Nonmalignant Hematologic Conditions Research Articles

Outcomes from hematopoietic stem cell transplantation following treosulfan-based conditioning: A clinical and pharmacokinetic analysis.

The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.

Defining the Impacts of Iron Overload in Children Receiving Hematopoietic Stem Cell Transplantation for Non-Malignant Hematologic Conditions

Background: Hematopoietic stem cell transplant (HSCT) is curative for patients with non-malignant blood disorders. Children with these conditions often require numerous red blood cell transfusions prior to HSCT, leading to iron overload. It has been hypothesized that pre-HSCT iron overload leads to poorer post-HSCT outcomes, and studies have demonstrated a prognostic link between portal fibrosis, hepatomegaly, and post-transplant survival in thalassemia. Ferritin and liver iron concentration (LIC) are used as surrogate markers of iron overload to determine eligibility for HSCT, but neither has been definitively associated with poorer HSCT outcomes in this population. Further, patients receiving HSCTs for non-malignant conditions may require post-transplant iron reduction therapy (IRT), but whether chelation or phlebotomy is more effective in reducing iron overload is unknown. Objectives: In children with non-malignant blood disorders, determine if higher pre-transplant ferritin and LIC are associated with poorer post-HSCT outcomes including GVHD-free, relapse-free survival (GRFS), overall survival (OS), higher rates of veno-occlusive disease (VOD), and longer neutrophil and platelet engraftment times. Determine whether post-HSCT chelation or phlebotomy is associated with a faster rate of ferritin reduction. Methods: We conducted a single-center retrospective cohort study of children with sickle cell disease, beta thalassemia major, aplastic anemia, and other disorders requiring RBC transfusion from a large pediatric academic center from 2010-2023 as a pilot study for our in-progress multi-center analysis. GRFS and OS were compared using a Kaplan-Meier survival analysis. GRFS analysis excluded autologous SCTs. Engraftment times were compared using a competing risks analysis. VOD rates were compared using logistic regression. Rate of ferritin reduction was analyzed using a Wilcoxon Rank-Sum test. Statistical analyses were conducted using StataBE v17.0. Results: Among 152 patients with non-malignant blood disorders who underwent HSCT, 136 patients received allogeneic SCTs and 16 received gene-modified autologous SCTs. 90 patients had a pre-transplant LIC &amp;lt;5mg/g dry tissue or if no LIC was available, ferritin &amp;lt;1000ng/mL (low iron). 41 patients had a pre-transplant LIC of 5-10mg/g dry tissue or ferritin 1000-3000ng/mL (moderate iron). 21 patients had a pre-transplant LIC ≥10mg/g dry tissue or ferritin ≥3000ng/mL (high iron). GRFS rates were 20% for the low iron group, 13% for moderate iron, and 22% for high iron, and were not statistically distinct ( p = 0.55). OS was 92.2% for low iron, 97.6% for moderate iron, and 95.2% for high iron. Survival analysis showed no significant difference in OS ( p = 0.51). Minimum detectable hazard ratios were 2.00 and 1.92 comparing high and low iron groups for GRFS and OS, respectively. Logistic regression showed an odds ratio of 3.25 for VOD in high iron versus low iron in patients who received busulfan, though this was not statistically significant, p = 0.38. Median time to neutrophil engraftment did not differ among groups (15 days for low iron, 15 days for moderate and 14 days for high). Median time to platelet engraftment was 18 days for low iron, 19 days for moderate iron and 26 days for high iron, though due to wide variance in engraftment times, this was not statistically significant ( p = 0.81). 11 patients underwent post-HSCT IRT with chelation and 12 with phlebotomy. Median rate of ferritin reduction for patients receiving post-HSCT chelation was 53 ng/mL/month on therapy, compared to 64 ng/mL/month for those who received phlebotomy ( p = 0.24). Conclusions: In this pilot study, higher pre-transplant LIC and ferritin were not significantly associated with poorer post-transplant outcomes. Patients in the high iron group showed a trend toward increased VOD risk and longer time to platelet engraftment, but GRFS and OS were not impacted. Post-HSCT phlebotomy and chelation showed similar rates of ferritin reduction as a marker for elimination of residual iron overload. These data suggest a need to reevaluate the utility of LIC and ferritin as prognostic markers for HSCT risk. Additional data are needed to determine if IRT targeting specific iron thresholds is truly needed prior to HSCT. This pilot study informs our in-progress multi-center analysis of the impact of iron overload on post-HSCT outcomes in children with non-malignant blood disorders.

International Society for Cell & Gene Therapy Stem Cell Engineering Committee: Cellular therapies for the treatment of graft-versus-host-disease after hematopoietic stem cell transplant

Background aimsAllogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment. MethodsWe conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords “Graft-versus-Host Disease (GVHD),” “Cellular Therapies,” “Regulatory T cells (Tregs),” “Mesenchymal Stromal (Stem) Cells (MSCs),” “Natural Killer (NK) Cells,” “Myeloid-derived suppressor cells (MDSCs),” and “Regulatory B-Cells (B-regs).” All the published and available clinical studies were included. ResultsAlthough most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario. ConclusionsThere are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.

