Bone Marrow Transplantation Therapy Research Articles

Post-GWAS Validation of Target Genes Associated with HbF and HbA2 Levels.

Genome-Wide Association Studies (GWASs) have identified a huge number of variants associated with different traits. However, their validation through in vitro and in vivo studies often lags well behind their identification. For variants associated with traits or diseases of biomedical interest, this gap delays the development of possible therapies. This issue also impacts beta-hemoglobinopathies, such as beta-thalassemia and sickle cell disease (SCD). The definitive cures for these diseases are currently bone marrow transplantation and gene therapy. However, limitations regarding their effective use restrict their worldwide application. Great efforts have been made to identify whether modulators of fetal hemoglobin (HbF) and, to a lesser extent, hemoglobin A2 (HbA2) are possible therapeutic targets. Herein, we performed the post-GWAS in vivo validation of two genes, cyclin D3 (CCND3) and nuclear factor I X (NFIX), previously associated with HbF and HbA2 levels. The absence of Ccnd3 expression in vivo significantly increased g (HbF) and d (HbA2) globin gene expression. Our data suggest that CCND3 is a possible therapeutic target in sickle cell disease. We also confirmed the association of Nfix with γ-globin gene expression and present data suggesting a possible role for Nfix in regulating Kruppel-like transcription factor 1 (Klf1), a master regulator of hemoglobin switching. This study contributes to filling the gap between GWAS variant identification and target validation for beta-hemoglobinopathies.

Bone marrow transplantation and bone marrow-derived mesenchymal stem cell therapy in epidermolysis bullosa: A systematic review.

Epidermolysis bullosa (EB) is a genodermatosis that lacks effective treatments and requires supportive care for its severe, life-threatening manifestations. Bone marrow transplantation (BMT) and its derived cells have been suggested to improve clinical symptoms and quality of life. A comprehensive search was conducted for publications evaluating BMT and bone marrow-derived mesenchymal stem cell (BM-MSC) therapy for EB in PubMed/MEDLINE, Google Scholar, and Cochrane databases from inception until June 2023. A total of 55 participants with severe forms of EB had BMT and/or BM-MSCs, with recessive dystrophic EB as the most common EB type; 53 (96.4%) patients had better wound healing, and 3 (5.5%) patients died of sepsis. The most common adverse events reported were graft failure, sepsis, graft-versus-host disease, and renal insufficiency. Allogeneic BMT is a high-risk procedure with possible benefits and adverse events. BM-MSCs revealed favorable outcomes to improve the safety of EB cell-based therapy by minimizing the risk of serious adverse events, reducing blisters, and accelerating wound healing. Further studies are needed to assess the treatment's long-term effects and clarify the risk/benefit ratio of procedure versus conventional therapy.

Impact of Hydroxyurea on Clinical and Biological Parameters of Sickle Cell Anemia in Children in Abidjan.

Background: The lives of individuals affected by sickle cell disease are marked by painful crises sometimes accompanied by complications. Curative treatments such as bone marrow transplantation or gene therapy exist, but are not currently performed in Côte d'Ivoire. Treatment with hydroxyurea remains an effective alternative. The aim of our study is to contribute to improving the management of children with sickle cell disease.
 Methods: We conducted a prospective observational study from November 2017 to April 2019 at the at the Yopougon University Hospital. Children aged 5 to 15 years experiencing at least 3 vaso-occlusive crises (VOC) per year were included in the study after obtaining informed and written consent from their parents. Each patient received a daily dose of 15mg/kg of hydroxyurea.
 Results: The mean age of the children was 9 years. More than 75% of patients were homozygous SSFA2 major sickle cell individuals. After 6 months on hydroxyurea, our study observed rates of 84.4%, 100%, and 97.8%, respectively, for the absence of vaso-occlusive crises, hospitalization, and transfusion. Biologically, from M0 to M12 the mean hemoglobin level increased significantly, from 7.24 to 8.55 g/dL; white blood cell (WBC) and platelet counts decreased; Fetal hemoglobin (Hb F) increased significantly from 10.3% to 19.7%. Biochemical parameters within normal ranges, except for a moderate treatment-related increase in transaminases.
 Conclusion: The induction of fetal hemoglobin (Hb F) production through hydroxyurea intake is the primary mechanism by which hydroxyurea modifies the pathogenesis of sickle cell disease

Coping in patients with hematologic malignancies undergoing hematopoietic cell transplantation

AbstractPatients undergoing hematopoietic cell transplantation (HCT) must cope with physical and psychological symptoms. Yet, studies examining pre-HCT coping are limited. We aimed to characterize pre-HCT coping, evaluate the association of coping with baseline quality of life (QOL) and psychological distress, and identify sociodemographic factors associated with pre-HCT coping. We conducted a cross-sectional analysis of baseline data from a multisite randomized supportive care intervention trial among patients with hematologic malignancies undergoing allogeneic or autologous HCT. We assessed patient-reported QOL, psychological distress, and coping within 72 hours of admission for HCT. We used the median split method to dichotomize coping and multivariate regression analyses to characterize the association of coping with psychological distress and QOL. Of patients awaiting HCT (n = 360; mean age, 55.4 years; 49.7% autologous), 43.5% were high users of approach-oriented coping, whereas 31.3% were high users of avoidant coping. Patients reported high use of emotional support (60.9%), acceptance (51.2%), self-blame (33%), and denial (31.3%). Older age (≥65 years) was associated with less frequent use of avoidant coping (odds ratio, 0.5; P = .01). Approach-oriented coping was associated with better pre-HCT QOL (Beta(B) = 6.7; P = .001), and lower depression (B = −1.1; P = .001) and anxiety (B = −0.9; P = .02) symptoms. Avoidant coping was associated with worse pre-HCT QOL (B = −13.3; P < .001) and symptoms of depression (B = 1.9; P < .001), anxiety (B = 3.1; P < .001), and posttraumatic stress disorder (B = 8.1; P < .001). Pre-HCT coping is strongly associated with psychological distress and QOL. These data support the need for interventions to address coping during HCT hospitalization. This clinical trial was registered at www.clinicaltrials.gov as #NCT03641378.

