; Novo Nordisk: Honoraria; Celgene: Honoraria. Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Conditioning Intensity and Probability of Live Birth after Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: The observed inter-individual variability in the probability of live birth after BMT is due to exposure to gonadotoxic agents (including total body irradiation [TBI]), age at exposure to gonadotoxic agents, sex of the BMT recipient, and post-BMT morbidity. The last decade has seen an increase in use of non-myeloablative (NMA) conditioning to reduce the risk of early post-treatment mortality. However, the impact of TBI in the context of conditioning intensity (NMA vs. myeloablative conditioning [MAC]) on the probability of post-BMT live birth remains unknown. We addressed this gap by utilizing the BMTSS - a multi-institutional collaborative designed to understand the burden of morbidity after BMT.Methods: This study included 1,607 BMT survivors who underwent BMT between 1974 and 2014 at age ≤45, had survived ≥2y, and were ≥18y of age at study. This study also included pair-matched nearest-age, same-sex biologic siblings (≥18y of age at study) to control for genetic or environmental factors that could affect fertility. Survivors and their siblings completed the BMTSS survey. Sociodemographic characteristics (race/ethnicity, annual household income, availability of health insurance, level of education), chronic health conditions, medical assistance for fertility assistance and details about all pregnancies and their outcomes were retrieved from the BMTSS survey. Clinical characteristics were obtained from the institutional BMT databases and/or participants' medical record. Within survivor analysis: Potential risk factors for not reporting a live birth after BMT were analyzed using multivariable logistic regression. Exposure to TBI and conditioning intensity were consolidated to create four distinct exposure groups: no_TBI/NMA (least intense), TBI/NMA, no_TBI/MAC, TBI/MAC (most intense). Matched-pair comparison with biologic siblings: We matched 172 survivors with their closest-age, same-sex, biological siblings and used conditional logistic regression to determine the failure to report live birth in BMT survivors when compared with their siblings.Results: In this cohort of 1,607 survivors, 599 (37.3%) were autologous BMT recipients, and 765 (47.6%) were female. Median age at BMT was 30y, and at study participation was 45y (IQR: 18-73); median length of follow-up from BMT to study was 14.4y (IQR: 2.4-41.4). The primary indications for BMT included HL/NHL (30.6%), AML/MDS (24.3%), CML (13.4%), ALL (12.2%), and other diagnoses (13.5%). Of the 1,607 survivors, 120 (7.5%) reported one or more live births after BMT. Within survivor comparison: Multivariable analysis (Figure) revealed that receipt of TBI/MAC (OR=2.9, 95%CI: 1.5-5.8; ref: no_TBI/ NMA) was associated with an increased risk of not reporting a post-BMT live birth. Of note, TBI/NMA (OR=1.5, 95%CI, 0.5-5.0), and no_TBI/ MAC (OR=0.9, 95%CI, 0.4-2.0) were at a similar risk of reporting a post-BMT live birth as no_TBI/NMA. Other factors associated with increased risk of not reporting a post-BMT live birth included older age at BMT (>35y: OR=3.5, 95%CI, 1.4-7.9; reference: <12y), lower income ($50k-100k: OR=2.0, 95%CI, 1.1-3.6; <$50k: OR=3.2, 95%CI, 1.6-6.4; reference: >$100k), no medical interventions to facilitate pregnancy (OR=2.7, 95%CI, 1.6-4.6), and history of pre-BMT live birth (OR=2.7, 95%CI, 1.6-4.6). Matched-pair comparison with biologic siblings: Multivariable conditional logistic regression revealed that BMT survivors were less likely to report live birth (OR=0.5, 95%CI: 0.3-0.8) compared to their siblings. However, once pregnant, they were also less likely to report a miscarriage (OR=0.4. 95%CI: 0.2-0.8).Conclusion: While full dose TBI in the setting of myeloablative conditioning is associated with a lower probability of live birth after BMT, lower doses of TBI in the setting of myeloablative or reduced intensity conditioning yield a similar probability of live birth as no TBI. These findings provide evidence for alternative conditioning regimens for patients who wish to have children after BMT. [Display omitted] DisclosuresWeisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding.