Effects of immune system cells in GvHD and corresponding therapeutic strategies.

Allogeneic tissue transplantation is one of the most effective treatments for several diseases and injuries, in particular, malignant and non-malignant hematological conditions. Following this procedure, transplanted tissue encounters various complications, one of the most serious being graft-versus-host disease (GvHD). The management of GvHD directly affects the success of transplantation and the survival rate of the patient; therefore, many studies have focused on GvHD prevention and control. This review briefly explains the transplantation process, causes of graft rejection, and importance of the human leukocyte antigen system. Initially, we address the pathophysiology and immunobiology of GvHD, the cells involved in this complication, the differences between chronic and acute GvHD, and the importance of graft-versus-leukemia. Interestingly, various types of immune cells are involved in GvHD pathogenesis. After explaining how these cells affect the GvHD process, we discuss the studies conducted to control and reduce GvHD symptoms.

Invasive Fusariosis in Pediatric Hematology/Oncology and Stem Cell Transplant Patients: A Report from the Israeli Society of Pediatric Hematology-Oncology.

Invasive Fusarium species infections in immunocompromised patients occur predominantly in those with hematological malignancies. Survival rates of 20–40% were reported in adults, but data in children are limited. Our retrospective, nationwide multicenter study of invasive fusariosis in pediatric hematology/oncology and stem cell transplant (SCT) patients identified twenty-two cases. Underlying conditions included hematological malignancies (n = 16; 73%), solid tumors (n = 2), and non-malignant hematological conditions (n = 4). Nineteen patients (86%) were neutropenic, nine (41%) were SCT recipients, and seven (32%) received corticosteroids. Sixteen patients (73%) had disseminated fusariosis, five had local infection, and one had isolated fungemia. Fifteen patients (68%) had skin involvement and eight (36%) had a bloodstream infection. Four patients (18%) presented with osteoarticular involvement and four with pulmonary involvement. Nineteen patients (86%) received combination antifungal therapy upfront and three (14%) received single-agent treatment. Ninety-day probability of survival was 77%: four of the five deaths were attributed to fusariosis, all in patients with relapsed/refractory acute leukemias. Ninety-day probability of survival for patients with relapsed/refractory underlying malignancy was 33% vs. 94% in others (p < 0.001). Survival rates in this largest pediatric population-based study were strikingly higher than those reported in adults, demonstrating that invasive fusariosis is a life-threatening but salvageable condition in immunosuppressed children.

Telemedicine in Malignant and Nonmalignant Hematology: Systematic Review of Pediatric and Adult Studies.

BackgroundTelemedicine, including video-, web-, and telephone-based interventions, is used in adult and pediatric populations to deliver health care and communicate with patients. In the realm of hematology, telemedicine has recently been used to safely and efficiently monitor treatment side-effects, perform consultations, and broaden the reach of subspecialty care.ObjectiveWe aimed to synthesize and analyze information regarding the feasibility, acceptability, and potential benefits of telemedicine interventions in malignant and nonmalignant hematology, as well as assess the recognized limitations of these interventions.MethodsStudies were identified through a comprehensive Medical Subject Headings (MeSH) search on the PubMed MEDLINE, Controlled Register of Clinical Trials (Cochrane CENTRAL from Wiley), Embase, and CINAHL (EBSCO) databases on February 7, 2018. A second search, utilizing the same search strategy, was performed on October 1, 2020. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the reporting of included evidence. Included studies were original articles researching the feasibility, acceptability, and clinical outcomes of telemedicine or telehealth interventions in pediatric or adult populations with malignant or nonmalignant hematological conditions. Data items in the extraction form included first author name, publication year, country, malignant or nonmalignant hematological condition or disease focus of the study, participant age, participant age subgroup (pediatric or adult), study design and setting, telemedicine intervention type and description, study purpose, and main study outcomes.ResultsA total of 32 articles met the preset criteria and were included in this study. Most (25/32) studies were conducted in adults, and the remaining (7/32) were conducted in the pediatric population. Of the 32 studies, 12 studied malignant hematological conditions, 18 studied nonmalignant conditions, and two studied both malignant and nonmalignant conditions. Study types included pilot study (11/32), retrospective study (9/32), randomized controlled trial (6/32), cross-sectional study (2/32), case study (1/32), pre-post study (1/32), noncomparative prospective study (1/32), and prospective cohort study (1/32). The three main types of telemedicine interventions utilized across all studies were video-based (9/32), telephone-based (9/32), and web-based interventions (14/32). Study results showed comparable outcomes between telemedicine and traditional patient encounter groups across both pediatric and adult populations for malignant and nonmalignant hematological conditions.ConclusionsEvidence from this review suggests that telemedicine use in nonmalignant and malignant hematology provides similar or improved health care compared to face-to-face encounters in both pediatric and adult populations. Telemedicine interventions utilized in the included studies were well received in both pediatric and adult settings. However, more research is needed to determine the efficacy of implementing more widespread use of telemedicine for hematological conditions.