Quality of life and financial toxicity of hematopoietic stem cell transplant recipients in COVID-19.

to evaluate and correlate the quality of life and financial toxicity of adult patients undergoing hematopoietic stem cell transplantation during the COVID-19 pandemic. observational, analytical study, carried out with 35 patients in a reference hospital for transplantation in Latin America. For data collection, the Functional Assessment Cancer Therapy Bone Marrow Transplantation and COmprehensive Score for Financial Toxicity questionnaires were used. Spearman and Mann-Whitney correlation tests were used for data analysis. general quality of life during COVID-19 had a low score (67.09/108) with greater impairment in functional well-being (14.47/28), social well-being (16.76/28) and additional concerns (23.41/40). The means of the allogeneic group were lower than those of the autologous group in all domains, showing a significant difference in relation to additional concerns (p=0.01) and in the treatment evaluation index (p=0.04). Financial toxicity was considered to have a slight impact (22.11/44). There was a relationship, albeit not significant, between quality of life and financial toxicity (p=0.051). the quality of life of the sample was low; there is a correlation between quality of life and financial toxicity, although not significant. The higher the financial toxicity, the lower the quality of life.

Qualidade de vida e toxicidade financeira dos transplantados de células-tronco hematopoéticas na COVID-19

Objective: to evaluate and correlate the quality of life and financial toxicity of adult patients undergoing hematopoietic stem cell transplantation during the COVID-19 pandemic. Method: observational, analytical study, carried out with 35 patients in a reference hospital for transplantation in Latin America. For data collection, the Functional Assessment Cancer Therapy Bone Marrow Transplantation and COmprehensive Score for Financial Toxicity questionnaires were used. Spearman and Mann-Whitney correlation tests were used for data analysis. Results: general quality of life during COVID-19 had a low score (67.09/108) with greater impairment in functional well-being (14.47/28), social well-being (16.76/28) and additional concerns (23.41/40). The means of the allogeneic group were lower than those of the autologous group in all domains, showing a significant difference in relation to additional concerns (p=0.01) and in the treatment evaluation index (p=0.04). Financial toxicity was considered to have a slight impact (22.11/44). There was a relationship, albeit not significant, between quality of life and financial toxicity (p=0.051). Conclusion: the quality of life of the sample was low; there is a correlation between quality of life and financial toxicity, although not significant. The higher the financial toxicity, the lower the quality of life.

Knowledge and Perceptions about Curative Therapies for Sickle Cell Disease and Hydroxyurea Among Caregivers and Patients at a Large Tertiary Care Center: A Survey Study

Background: Sickle Cell Disease (SCD) affects approximately 100,000 individuals in the United States. Patients require regular follow-up and monitoring to prevent serious complications. Even with rigorous monitoring, health outcomes can be poor due to pain-seeking stigma and other social determinants of health, namely racial, social, and economic disparities. According to the National Assessment of Health Literacy published in 2006, 36% of adults have limited health literacy in the United States. Among SCD populations, disease-specific knowledge can play a vital role in improving pain control and access to appropriate maintenance therapies. Aims:The purpose of this study is to investigate the knowledge and perceptions of patients with SCD and their caregivers attending The Valerie Fund Pediatric Hematology-Oncology Center at the Children's Hospital of New Jersey in Newark, NJ regarding their disease, complications, genetic impact, general anticipated course of treatment or natural history of disease. Hydroxyurea (HU) and curative therapies include bone marrow transplant (BMT) and gene therapy (GT). Methods: We surveyed 85 participants, accounting for 79 patients as some surveys were completed by each the patient and caregiver. Sixty-six (83.5%) participants were caregivers and 13 (16.5%) were children with sickle cell disease between 12- and 20-years-old. Most patients identified as black, African, or African American (76; 96.2%) with 2 (2.5%) Hispanic patients, and 1 (1.3%) white patient. Forty-three patients (54.4%) were female and 36 (45.6%) were male. The average age of the patients was 10.9 years with a standard deviation of 5.7 years. More than half of patients were HbSS genotype (51; 64.6%). Remaining genotypes were HbSC (21; 26.6%), HbS-β 0-thalassemia (5; 6.3%), and HbS-β +-thalassemia (2; 2.5%). Forty-six (58.2%) of patients had received HU and 33 (41.8%) had not. Results: When assessing background knowledge of sickle cell and heritable risk, most participants could correctly identify the patient's sickle cell genotype (74; 87.1%) and most caregivers could correctly identify their own genotype (49; 74.2%). However, many caregivers exhibited limited understanding of genetic risk with only 18 (27.2%) correctly identifying the one in four chance of having a subsequent child with SCD when both parents are carriers. The results revealed participants could not distinguish between treatment for SCD and sickle cell trait; few participants correctly identified that sickle cell trait is not an indication for treatment with HU (8; 10.1%), BMT (4; 5.1%) or GT (6; 7.6%). Baseline knowledge about BMT and GT was limited. Only 27 (34.1%) participants correctly identified that BMT is indicated for treating patients with HbSS or HbS-b 0-thalassemia, and only 9 (11.4%) participants correctly identified this treatment population for GT. BMT knowledge was slightly greater than GT knowledge, namely that 60.1% (48) correctly identified the benefits of BMT for SCD patients, including decreased pain, decreased need for pain medication, decreased length of hospital stay, and cure, and that either bone marrow, stem cells, or blood could be transplanted materials. Most patients did not correctly identify these benefits of GT (55; 70%), nor could they identify the source of blood or stem cells for GT (65; 82.3%). The ability to correctly identify the benefits of HU for sickle cell disease (48; 60.8%) was positively associated with the ability to correctly identify the benefits of BMT (p-value 0.0091) and GT (p-value 0.0438) using Fisher's exact test with 95% confidence interval. Conclusion: These results suggest that dedicated teaching about HU, a common treatment for SCD, can result in greater patient knowledge about newer and curative treatment options of bone marrow transplant and gene therapy. These findings underscore the necessity of implementation of comprehensive patient teaching that is inclusive of population education levels, literacy rates, health literacy rates, and other cultural and societal factors.