Use of Belimumab for Prophylaxis of Chronic Graft-Versus-Host Disease

The most transformative approach for controlling chronic Graft-versus-Host Disease (cGvHD) after allogeniec hematopoietic cell transplantation (alloHCT) would be the prevention of its most severe and irreversible clinical manifestations instead of treating already established disease. Belimumab is a monoclonal antibody, approved for treatment of systemic lupus erythematosus and active lupus nephritis, which inhibits binding of B-cell-activating factor (BAFF) to its receptors on B cells, thus inhibiting the survival of autoreactive B cells. Given the role of B cells in cGvHD pathophysiology and the now substantiated role of BAFF in promoting B Cell Receptor signaling in cGvHD (Jia W et al Blood 2021), belimumab might have a role in prevention of cGvHD. We hypothesized that targeting BAFF early after alloHCT would be well-tolerated and have a favorable effect on the incidence and severity of cGvHD.We are presenting data on the first 8/10 patients (Pts) enrolled in the single-center, investigator-initiated phase-1 trial. Belimumab was administered i.v. at 10 mg/kg every 2 weeks for 3 doses followed by 4 doses at monthly intervals, for a total of 7 doses, starting 50-80 days after alloHCT. All Pts were adults who received mobilized peripheral blood grafts from fully matched related or unrelated donors after myeloablative or non-myeloablative conditioning. GvHD prophylaxis was with tacrolimus and methotrexate; one Pt received post-transplant cyclophosphamide. All Pts were in complete remission on day +30 after alloHCT. Pts who received ≥1 dose of belimumab were evaluable for safety and ≥2 doses for efficacy assessment. cGvHD was diagnosed according to the NIH criteria. All analyses are descriptive. Specimens for correlative studies are cryopreserved until the study end.We found that Pts tolerated belimumab well, with no reported grade ≥3 treatment-related adverse events. There were no significant infections or myelosuppression. Seven out of eight Pts on the study received all 7 doses of belimumab, as planned. Of those 7 Pts, 5 Pts are without any evidence of cGvHD and completely off immunosuppression at the median of 18 months (mo) after completing belimumab (median of 24 mo after alloHCT). Seven mo after completing belimumab on study, 1 Pt developed cGvHD involving skin, eyes and liver, and died from complications of pneumonia and liver failure due to longstanding hemochromatosis, iron overload and possible liver GvHD. Another Pt relapsed with leukemia 1 mo after completing belimumab. He is now in remission after treatment with enasidenib and 2 donor lymphocyte infusions (DLI), 12 mo after completing belimumab (18 mo after alloHCT); he developed mild eye GvHD following DLI. One out of eight Pts on the study stopped treatment early, after receiving only 3 doses, due to thrombocytopenia (unrelated to belimumab) and insurance issues. He was found to have relapsed lymphoma 3 mo later, was treated with venetoclax and DLI, and remains in remission with no evidence of cGvHD 15 mo after stopping belimumab. Two additional patients are being enrolled. Immune reconstitution studies are showing that B-cell counts remain low 1 year out of transplant in all Pts (Figure 1).This preliminary data describes for the first time the use of belimumab for prophylaxis of cGvHD. Overall, belimumab was very well tolerated. Only 1 Pt on the study developed cGvHD. It is worth noting that his cGvHD developed 7 mo after completing belimumab suggesting that a longer duration of therapy should be tested in future studies. The 2 Pts with relapsed disease both had high risk malignancies. Risk stratification of high risk patients will be critical in future prospective studies. While more Pts are needed to further assess the impact of prophylactic belimumab on the incidence of cGVHD, these preliminary results are encouraging. Absence of severe infections is reassuring. B-cell reconstitution was delayed, as expected. Ongoing correlative studies will further evaluate BAFF levels and B-cell subset reconstitution after alloHCT. [Display omitted] DisclosuresPusic: Syndax: Other: Advisory Board. Sarantopoulos: Rigel: Other: Advisory Board. Uy: Macrogenics: Research Funding; Jazz: Consultancy; Genentech: Consultancy; Astellas: Honoraria, Speakers Bureau; Novartis: Consultancy; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Agios: Consultancy. OffLabel Disclosure:Drug: Belimumab This study: Belimumab for prophylaxis of chronic GvHD. Approved indication: Belimumab is approved for treatment of systemic lupus erythematosus and active lupus nephritis.