Determinants of Hematology-Oncology Trainee's Post-Fellowship Career Pathways with a Focus on Non-Malignant Hematology

Background: Non-malignant hematologic conditions are extremely prevalent and contribute significantly to the global burden of disease. Most training programs in hematology are combined with training in medical oncology, and there is no longer a specific requirement for a certain amount or percentage of fellowship time to be dedicated to training in non-malignant hematology. As a result, our health care system may soon face a shortage of specialists in non-malignant hematology. We sought to identify factors that lead hematology-oncology fellows to pursue (or not to pursue) careers in non-malignant hematology.Methods: We conducted a cross-sectional web-based survey of our institution's hematology/oncology graduates from 1998 through 2016. Of 164 alumni, 151 had available contact information. We emailed all 151 alumni and received 2 “bounceback” emails indicating the email on file was no longer valid, leaving a total of 149 alumni who were emailed the questionnaire.Results: Of the 149 alumni emailed the questionnaire, 86 responded (response rate 57.7%). The median age of the responders was 44 years (range 33-63) and 62 (72.1%) were male. 59 (68.6%) of respondents practice at an academic medical center, 24 (27.9%) in a community center or private practice, and 3 (3.5%) are in other areas (industry, government, etc). Respondents reported spending a median of 65% of their time in clinical practice, 12.5% in research, 2.0% in education, and 5.0% in administration. Those in clinical practice reported spending a median of 60% of their time in solid tumor oncology, 20% in hematologic malignancies, and 5% in benign hematology. 46 (54.8%) of respondents indicated that they spent at least some time practicing non-malignant hematology, but only 1 respondent reported spending more than 50% of their time seeing patients with non-malignant hematologic conditions. Factors affecting choice of patient population are shown in the top component of the Table. For those who did not report practicing non-malignant hematology, the bottom component of the Table and the Figure show the degree to which respondents indicated that each of these factors could have positively influenced them to pursue a career in non-malignant hematology. Overall, respondents involved in clinical practice reported a median job satisfaction level of 85 on a scale of 1-100. Those who practice non-malignant hematology reported a slightly but non-significantly lower job satisfaction rate as compared to those who do not practice non-malignant hematology (median 81.5 versus 87.0, p=0.14), but there was no correlation between the percentage of time spent on non-malignant hematology and reported job satisfaction amongst those practicing non-malignant hematology (Spearman correlation = 0.05, p=0.75).Conclusions: Graduates of an academic hematology-oncology fellowship spend over 50% of their time in clinical practice, but only about half spend at least some time practicing non-malignant hematology and almost none practice non-malignant hematology for a majority of time. Factors most influencing graduates' career choices include clinical experience during fellowship, intellectual stimulation of the patient population/disease type, and a supportive mentor. Graduates report that the factor most likely to have led to spending more time in non-malignant hematology would be increased exposure to role models and mentors in this area. Overall, graduates report being satisfied with their careers. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incidence and Risk Factors of Epstein-Barr Virus Viremia in Patients Undergoing Haploidential Transplantation with Post Translant Cyclophosphamide

INTRODUCTIONHaploidentical stem cell transplants are increasingly performed for a wide variety of malignant and non-malignant hematological conditions. Epstein - Barr virus (EBV) viremia and subsequent development of Post-Transplant Lymphoproliferative Disorder (PTLD) are potential adverse sequelae of the transplantation process and associated immunosuppression. Traditionally, haploidentical transplants have been associated with increased risk of EBV reactivation and subsequent PTLD. This was largely due to graft versus host disease (GVHD) prophylaxis protocols using intense immunosuppression with either Ex-vivo T-cell depletion or in-vivo T- cell depletion with anti-thymocyte globulin (ATG) and Alemtuzumab. However, most haploidentical transplants in recent years have utilized post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. Rituximab has been used for preemptive treatment of EBV viremia/PTLD, but there is scarce data on its use in this setting, as well as the risk factors and outcomes of EBV viremia associated with haploidentical transplants with PTCy. RESULTSA total of 63 patients with hematological malignancies received haploidentical transplant at our institution from 2013 from 2016. Patient characteristics are summarized in Table 1.All patients received EBV monitoring using plasma viral copies once weekly starting 20 days post-transplant. EBV monitoring continued for 6 months after immunosuppression ended or when CD4 count >200. Among these 63 patients, 18 (28.5%) became EBV DNA positive upon follow-up. Per institutional protocol, EBV titer was confirmed by repeat testing when viral load was 1000 copies/mL and treatment with Rituximab was initiated if repeat titer was >1000 copies/ml.The median time to detection of EBV viremia from the time of transplant was 99 days (range: 20-277). The median peak level for the EBV reactivation cohort was 7650 viral copies /ml. The median time from detection of viremia to peak viremia was 1.5 days (range 0-253).8 of the 18 (44.4%) patients that developed EBV viremia required Rituximab due to rising or persistent EBV viremia. The median EBV level at initiation of therapy was 31,000 copies/ml for the 8 patients that received Rituximab treatment. EBV seronegativity was achieved in 6 patients (75%) with treatment at a median of 13.5 days (range 3-26). The median number of Rituximab cycles administered was 1.5 (range: 1-16). None of the patients in either cohort developed PTLD or other EBV associated diseases.A univariate analysis was performed comparing EBV reactivation cohort and no EBV reactivation cohort to look for risk factors predisposing to EBV reactivation (Table 1) There were no statistically significant differences seen in the variables studied other than patients not in complete remission at the time of transplant were statistically more likely to develop EBV viremia. 9 out of 18 patients (50%) that developed EBV viremia were not in complete remission at the time of transplant, whereas 11 out of the 45 patients (24.44 %) that did not develop EBV viremia were in an incomplete remission at the time of transplant (p value: 0.05) (Table 1).With a median follow up of469 days, there were a total of 22 deaths among the 45 (48.9 %) patients that had no viremia, and 8 deaths amongst the 18 (44.4 %) patients that had viremia (p value: 0.75). There was no statistically significant difference in graft versus host disease (GVHD) incidence (p value: 0.79) or overall survival (555 days for patients with EBV reactivation versus not reached for patients without EBV reactivation, p value: 0.45) between these two groups (p value: 0.79) CONCLUSIONSIn this retrospective study assessing risk factors and outcomes of EBV viremia in patients following haploidentical transplants, we observed a 28.5 percent incidence of EBV viremia. Rituximab was effective in preemptive treatment of EBV viremia. However, no cases of PTLD were observed, even in those patients with sustained elevation in EBV titers. It is unclear how to manage asymptomatic elevations in viral titers after allogeneic transplantation in patients who are otherwise at low risk for development of PTLD. Previous data suggests that even high levels of EBV viremia lacks specificity for prediction of PTLD in post-transplant setting. Given these results, the utility of routine monitoring of EBV viral load after haploidentical transplant should be questioned in those who have received PTCy. [Display omitted] DisclosuresLin:Jazz Pharmaceuticals: Consultancy. Ganguly:Amgen: Other: Advisory Board; Seattle Genetics: Speakers Bureau.