Checkpoint Inhibitors and Allo-SCT in Hodgkin Lymphoma: A Matter of Time - a Study By the SFGM-TC

Introduction: Allogeneic stem cell transplantation (allo-SCT) for patients with relapsed/refractory Hodgkin lymphoma (r/R HL) after autologous transplantation is now an established option. Many patients receive Check-Point Inhibitors (CPI) as relapse treatment. Nevertheless, concerns have been previously reported on higher risk of acute graft versus host disease (aGVHD) after CPI exposure, without any control group to elucidate risk factors. Methods: We conducted a multicentric retrospective case control study on behalf of the Francophone Society for Bone Marrow Transplantation and Cell Therapy to compare outcomes after allo-SCT for patients with r/R HL who were exposed or not exposed to CPI. Results: Between 2015 and 2018, 149 patients underwent allo-SCT for r/R HL in 21 centers. CPI was used for 50 patients (n=48 Nivolumab, n=2 Pembrolizumab). We did not identify any differences regarding baseline characteristics. Reduced intensity conditioning (RIC) was commonly used (90.2%), with Peripheral Blood Stem Cells (75.7%). A majority of patients had haploidentical (44.6%), followed by siblings (28.4%), matched unrelated (24.3%) and mismatched unrelated donors (2.7%). Cumulative incidence (CI) of aGVHD grade ≥II in the whole cohort was 39.6% and 14.8% developed a severe form (grade III-IV). There were no differences between CPI (n=50) and no CPI cohorts (n=99), regarding CI of aGVHD of any grade (respectively 58% and 57.6%, p=1.00), grade ≥II (respectively 36% and 41.4%, p=0.65), severe aGVHD (grade III-IV, respectively 12% and 16.2%, p=0.67) and chronic GVHD (respectively 26% and 34.3%, p=0.24), as described in Table 1. We did not observe excess of mortality from GVHD between both groups. The time interval between the last CPI injection and allo-SCT was found to be the only significant factor associated with a higher incidence and severity of aGVHD, as depicted in Figure 1. The median time from the last CPI injection and allo-SCT was 50 days [33;103]. Specifically, within 30 days, the incidence of severe aGVHD was significantly increased at 41.7% compared to only 2.7% in the control group (p=0.002). No severe forms were observed after 60 days, but it persisted a higher risk of aGVHD grade ≥II even after 60 days of delay. Thus, a higher percentage of patients required systemic therapy for aGVHD within 120 days compared to after 120 days (45% vs 0% respectively, p=0.03). The delay of CPI treatment did not impact the CI and severity of chronic GVHD or CI of relapse after allo-SCT. Of note, post-transplant cyclophosphamide did not reduce CI of aGVHD. With a median follow-up of 34.7 months, the 2-year Overall Survival, Relapse Free Survival and GVHD free, Relapse Free Survival (GRFS) were respectively 69.9% (IC95 41.1-78.5), 67.1% (IC95 58.8-76.7) and 48.5% (IC95 40.3-58.4), without differences between CPI and no CPI cohorts. Two-year non relapse mortality was 17.4% in whole cohort, without hepatic sinusoidal obstruction syndrome nor steroid-requiring febrile syndrome in CPI cohort. Conclusion: CPI use before allo-SCT within 60 days before allo-SCT can lead to significant severe aGVHD, with persisting higher risk of aGVHD grade ≥II even after 60 days of delay. This highlights the importance of exercising caution when administering CPI injections within 60 days before allo-SCT. There is need to develop GVHD prophylaxis strategies in this population at risk. The findings from this study may help inform clinical decision-making and management of HL patients undergoing allo-SCT.

Patients, Parents and Providers Perspectives Toward Treatment Options for Sickle Cell Disease