Higher Grade Cytokine Release Syndrome Is a Predictive Factor for Gvhd in Haploidentical Stem Cell Transplantation with Peripheral Blood Cell

Background:Early Cytokine Release Syndrome (CRS) is a common complication following haploidentical stem cell transplantation (Haplo-HSCT) induced by the proliferation of alloreactive T-Cells. CRS is occurring more frequently in patients receiving peripheral blood stem cells (PBSC) comparatively to bone marrow transplant, however its impact on outcome, notably graft versus host disease (GVHD) remain unclear. The main objective was to evaluate the impact of severity of CRS on the risk of GVHD.Patients and Methods:This retrospective single-center study included patients who had received a first haplo-HSCT for hematological malignancies, with PBSC as graft source. All patients received either a reduced-intensity conditioning (RIC) based on thiotepa (5mg/kg), busulfan (260 mg/m²) and fludarabine (120 mg/m²) [TBF], or a non-myeloablative conditioning (NMAC) based on fludarabine (150 mg/m²), cyclophosphamide (29 mg/kg) and 2 Gy TBI [CyFluTBI]. GVHD prophylaxis was based on PT-Cy 50 mg/kg (day+3 and +4) and cyclosporine A plus mycophenolate mofetil starting at day+5. All patients were given GSCF from day+5 to neutrophil recovery.Results:241 consecutive patients were analyzed. One hundred patients (54%) had myeloid malignancies, and 111 (46%) had lymphoid malignancies. Most patients had intermediate or low risk DRI (n = 180, 75%) and HCT-CI was ≥ 3 for 159 patients (66%). Using ASTCT consensus criteria, 226 patients (94%) developed CRS, including 183 grade 1 and 43 grade ≥ 2. Transplantation and patient characteristics were not significantly different between patients with CRS grade 0-1 vs. ≥ 2, except for age. Indeed, patients with CRS grade ≥ 2 were significantly older than patients with CRS grade 0-1 (median 65 vs 60 yo respectively, p = 0.01).Patients with grade ≥ 2CRS had significantly higher cumulative incidence of day-100 grade II-IV acute GVHD (grade 0-1 vs. ≥ 2 : 28% and 44%, p = 0.028) and 4-year moderate to severe chronic GVHD (grade 0-1 vs. ≥ 2 : 16% and 30%, p = 0.024) compared to patients with grade 0-1 CRS (Figure 1). No difference in the cumulative incidence of relapse was observed between CRS groups (grade 0-1 vs. ≥ 2 : 22% and 21%, p = 0.802).By multivariate analysis, CRS grade ≥ 2 was the only factor associated with grade II-IV acute GVHD (HR = 1.99; 95%CI = [1.17-3.39], p = 0.011). CRS grade ≥ 2 was significantly associated with a higher risk of moderate to severe chronic GVHD (HR = 2.67; 95%CI = [1.36-5.21], p = 0.004) and poorer GVHD- and relapse-free survival (GRFS) (HR = 1.78 ; 95%CI = [1.19-2.67], p = 0.005). Progression free survival, overall survival and non-relapse mortality were not influenced by the severity of CRS.Conclusion:In the context of PBSC haplo-HSCT, the occurrence of grade ≥ 2 CRS following graft infusion is significantly associated with an increased risk of both acute and chronic GVHD. This may improve the early identification of patients with high risk of GVHD for whom specific enhanced GVHD prophylaxis should be investigated. [Display omitted] DisclosuresChabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.