Kidney Biopsy in Patients With Monoclonal Gammopathy: A Multicenter Retrospective Cohort Study.

Objectives: To analyze the clinical characteristics and renal pathological manifestations of patients with monoclonal gammopathy (MG) and kidney injury.Methods: This was a multicenter retrospective cohort study conducted at four tertiary hospitals in China. The study population comprised patients with MG admitted from January 1 2013 to December 31 2020. Hospitalization records, laboratory data, and kidney biopsy reports of all patients were collected from the electronic hospital information systems. The study outcomes included kidney disease progression and major hemorrhagic complications after kidney biopsy.Results: We identified 1,164 patients with MG, 782 (67.2%) of whom had underlying kidney injury. Of 101 patients who underwent kidney biopsy, 16 had malignant neoplasms. Amyloid nephropathy was the most common finding (n = 34, 33.7%), followed by membranous nephropathy (n = 18, 17.8%) and membranoproliferative nephritis (n = 8, 7.9%). Among 85 patients with non-malignant hematologic conditions who underwent kidney biopsy, 43 had MG of renal significance (MGRS) related lesions and 42 had MG-unrelated lesions. The risk of kidney disease progression was higher in patients with kidney injury than in patients without kidney injury.Conclusion: Among patients with MG and kidney injury, only 12.9% underwent kidney biopsy and more than 40% of these patients had MG-unrelated lesions. A kidney biopsy is safe and essential to maximize the possibility of correct diagnosis for patients with clinically suspected MG of renal significance (MGRS).

Activity report of the Bone Marrow Transplant Department of the Mohammed VI University Hospital, Marrakech, Morocco, over the period 2012- 2018

Introductionla greffe de cellules souches hématopoïétiques (GCSH) fait partie de l´arsenal de l´immunothérapie cellulaire à but curatif, elle est utilisée dans le traitement de plusieurs affections hématologiques malignes et non malignes ainsi que d´autres pathologies extra-hématologiques. Décrite depuis 1950 et introduite au Maroc depuis les années 2000, la GSCH reste encore jeune dans notre contexte avec plusieurs obstacles juridiques, financiers et organisationnels. L´objectif de notre travail est de rapporter l´expérience en matière de la greffe des cellules souches hématopoïétiques au sein du service d´hématologie clinique et de greffe de moelle osseuse du centre hospitalo-universitaire (CHU) Mohammed VI de Marrakech, étant un exemple d´un service des pays en voie de développement.Méthodesnous avons mené une étude rétrospective descriptive sur une durée de 7 ans.Résultatssoixante-six GCSH ont été réalisées, le myélome multiple représente la première indication dans notre série avec 30 autogreffes. Dans notre série, Le taux de mortalité avoisine les 20%, celui de rechute est à 23% et celui des complications est à 38%. Nos résultats malgré les difficultés restent encourageants, avec un recul assez important.Conclusiondes efforts restent à fournir pour améliorer les résultats de cette thérapie.