Introduction Sickle cell disease (SCD) is the most common hemoglobinopathies in the world. It is more prevalent in malaria endemic areas where most low-and-middle-income countries (LMIC) are found. Because of challenges in accessing care, persons with SCD (PWSCD) in these settings have a poor outcome and up to 50% die before the age of five years in some places. Those who survive early childhood develop complications at a young age causing their families significant emotional and socioeconomic distress. Effort in LMIC is being directed toward screening for SCD and early initiation of treatment which has improved overall survival and quality of life of PWSCD. However, there are concerns about adherence to treatment due to pill fatigue, persistent SCD symptoms, end organ damage despite available treatment, and side effects of medications. With improved care, SCD is evolving into a chronic illness even in LMIC and PWSCD are surviving into adulthood. These countries will soon face the challenge of handling lifestyle and health demands of an emerging adult and aging PWSCD. There have been significant advances in disease modifying (DM) and curative treatment for SCD in high-income-countries (HIC) and the two promising treatment modalities for cure are bone marrow transplant and gene therapy which can be life changing for PWSCD and their families despite treatment related adverse events. Curing SCD may help prevent long-term complications. It is therefore important to explore the perspectives of PWSCD, their parents and SCD providers toward traditional and novel therapies for SCD as the initial step in planning for improved access to SCD treatment in LMIC. Objective To explore the attitudes of PWSCD, Parents (caregivers) of PWSCD and SCD care providers toward traditional and novel therapies for SCD in a LMIC setting. Methodology This was a mixed methods study conducted at a referral facility for PWSCD in western Kenya. It included 5 focused group discussions (FGD) of 6 - 7 consented participants; 2 with patients, 2 with parents and 2 with SCD providers. FGDs were conducted by trained clinicians and lasted 2 hours. A discussion guide which included information on novel therapies was applied to direct the audio-recorded sessions conducted in local dialect. FGD and analysis were iterative with each thematic content analyzed independent of the others and key concepts arising from these sessions explored. Necessary adjustments were made to the discussion guide for subsequent sessions based on emerging themes. The recorded material was then transcribed in verbatim and translated for analysis using a qualitative analysis tool. Results and Discussion This study enrolled 13 PWSCD, 13 parents of PWSCD and 6 SCD providers (n=32). Participants had similar attitudes towards SCD barriers and novel treatments. 96.9% of participants reported using hydroxyurea and folic acid for themselves, their loved one, or their PWSCD. Over the past year, 83.1% of PWSCD reported painful crisis while 33.% had been hospitalized despite adherence to treatment (table 1). Most participants (65.4%) would consider using novel SCD treatments with hesitations being cost, treatment adverse effect, and distance to treatment location. After the educational intervention, participants were more likely to opt for gene therapy (65.4%) than stem cell transplant (19.2%) or remaining on their current regimen (15.6%) (Table 2). Only one SCD providers' FGD was conducted due to their limited availability from competing clinical duties. Some patients who reported being on recommended treatment continued to have health events and complications that made them, their parents or providers want an alternative treatment. Most participants preferred a curative treatment option for their disease despite the challenges mentioned, which highlighted their willingness to participate in clinical trials. While there are infrastructural challenges in LMIC, they have the highest number of PWSCD that would benefit from new DM and curative treatment for SCD despite being underrepresented in clinical trials. They are the most impacted by complications associated with SCD due to sub-optimal care thus need for action to reverse this. Conclusion This study highlights the importance of involving population in LMIC in efforts to find better treatment for PWSCD. There is a need to conduct a similar study involving a larger cohort in future to further explore more perspectives.

Clinician and Administrator Perspectives on Chimeric Antigen Receptor (CAR) T-Cell Therapy Outpatient Administration in Relapsed or Refractory Multiple Myeloma (RRMM) in the United States (US): A Qualitative Study

Background: The use of CAR-T cell therapy has transformed treatment paradigms in B-cell malignancies. Ciltacabtagene autoleucel (cilta-cel) was approved for use in RRMM after four or more prior lines of therapy in 2022. While the pivotal studies exclusively treated patients in an inpatient setting, robust infrastructure planning at some centers across US has fostered outpatient administration of the commercially available product. Outpatient administration of CAR-T is more desirable due to superior financial sustainability, lower healthcare resource utilization, and greater patient autonomy during the treatment. Hence, we conducted a qualitative study to evaluate clinical and administrative perspectives and trends in outpatient administration of commercialized cilta-cel with an aim to understand best practices from certified CAR-T centers in the USA. Methods: A targeted literature review was conducted to better understand current practices around outpatient administration of CAR-T, and inform the development of primary research materials for designing subsequent interviews. Next, two 60-minute exploratory interviews were conducted with multi-stakeholder participants (n=5) from two certified cilta-cel centers, each with significant volume of outpatient administration of cilta-cel. Following the qualitative analysis of interviews, two 90-minute panels were conducted with multi-stakeholder participants (n=14) from six certified cilta-cel centers, including centers from exploratory interviews, focusing on clinical and administrative topics across the patient journey. Results: Each center in the study treated approximately 15-30 patients with cilta-cel in the outpatient setting. Using Likert scales, participants from all centers ranked space/capacity as the most important factor in decision-making process for outpatient cilta-cel administration, and ranked reimbursement incentives as a highly (67% of participants) or a moderately (33%) important factor. All participants agreed that having a dedicated outpatient infrastructure (dedicated space such as bed availability and internal processes including standard operating procedures (SOPs)), 24/7 support, outpatient bone marrow transplant (BMT) or cell therapy experience, and robust multidisciplinary teams were key to setting-up successful outpatient centers for cilta-cel therapy. The participants agreed that cilta-cel can be administered safely in an outpatient setting due to generally predictable, delayed onset of potential AEs, except in patients with significant comorbidities or organ dysfunction. Participants also considered caregiver support and lodging availability as factors of importance for outpatient administration. Institutionally established AE monitoring protocols are critical for safe use of cilta-cel in an outpatient setting. Over 50% of the centers interviewed have recently started to administer tocilizumab to treat mild grade 1 cytokine release syndrome (CRS) in an outpatient setting. Based on the findings across the phases of research, the patient journey for outpatient administration of cilta-cel was updated (Figure 1). While patients may be admitted for toxicity events, 100% of centers interviewed had 24-hour coverage and bed availability for these patients if needed. Conclusions: Overall, this study further supports the notion that centers can safely administer cilta-cel in an outpatient setting, if appropriate infrastructure is in place. Additional best practices for new outpatient sites include adequate infrastructure, SOPs, a well-trained and multidisciplinary team, and education of patients and caregivers (Table 1). Outpatient management and earlier intervention for low-grade AEs is currently evolving, with more real-world research required. Continued expert sharing of best practices can aid centers in implementing outpatient administration of CAR-T therapies. Funding: This analysis was supported by Janssen Research &amp; Development, LLC and Legend Biotech USA, Inc

1015. A multicenter evaluation of antimicrobial utilization in hospitalized bone marrow transplant (BMT) and T-cell therapy (CAR-T) patients, and the impact on rates of C. difficile infection (CDI)

Abstract Background Benchmarking antimicrobial utilization through the National Healthcare Safety Network (NHSN) will be a CMS requirement in 2024. NHSN benchmarking is available for some hospitalized populations, but there are currently no benchmarking capabilities for BMT units. Additionally, there are no published manuscripts describing antimicrobial utilization in BMT hospitals. Intra-Hospital BMT Antimicrobial Utilization Data from the Vizient Clinical Data Base used with permission of Vizient, Inc. All rights reserved. Methods This retrospective multicenter study was conducted by the Vizient Pharmacy Network AMS Committee. Antimicrobial utilization was evaluated for Vizient-member hospitals that treat at least 50 BMT patients per year. Vizient Clinical Database was used to identify patients via ICD10 codes for allogeneic transplant, autologous stem cell transplant and CAR-T therapy. Total antimicrobial days of therapy (DOTs) per 1,000 patient days was evaluated across all hospitals for each type of transplant, and for 9 different groups of antimicrobials (anti-pseudomonal beta-lactams, carbapenems, MDRO gram-negatives, fluoroquinolones, MRSA-active agents, antifungals, CMV-active agents, high-risk C. difficile agents, and C. difficile treatments). ANOVA was used to compare antimicrobial utilization across hospitals and across antimicrobial types. Results A total of 90 hospitals and 63,379 patient encounters were included in the analysis from 2018-2021. The median total antimicrobial utilization for allogeneic, autologous, and CAR-T patients were 2,562, 2,083, and 2,187 DOTs per 1,000 patient days, respectively. Figure 1 describes the variability in intra-hospital prescribing for 9 antimicrobial categories. Hospitals with higher antimicrobial utilization rates in allogenic transplant patients were associated with a higher incidence of CDI in this population (p=0.0368). Conclusion Significant variation in intra-hospital antimicrobial utilization exists for allogeneic transplant, autologous stem cell transplant, and CAR-T patients; and across 9 different categories of antimicrobials! Increasing rates of antimicrobial utilization were associated with increases in C. difficile infections in allogeneic transplants. Benchmarking antimicrobial utilization in BMT patients may help improve systematic approaches to minimize unnecessary antimicrobial exposure. Disclosures All Authors: No reported disclosures

Generation of two isogenic sickle cell disease induced pluripotent stem cell lines from testicular fibroblasts

Curative bone marrow transplantation (BMT) therapies for sickle cell disease (SCD) can cause infertility. The Fertility Preservation Program (FPP) in Pittsburgh cryopreserves testicular tissues for SCD patients prior to BMT in anticipation that those tissues can be thawed in the future and matured to produce sperm. Here, we generated and validated two isogenic patient-derived induced pluripotent stem cell (iPSC) lines from testicular biopsy fibroblasts of a 12-year-old SCD patient.

Oncology Care at Home: A Patient-Centered Approach to Managing Care for Bone Marrow Transplant and CAR-T Cell Therapy Patients

Introduction. More than half of patients with cancer who receive cytotoxic chemotherapy and/or immunotherapies experience deleterious side effects such as febrile neutropenia, infection, neurotoxicity, and cytokine release syndrome. Early intervention and treatment for these side effects can help avoid complications and improve outcomes, but delays in treatment administration are common as most outpatient management approaches depend on patient self-assessment and patient-initiated pursuit of follow-up care. Remote patient monitoring through digital health technologies offers the opportunity to bridge this gap without imposing undue burden on either patients or healthcare providers. This feasibility study assessed the results of a technology-assisted in-home oncology care program to remotely monitor bone marrow transplant and CAR T-cell therapy patients and provide early intervention for symptomatic episodes needing clinical management. The program also offered support for patients to obtain routine lab draws, hydration, antiemetics, intravenous antibiotics, and a provider assessment at home. Technical and operational feasibility were evaluated together with perceived user experience among patients, caregivers, and providers. Methods. Ten patients between 18-89 years old participated in the study for up to 90 days following allogeneic bone marrow transplant and up to 30 days following CAR T-cell therapy or autologous bone marrow transplant. Patients used continuous-wear biometric sensors for passive vital sign monitoring around the clock seven days per week and engaged with a chatbot by SMS text for health status checks and symptom reporting. Scheduled home care was administered by licensed home health providers. Virtual care center personnel evaluated patient status based on wearable data and patient messaging and followed up directly with patients or engaged patients' treating clinicians for notification and management of urgent issues as needed. Patients and caregivers were asked to complete surveys about their experience with and perceptions of the program at midpoint and study completion, while providers were asked to complete end-of-study surveys to capture their perspectives across all patients. Patients were also asked to participate in brief interviews at study midpoint and at the end of the study. Interim Results. Eighty percent of patients participated in the program as intended through wearing devices and responding to engagement prompts. Wearable sensors detected a total of 184 outpatient alerts from patients between April and July 2023, of which 57 led to follow up with patients, 12 required further follow up with the clinical care team, and 5 required follow up care in a clinical setting due to elevated temperature or respiratory rate. Sixty percent of patients responded more than 50% of the time to requested health assessment surveys. Patient engagement with the chatbot and symptom reporting system led to 48 events needing virtual care team follow up, of which 20 were to answer patient questions and 28 were in response to reports of concerning symptoms. A total of 11 events were further referred by the virtual care team to the clinical care team, of which 5 required follow up care in a clinical setting. Study data collection will complete in August 2023. Initial Conclusions. Technology-assisted remote patient monitoring is feasible for use with bone marrow transplant and CAR T-cell therapy patients at home. Successful integration with clinical practice settings requires tailoring to existing workflows. Further assessment of patient acceptance for short-term versus long-term monitoring is recommended.