Omitting Fluoroquinolones Antibiotic Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation Does Not Increase Gram-Negative Bacteremia Rate or Transplant-Related Mortality

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely utilized as a curative treatment for malignant and non-malignant hematological conditions. Fluoroquinolone prophylaxis (FQ-P) is demonstrated to reduce the rate of blood stream infections (BSI) caused by gram-negative bacteria (GNB) during allo-HSCT and increases overall survival (OS), making this approach the standard of care. The available data show that during the transplantation period, the intestinal microbiome diversity profoundly decreases, which is associated with a significant increase in transplant-related mortality (TRM), acute graft-versus-host disease (aGVHD) related mortality and decrease in OS. FQ-P is reported to be a dominant factor in the perturbation of the gut microbiota, leading some centers to omit or modify transplant antibiotic prophylaxis regimens. The aim of the present study has been to evaluate the effects of FQ-P omission on the prevalence of gram-negative bacteria blood stream infections (GNB-BSI), GNB susceptibility to antibiotic treatment, mortality of patients with sepsis and overall TRM. This retrospective single-center study included all consecutive patients, admitted to the Rambam Department of Hematology for allo-HSCT between 01.01.2017 and 31.12.2019. The fact that at our center, FQ-P in allo-HSCT recipients was discontinued on 01.12.2018 allowed comparison of the outcomes in patients treated with and without such prophylaxis. GNB-BSI events registered within 30 days of admission were analyzed. The proportion of first-time GNB-BSI, the antibiotic susceptibility profile, day 30 and day 90 mortality among patients with GNB-BSI were compared. The assessment also included day 30 and day 90 overall TRM, mortality related to sepsis and aGVHD. During the evaluated period, 189 patients underwent allo-HSCT and were included in the analysis. FQ-P was administered to 125 patients and omitted in 64 individuals. GNB-BSI events occurred in 23 (18.4%) patients receiving FQ-P and in 17 (26.6%) patients who did not receive it (p=0.19). GNB susceptibility to FQ, piperacillin/tazobactam and meropenem increased from 38.1% to 58.8%, from 60% to 70.6% and from 85.7% to 94.1%, respectively, after FQ-P had been stopped (p=non-significant, NS). 30-day and 90-day mortality among patients with GNB-BSI did not increase in the post-FQ-P period (Table 1). Day 30 and day 90 overall TRM rates were 10.6% and 18.9%, respectively, with FQ-P versus 13.5% and 21.9%, respectively, without FQ-P (p=NS). Before FQ-P was stopped, sepsis was the cause of death in 56% of events and aGVHD in 16% and after FQ-P was stopped, the corresponding values were 46% and 23%, respectively (p=NS). FQ-P omission has not significantly increased the rate of GNB-BSI or affected the profile of GNB susceptibility to antibiotic treatment in patients undergoing allo-HSCT. Moreover, it has not significantly changed day 30 and day 90 mortality either among patients with GNB-BSI or in the entire study population. FQ-P omission in allo-HSCT recipients appears to be safe and its implementation could contribute to the preservation of intestinal microbiome diversity, potentially leading to improved post-transplant outcome. The findings of this study need to be further evaluated in large randomized trials. Disclosures No relevant conflicts of interest to declare.

Management of Primary Ovarian Insufficiency Among Childhood and Adolescent Leukemia and Lymphoma Survivors and Hematopoietic Stem Cell Transplant Recipients with Benign Hematological Conditions

Introduction: Primary ovarian insufficiency (POI) is a well-documented late effect of cancer survivors that increases risk for primary or secondary amenorrhea, osteoporosis, cardiovascular disease, vasomotor symptoms, infertility, urogenital atrophy, cognitive decline, and overall increased mortality. There is limited data on the existing management and follow up of POI among female patients exposed to cancer treatments. The purpose of this study was to describe outcomes and management of POI in childhood leukemia and lymphoma survivors and patients with non-malignant hematological conditions treated with hematopoietic stem cell transplant (HSCT) at Children's Medical Center (CMC) in Dallas, Texas. Methods: A retrospective analysis was performed for 26 female patients identified through electronic survivorship database containing about 1200 records of female survivors followed at the CMC long-term follow-up (LTFU) program. Inclusion criteria were female patients diagnosed with a hematological malignancy or underwent HSCT due to a benign hematological condition, less than 18 years old at the time of diagnosis, and documented POI as a late effect. Moreover, ICD-9 codes for ovarian dysfunction, amenorrhea, oligomenorrhea, delayed puberty, and infertility were used to identify additional patients. Results: The mean age of the cohort was 7.8 ± 5.2 years at hematological diagnosis. Fifty-four percent of patients were leukemia survivors and 23% had lymphoma. Benign hematological conditions requiring HSCT were aplastic anemia (n = 2), sickle cell disease (n = 1), hemophagocytic lymphohistiocytosis (n = 1), macrophage activation syndrome (n = 1), and thrombocytopenia-absent radius syndrome (n = 1). Almost all survivors (24/26) were HSCT recipients; one patient received two HSCTs. Average age at diagnosis of POI was 14.3 ± 3.2 years with average follow-up of 3.1 ± 2.7 years. At the time of POI diagnosis, 62% of survivors (16/26) were premenarchal. Average cyclophosphamide equivalent dose was 9.8 g/m2 for premenarchal and 13.8 g/m2 for postmenarchal females. In addition, 44% (7/16) of premenarchal compared to 50% (5/10) of postmenarchal female patients received either abdominopelvic or total body radiation. Thirteen out of 16 premenarchal females received estrogen replacement therapy (ERT; 10 oral, 3 transdermal; Table 1). The other 3 patients achieved spontaneous menarche; one was initiated on oral contraceptive pills (OCPs) subsequently. Five premenarchal patients were monitored for growth or pubertal progression prior to initiating treatment; one was monitored due to improving gonadotropins. In 9 out of 10 premenarchal patients prescribed oral ERT, the dose was increased until vaginal spotting occurred. All patients that developed vaginal spotting while on ERT were eventually transitioned to OCPs. Four patients received progesterone challenge or combined replacement therapy prior to transition from ERT to OCPs. Five out of 10 postmenarchal patients received oral ERT; all were eventually treated with OCPs, either after oral ERT or as initial treatment, except for one patient that was lost to follow-up. Two patients were treated with progesterone as challenge or combined replacement therapy but both received ERT previously and OCPs subsequently. Eight out of 10 postmenarchal patients resumed menses after POI treatment; the other two patients were not taking prescribed ERT or OCPs regularly. Conclusions: About 2% of females in our LTFU program were identified to have POI as a late effect, which is lower than reported in the literature, possibly due to younger age in our cohort. Almost all patients with POI were HSCT survivors. Our study shows that management of POI consists primarily of oral ERT with transition to OCPs and achieves resultant menarche in premenarchal female patients. Some premenarchal patients are monitored for growth and pubertal progression prior to treatment. In postmenarchal patients, treatment consists of OCPs that is sometimes preceded by ERT and leads to resolution of amenorrhea. Although OCPs demonstrated short-term benefit, perhaps replacement therapy at physiologic doses that imitate normal ovarian function more closely would have improved long-term outcomes. Additional studies are needed to investigate differences between hormone replacement therapy and OCPs and to identify the optimal approach in treating POI in cancer and HSCT survivors. Disclosures No relevant conflicts of interest to declare.