Comparison of Two Reduced Intensity Conditioning Regimens (Baltimore with Clofarabine vs Thiotepa-Busulfan-Fludarabine) in Adults Receiving Peripheral Blood Stem Cell Haploidentical Transplantation for Myeloid Malignancies: A Retrospective Study of the SFGM-TC

Background: Haploidentical transplantation (haploT) has become a routine practice in many centers but the optimal conditioning regimen has yet to be determined. Indeed, the historic Baltimore reduced intensity conditioning (RIC) regimen has been associated with poor outcomes in myeloid malignancies. Two alternative RIC regimens have recently demonstrated promising results in this setting. One of them replaces fludarabine with second-generation nucleoside analogue clofarabine (Clo-Baltimore regimen [CloB], Chevallier et al., Oncotarget 2018) and the other combines thiotepa-busulfan-fludarabine (TBF, Duléry et al., BBMT 2019). Here we compared outcomes in order to determine if one of these two regimens was superior for the treatment of myeloid malignancies. Methods: This was a multicenter retrospective study conducted by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). All consecutive adults having received a haploT after a CloB or a TBF RIC regimen for a myeloid malignancy between September 2013 and May 2023 were eligible. Patients data were extracted from the PROMISE database. CloB consisted of clofarabine 30 mg/m²/day (d) 5 d, cyclophosphamide (Cy) 14.5mg/kg/d 2 d, and 2-Gy TBI on d-2. TBF consisted of thiotepa 5mg/kg 1 d, busulfan 3.2 mg/kg 2 d, a fludarabine total dose of 120 to 150 mg/m². Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant Cy (2 doses of 50mg/kg), followed by cyclosporine A and mycophenolate mofetil starting on d+5. Some patients received antithymocyte globulin (ATG) 2.5mg/kg/d on d-2. Graft source was exclusively peripheral blood stem cells (PBSC). To minimize bias between the CloB and the TBF groups, a propensity score matching (PSM) was constructed using a logistic regression model that included age, donor and recipient sex, hematopoietic cell transplantation-specific comorbidity index (HCT-CI), disease, cytogenetic risk (European LeukemiaNet [ELN] 2022), previous transplant, use of ATG, and cytomegalovirus (CMV) status, with the nearest-neighbor algorithm, and strict matching of key factors. Matched groups were then compared for time to engraftment (absolute neutrophil count &amp;gt; 0.5 x 10 9/L) and platelet (PLT) recuperation (&amp;gt;50 x 10 9/L), overall survival (OS), progression-free survival (PFS), GVHD-free, progression-free survival (GRFS), non-relapse mortality (NRM), and incidences of relapse as well as acute and chronic GVHD. Results: A total of 329 patients from 25 centers were included, 267 (81%) receiving TBF and 62 (19%) CloB. After PSM, 51 patients remained in each group, with comparable baseline characteristics except for the proportion of previous allotransplants ( Table). Median age was 60 years, and median HCT-CI score was 2. Main diagnoses comprised acute myeloblastic leukemia (AML, n=72 [71%]), including 42% with adverse genetic risk, and myelodysplastic syndrome (MDS, n=22 [22%]), including 25% with high or very high Revised International Prognostic Scoring System (R-IPSS). Thirty-eight (37%) patients received ATG. Time to engraftment was equivalent after both TBF and CloB (19 d vs 19.5 d, respectively, p=0.70), but TBF patients achieved PLT recuperation faster (27 d vs 31 d, p=0.03). Median follow-up was 24 months. Two-year OS, PFS and GRFS were 55% vs 60% (p=0.19), 52% vs 60% (p=0.25), and 37% vs 50% (p=0.15) for TBF and CloB patients, respectively. No differences were observed in terms of grade 3-4 acute GVHD at 3 months (18 vs 20%, p=0.86) nor two-year extensive chronic GVHD (16% vs 8.3%, p=0.25). However, two-year NRM was significantly higher after TBF (41% vs 16%, p=0.003), while relapse incidence was lower (7.1% vs 24%, p=0.02, Figure). In multivariate analysis, CloB was associated with a lower risk of NRM (hazard ratio [HR] 0.31, 95%CI: 0.1-0.7, p=0.008) and a higher risk of relapse (HR 4.03, 95%CI: 1.2-13.9, p=0.03). Finally, in patients aged &amp;gt;60y, two-year OS was significantly lower for those receiving TBF conditioning (39% vs 61%, p=0.02, Figure) due to higher NRM (56% vs 23%, p=0.005). Conclusions: In this retrospective study, a TBF RIC regimen used for PBSC haploT in adults with myeloid malignancies appeared substantially more toxic than a CloB RIC regimen. However, its enhanced anti-leukemic effect suggests that it should be offered to younger patients with no comorbidities or to those with high-risk disease. Conversely, CloB should be proposed for older or frail patients.

Evaluating Inpatient Care Team Models in Hematology and Oncology Fellowship Programs in the United States