107 A Novel Transition Clinic For Adolescents and Young Adults With Non-Malignant Blood Disorders

Abstract Background Transition clinics have been introduced as a way to address the unique needs of adolescent and young adult populations (AYA). AYA transition clinics for non-malignant blood disorders that require continuous care and management such as chronic immune thrombocytopenia (ITP) and Hereditary Spherocytosis (HS), have not been evaluated to date. In addition, the concerns and barriers to accessing care among this population have not been previously described. Objectives To explore the needs of AYA patients with a non-malignant hematological condition in order to improve their transition to the adult healthcare system through a transition clinic. Design/Methods A prospective cross-sectional survey study was conducted with AYA patients with a new or existing non-malignant hematological condition attending an AYA clinic in Toronto. Patients were prospectively provided a survey prior to their clinic appointment via text message. Results Twenty eight patients completed the survey. Most of the patients were female (84.6%) and between 16-25 years of age. Patients were in school (57%) or working (25%). Over half of the patients (53%) reported to seeing a doctor at least once a year. In order to attend clinic appointments, 61% reported taking public transportation, 10% of patients receive a ride from their family and 29% of patients either drove themselves or walked/biked to clinic. Twenty-seven percent of patients were unsure of their condition, 50% did not know the cause of their condition, and over 70% of patients were concerned about their health at least once a day. Almost all patients had concerns about transitioning to adult care with concerns including 1) Adult care not understanding their needs, 2) Increased responsibility of their care and 3) Working with a new clinical care team. Despite their concerns of transition to an adult healthcare system, 67% of patients reported taking on most of the responsibility of their health including booking appointments, and taking their medication. However, the proportion of patients who wanted their parents at their appointments equaled those that did not. Finally, patients reported the following areas of their life their health has negatively impacted; 1) School, 2) Social interactions with family and friends, and 3) Work. Conclusion As seen in other diseases, AYA patients with non-malignant hematological conditions have concerns about transitioning to adult care. Young adults have varying degrees of interest and abilities regarding self-care, and are particularly vulnerable to the impact of health issues. Several factors need to be considered when caring for this unique population, that if addressed can improve the transition experience.

Infusion of Hematopoietic Stem Cell Products Using Pump Mechanism: An Approach Worth Consideration?

Hematopoietic stem cell transplantation using progenitor cells is a potentially curative treatment option for patients with high-risk malignancies and nonmalignant hematologic, immunologic, and genetic conditions. There is a need for evidence regarding safe practices and controlled infusion processes. Syringe and intravenous infusion pumps are not commonly used to deliver hematopoietic stem cell products (HPCs) due to a paradigm of thought that suggests that the pressure from the pump might damage the HPCs. Here, we describe a retrospective analysis of 114 patients who received HPC infusions using either a syringe or intravenous pump, providing support for this method along with successful engraftment data. This method may be a viable option to obtain reliable and consistent infusion rates, especially in pediatrics. To the best of our knowledge, this is the only study to date demonstrating safely using syringe and intravenous pump mechanisms in the setting of autologous and allogeneic pediatric stem cell transplantation.

A systematic approach to the endocrine care of survivors of pediatric hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is used in children to treat a variety of malignant and nonmalignant hematologic conditions and certain inborn errors of metabolism. Survivors of HSCT are markedly affected by disease and treatment toxicity. Endocrine complications are among the most commonly reported chronic health conditions in this population. In this review, we summarize the most common endocrine late effects after pediatric HSCT. We also highlight the importance of systematic and longitudinal evaluations to achieve early diagnoses and treatment for these conditions and improve the long-term health outcomes for patients who received HSCT as children.