Introduction. In response to a growing and increasingly older population with complex medical needs, the hematology and oncology (HO) care system has integrated the hospitalist model into inpatient systems alongside HO trainees and faculty. The inclusive workforce is comprised of hospitalists and advanced practice providers (APPs) who co-manage patients with specialists or form separate non-trainee (NT) teams. Despite multiple advantages of the hospitalist model, the optimal care team structure and the impact on HO fellowship training have not been previously explored. We aimed to survey HO fellowship programs in the United States to identify the structure of inpatient HO staffing models implemented at their institution, and collect data on perceptions of the NT model within the fellowship programs. Methods. We constructed and distributed two national web-based surveys targeting all adult HO fellowship program directors (PDs) and fellows from Accreditation Council for Graduate Medical Education (ACGME)-accredited programs. The surveys were designed to assess various aspects of HO inpatient services, including team compositions, individual responsibilities, and availability of NT services. We also assessed the PDs' and fellows' perception on the impact of NT teams on their training and education. The surveys were emailed weekly between 6/20/23-7/29/23. Results.We identified 147 HO training programs.A total of 35 PDs and 101 fellows responded our survey (Table 1). The majority of PDs (83%) were from university training programs in the Midwest (43%) and Northeast (33%), with fellow class sizes of 6-12 (47%). Most (67%) programs had both trainee (T) and NT teams included in their inpatient medicine models (Figure 1). The most commonly reported NT team was the bone marrow transplant and cellular therapy service (BMT) (57%), supported primarily by APPs (55%). Only 33% of respondents reported a dedicated sickle cell disease (SCD) inpatient team within their institution. Hospitalists were included in the care model of the inpatient oncology (27%), inpatient malignant hematology (23%) and SCD (13%) teams. Most PDs agreed that the fellows are primarily responsible for most inpatient tasks and over 50% agreed that APPs are responsible for direct patient care, admissions and discharge planning. 83% of PDs reported that their program had an appropriate balance between inpatient and outpatient care. Half (50%) of PDs reported that fellows had a positive perception of NT teams at their institution, and 35% were neutral. The fellows who responded were predominantly second-year fellows (43%) in Northeastern (43%) university hospitals (92%) from programs with 6-12 fellows (63%). Most (71%) respondents had both T and NT teams included in their inpatient model. Inpatient malignant hematology (53%) and inpatient solid oncology (53%) teams were the most commonly reported NT teams, followed by BMT (40%) (Figure 1). Fellows reported their primary responsibilities to include procedures and tumor board discussions (94%), communication with outpatient teams (91%) and resident education and supervision (89%). APPs were primarily responsible for discharge planning (63%), admissions (59%) and direct patient care (58%). Most (85%) fellows agreed that their program had an appropriate balance between inpatient and outpatient care. Most fellows (69%) reported the impact of NT teams on fellows' inpatient and training experience to be neutral. Fellows from institutions without NT teams responded that the addition on NT team would have a positive impact in their training experience (69%). Most PDs and fellow respondents perceived a financial barrier to the implementation of NT teams at their institutions. Conclusions.Our findings highlight the existing heterogeneity in the distribution and composition of services among HO programs nationwide. PD respondents and fellows without NT teams perceived these teams as a beneficial addition to the program, in contrast to fellows in programs with existing NT teams who reported a neutral impact. Further investigation of the reasons for this discrepancy is essential to identify areas of improvement. Additional insights from the ongoing survey will be presented during the meeting.

Improvements in Health-Related Quality of Life after Exagamglogene Autotemcel in Patients with Transfusion-Dependent Beta-Thalassemia

Background: Transfusion-dependent β-thalassemia (TDT), an inherited hematological disorder which requires life-long, chronic red blood cell transfusion (RBC) and regular iron chelation therapy, has a substantial negative impact on health-related qualify of life (HRQoL). Exagamglogene autotemcel (exa-cel) is a one-time, non-viral, ex vivo CRISPR-Cas9 gene-edited cell therapy in phase 3 clinical trials that has been shown to eliminate the need for RBC transfusions and achieve transfusion independence. Here, we report HRQoL data from a pre-specified interim analysis of the exa-cel CLIMB TDT-111 study. Methods: CLIMB TDT-111 is an ongoing, 24-mo, phase 3 trial of a single dose of exa-cel in patients aged 12-35 years with TDT and a history of ≥100 mL/kg/year or ≥10 U/year of packed RBC transfusions for 2 years prior to screening. Changes in patient-reported outcome (PRO) measures including EuroQol Quality of Life Scale 5 dimensions 5 levels of severity (EQ-5D-5L, including descriptive system and visual analog scale [VAS]) and Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, including FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]) for adults and the EuroQol Quality of Life Scale 5 dimensions youth (EQ-5D-Y) and Pediatric Quality of Life Inventory (PedsQL) for adolescents were assessed through month 24 as a secondary endpoint in the trial. Data are presented as of 16 January 2023 for the 24 adults (aged ≥18-35 years) and 11 adolescents (aged ≥12 to &amp;lt; 18 years) who had been followed for ≥16 months after exa-cel infusion. Results: Clinically meaningful improvements, exceeding the minimal clinically important difference (MCID) thresholds, were observed in all PRO measures in adults. Baseline mean EQ-5D-5L health utility US index score (n=24, mean [SD]: 0.85 [0.18]) was near the general population norm and in line with baseline scores previously reported for adult patients with TDT. By month 24, both EQ-5D-5L health utility US index scores and EQ VAS scores showed substantial improvement (mean [SD] changes at month 24 [n=15]: 0.12 [0.26] and 10.2 [20.9] points; MCIDs 0.078 and 7 to 10, respectively). FACT-G Total Score improved from baseline by month 12 and was sustained through month 24 (mean [SD] change at month 24 [n=15] 10.3 [17.0] points; MCID 3 to 7), with improvements observed in all 4 subscales (physical, social/family, emotional, and functional well-being). BMTS score improved by month 12 and was sustained through month 24 (mean [SD] change at month 24 [n=15] 6.8 [4.7] points; MCID 2 to 3). For adolescents, EQ VAS scores improved through month 18 (mean [SD] change from baseline 4.8 [6.1] points). Total PedsQL score improved by month 6 and was sustained through month 18 (mean [SD] change from baseline [n=7] 14.1 [9.2] points; MCID 4.36). Physical functioning and psychosocial health scores, sub-components of PedsQL, both showed sustained improvement through month 18 (mean [SD] change [n=7] 19.2 [9.1] and 11.4 [10.9] points; MCID of 6.66 and 5.30 points, respectively). Improvement in psychosocial score was observed in all 3 subscales (social, emotional, and school functioning). Conclusion: Adults and adolescents infused with exa-cel reported sustained and clinically meaningful improvements in their HRQoL, with improvements observed across different instruments and domains, including physical, emotional, social/family and functional well-being and overall health status. These results demonstrate the broad clinical benefits of exa-cel in patients with TDT.