Post-Transplant Cyclophosphamide in Allogeneic Bone Marrow Transplantation for the Treatment of Benign Hematologic Diseases

Post-transplant cyclophosphamide (PTCy) based GVHD prevention regimens are an emerging platform in allogeneic transplantation for hematological malignancies and are being prospectively compared to traditional standards. We present a single-center retrospective series of adult allogeneic bone marrow transplantation with the use of post-transplant cyclophosphamide in the setting of benign hematological conditions. Ten patients were treated between 2013 to 2019. Non-myeloablative conditioning consisted of rATG 0.5mg/kg on day (D) -9, 2mg/kg on D-7,-8 (ATG was in one patient with DBA), fludarabine 30mg/m2 daily from D-6 to D-2, cyclophosphamide 14.5mg/kg D-6 and D-5, and 200cGy of total body irradiation D-1. The bone marrow graft was administered on D0. GVHD prophylaxis consisted of post-transplant cyclophosphamide at 50mg/kg/day IV D+3, and +4 mycophenolate mofetil (MMF) at 15 mg/kg 3 times daily (maximum daily dose 3000 mg) starting on D+5 with taper beginning at D+35 to be off around D+100, and tacrolimus on D+5 with a target trough of 5-10 ng/mL with tapering beginning at D+180 with a goal to be off at D+360 in the absence of any GVHD. The median age at the time of transplantation was 42 (range 24-73) and 4 of 10 were female. Diagnoses include severe aplastic anemia (n=6), Diamond-Blackfan Anemia (n=2), paroxysmal nocturnal hemoglobinuria (n=1), and pure red cell aplasia (n=1). Median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) was 0 (range 0-5). Bone marrow donors were haploidentical donors (n=6), fully matched unrelated donors(n=3), and fully matched sibling (n=1). The median donor age was 31 (range 22-53). Donor marrow grafts had a median CD34+ cell count of 4.41 x 106/kg recipient ideal body weight (range 1.12 x 106 to 20.5 x 106). At a median follow-up of 17 months (range 3, 63) after transplantation, all patients are alive, with donor-derived hematopoiesis and free of significant acute or chronic GVHD. Neutrophil and platelet engraftment occurred at a median of 21 (range 16-34) days and 33 (21-65) days, respectively, after transplantation. The patient with pure red cell aplasia developed secondary graft failure and required a second transplant using a peripherally collected graft with the same fully matched unrelated donor. For all recipients, median day +30 unsorted chimerism was 100% (range 71-100%). Patients have not experienced significant acute or chronic GVHD. There were no cases of grade II-IV acute GVHD observed. Chronic GVHD was observed in 3 patients with ocular disease (two mild, one moderate). All patients who are over 12 months after transplantation are off systemic immunosuppression. Three patients experienced CMV reactivation, two required preemptive treatment with oral valganciclovir, while the third had a single positive low level positive CMV PCR that resolved spontaneously. Three patients had low level positive EBV viremia, none of which required pre-emptive treatment. Other significant infectious complications before day +100 included BK cystitis in three patients, influenza, adenovirus cystitis, clostridium difficile colitis, streptococcal and enterococcal polymicrobial endocarditis, and enterococcal bacteremia. Significant non-infectious complications were rare. One patient experienced engraftment syndrome which resolved quickly with systemic steroid administration. Another patient suffered a small spontaneous subdural hemorrhage day +10 after transplantation, but subsequently made a full neurologic recovery. Post-transplant cyclophosphamide based non-myeloablative allogeneic bone marrow transplantation appears safe and effective for patients with non-malignant hematologic conditions and should be prospectively compared to historical regimens. Table 1. Cohort Characteristics. SAA - Severe aplastic anemia, DBA - Diamond Blackfan anemia, ATG- anti-thymocyte globulin, CSA- cyclosporine, Cy-cyclophosphamide, haplo- haploidentical Disclosures Defilipp: Incyte: Research Funding. Frigault:Nkarta: Consultancy; Novartis: Consultancy; Foundation Medicine: Consultancy; Xenetic: Consultancy; Juno/Celgene: Consultancy; Kite/Gilead: Honoraria; Incyte: Consultancy. Chen:Incyte: Consultancy; Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy; Abbvie: Consultancy.

Hematopoietic Stem Cell Transplantation Without the Use of Blood Components by the Patient's Choice: Experience of 2 Brazilian Centers.

Hematopoietic stem cell transplantation (HSCT) has been used to treat many malignant and nonmalignant hematologic conditions; however, the use of HSCT in patients who refuse blood transfusions has rarely been described in the literature, and no data have been published concerning haploidentical HSCT without the use of blood products. The aim of this study is to describe the experience of a Brazilian group in performing 21 HSCTs without the use of blood components in the first 100 days after transplantation, which is the period corresponding to the greatest risk of toxicity for this procedure. We developed 21 HSCTs without transfusion support in 19 patients admitted to 2 Brazilian transplantation centers. The patients were subjected to stem cell mobilization and different conditioning regimens. No mortality related to the procedure occurred among the transplant recipients. The global survival rate after 100 days, which is the period related to the immediate toxicity of HSCT, was 94.7%, and the median duration of follow-up was 980 days, with an overall survival rate of 68.4%. Thus, refusal of blood transfusion is not an absolute contraindication for HSCT. This therapy is feasible in specific situations when the patient clearly expresses a desire to avoid blood transfusions and when favorable clinical conditions are achievable with strict, specialized medical monitoring.

Posttransplant cyclophosphamide in allogeneic bone marrow transplantation for the treatment of nonmalignant hematological diseases.

We present a single-center retrospective series of allogeneic bone marrow transplantation (BMT) with the use of posttransplant cyclophosphamide (PTCy) in the setting of nonmalignant hematological conditions. Nine patients were treated between 2013 and 2019. Nonmyeloablative conditioning consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation (200cGy) followed by allogeneic bone marrow infusion. Post-BMT GVHD prophylaxis was with PTCy, tacrolimus, and mycophenolate mofetil. At a median follow-up of 24 months (range 4, 63), all patients are alive, with donor-derived hematopoiesis and free of significant acute or chronic GVHD. Donors were haploidentical (n = 6), fully matched unrelated (n = 2), and fully matched sibling (n = 1). Neutrophil and platelet engraftment occurred at a median of 21 days and 33 days, respectively, after transplantation. Three patients (3/9, 33%) experienced stage 1-2 acute skin GVHD. The only cases of chronic GVHD are in three patients (3/9, 33%) with ocular disease (two mild, one moderate). No patient has required systemic immunosuppression beyond 12 months after BMT. PTCy-based nonmyeloablative allogeneic BMT is safe and effective for nonmalignant hematologic conditions and should be prospectively compared with historical regimens.

Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation

BackgroundIncreasing evidence reveals the importance of the microbiome in health and disease and inseparable host-microbial dependencies. Host-microbe interactions are highly relevant in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), i.e., a replacement of the cellular components of the patients’ immune system with that of a foreign donor. HSCT is employed as curative immunotherapy for a number of non-malignant and malignant hematologic conditions, including cancers such as acute lymphoblastic leukemia. The procedure can be accompanied by severe side effects such as infections, acute graft-versus-host disease (aGvHD), and death. Here, we performed a longitudinal analysis of immunological markers, immune reconstitution and gut microbiota composition in relation to clinical outcomes in children undergoing HSCT. Such an analysis could reveal biomarkers, e.g., at the time point prior to HSCT, that in the future could be used to predict which patients are of high risk in relation to side effects and clinical outcomes and guide treatment strategies accordingly.ResultsIn two multivariate analyses (sparse partial least squares regression and canonical correspondence analysis), we identified three consistent clusters: (1) high concentrations of the antimicrobial peptide human beta-defensin 2 (hBD2) prior to the transplantation in patients with high abundances of Lactobacillaceae, who later developed moderate or severe aGvHD and exhibited high mortality. (2) Rapid reconstitution of NK and B cells in patients with high abundances of obligate anaerobes such as Ruminococcaceae, who developed no or mild aGvHD and exhibited low mortality. (3) High inflammation, indicated by high levels of C-reactive protein, in patients with high abundances of facultative anaerobic bacteria such as Enterobacteriaceae. Furthermore, we observed that antibiotic treatment influenced the bacterial community state.ConclusionsWe identify multivariate associations between specific microbial taxa, host immune markers, immune cell reconstitution, and clinical outcomes in relation to HSCT. Our findings encourage further investigations into establishing longitudinal surveillance of the intestinal microbiome and relevant immune markers, such as hBD2, in HSCT patients. Profiling of the microbiome may prove useful as a prognostic tool that could help identify patients at risk of poor immune reconstitution and adverse outcomes, such as aGvHD and death, upon HSCT, providing actionable information in guiding precision medicine.

Preconditioning Risk Factors Affecting Survival and Remission of Adult Egyptian Patients with Hematological Malignancies Undergoing Hematopoietic Stem Cell Transplantation

malignant and non-malignant hematologic conditions and in the treatment of various solid tumors. Since the 1970s, steady progress has been made and HSCT is now regarded as a routine, rather than an experimental, approach in the treatment of a number of conditions, which would have proven fatal earlier on. Objective: Our study aimed to determine the most important preconditioning prognostic factors affecting the overall survival (OS), disease free survival (DFS) and relapse rate (RR) of adult Egyptians with hematological neoplasms who are treated with HSCT, whether autologous or allogeneic, and in turn minimizing the morbidity and mortality of those patients and improving their quality of life. Patients and methods: The study evaluated 98 adult patients with different hematological malignancies who underwent HSCT (whether autologous or allogeneic) at Stem Cell Transplantation Unit of Ain-Shams University from January 2014 to December 2018. Results: In our study, in the group of allogenic transplantation, There was a statistically significance at overall survival with number of chemotherapy cycles with P =0.028. Regarding post HSCT relapse and post HSCT mortality 11 patients (37.9%) died in the group that received ≤4 cycles of chemotherapy and 16 patients (55.2%) died in the group that received > 4 cycles of chemotherapy. Conclusion: Five-year overall and progression-free survival rose for allogeneic and autologous HSCT after the decade of their introduction