Improvements in Health-Related Quality of Life after Exagamglogene Autotemcel in Patients with Severe Sickle Cell Disease

Background: Severe sickle cell disease (SCD), which is characterized by recurrent vaso-occlusive crises (VOCs), has a substantial negative impact on health-related quality of life (HRQoL). Exagamglogene autotemcel (exa-cel) is a one-time, non-viral, ex vivo CRISPR/Cas9 gene-edited autologous cell therapy in phase 3 clinical trials that has been shown to eliminate VOCs. Here, we report HRQoL data from a pre-specified interim analysis of the exa-cel CLIMB SCD-121 study. Methods: CLIMB SCD-121 is an ongoing phase 3 trial of a single dose of exa-cel in patients ages 12-35 years with SCD and a history of ≥2 VOCs/year in each of the 2 years prior to screening. Changes in patient reported outcomes measures EuroQol Quality of Life Scale 5 dimensions 5 levels of severity (EQ-5D-5L, including descriptive system and visual analog scale [VAS]), Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, including FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]), Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), and the 11-point pain Numerical Rating Scale (NRS ) were assessed from baseline through month 24 as a secondary endpoint in the trial. Data is presented as of 10 Feb 2023 for the 17 adult patients (aged ≥18-35 years) who had been followed for ≥16 months after exa-cel infusion. Results: Substantial and clinically meaningful improvements exceeding minimal clinically important difference (MCID) thresholds were observed in all assessed patient reported outcomes measures. At baseline, the EQ-5D-5L health utility US index (n=17; mean [SD]: 0.71 [0.23]) and EQ VAS (63.5 [22.5]) scores were lower than the US general population norm and similar to baseline scores reported for adult SCD patients with recurrent VOCs. By month 6, both EQ-5D-5L health utility US index score and EQ VAS score showed substantial improvements, which were maintained through month 24 (mean changes [SD] at month 24 [n=8]: 0.23 [0.20]; MCID 0.078 and 28.3 [16.2]; MCID 7 to 10, respectively). FACT-G Total Score improved from baseline at month 24 (mean [SD] change at month 24 [n=8]: 29.8 [17.2]; MCID 3 to 7), with improvements observed in all 4 subscales (physical, social/family, emotional, and functional well-being). BMTS score improved by month 6 and was sustained through month 24 (mean [SD] change at month 24 [n=8]: 3.9 [5.7]; MCID 2 to 3). All subscales of the ASCQ-Me, including emotional (mean [SD] change [n=7] 17.7 [9.8]), social (23.8 [6.7]), stiffness (7.9 [12.9]), and sleep impact (8.4 [8.3]), demonstrated clinically meaningful improvements from baseline through month 24. For the ASCQ-Me pain-related subscales evaluating pain impact, pain episode frequency and pain severity, the largest numerical improvement was observed in pain episode frequency (mean [SD] change at month 24 [n=8]: -22.8 [8.2]; MCID -5). Improvements in the pain NRS were observed by month 12 and sustained through Month 24 (mean [SD] change at month 24 [n=8]: -1.8 [3.1]; MCID -1). Conclusion: Adults infused with exa-cel reported sustained and clinically meaningful improvements in their HRQoL, with improvements observed across different instruments and domains, including physical, emotional, social/family, and functional well-being, pain experience, and overall health status. These results demonstrate the broad clinical benefits of exa-cel in patients with SCD.

Unfavorable transcriptome profiles and social disadvantage in hematopoietic cell transplantation: a CIBMTR analysis

AbstractPatient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population.

Current challenges and new approaches to implementing optimal management of sickle cell disease in sub-Saharan Africa

Sickle cell disease (SCD) is the most common life-threatening monogenic disorder in the world. The disease is highly prevalent in malaria endemic areas with over 75% of patients residing in Sub-Saharan Africa (SSA). It is estimated that, without proper care, up to 90% of children with SCD will not celebrate their fifth birthday. Early identification and enrolment into comprehensive care has been shown to reduce the morbidity and mortality related with SCD complications. However, due to resource constraints, the SSA is yet to implement universal newborn screening programs for SCD. Furthermore, care for patients with SCD in the region is hampered by the shortage of qualified healthcare workers, lack of guidelines for the clinical management of SCD, limited infrastructure for inpatient and outpatient care, and limited access to blood and disease modifying drugs such as Hydroxyurea which contribute to poor clinical outcomes. Curative options such as bone marrow transplant and gene therapy are expensive and not available in many SSA countries. In addressing these challenges, various initiatives are ongoing in SSA which aim to enhance awareness on SCD, improve patient identification and retention to care, harmonize the standards of care for SCD, improve the skills of healthcare workers and conduct research on pertinent areas in SCD in the SSA context. Fortifying these measures is paramount to improving the outcomes of SCD in SSA.

Quality control in blood irradiation

Irradiation is a technique used in hemotherapy to functionally inactivateviable lymphocytes, in cellular blood components, to reduce the risk of Transfusion-associated Graft-versus-Host Disease (AT-GVHD), is rare but letal. One way to avoid it is to irradiate blood componentes in situations such as: intrauterine transfusion, newborns, patients receiving immunosuppressive therapy in bone marrow transplantation. Thus, it is extremely important that blood component is irradiated and, above all, ensure that the minimum dose is 25 Gy.The blood policy in Brazil is implemented through laws and normative decrees, giving rise to a legal system that underpins the actions of hemotherapy services. In order to correct verify absorbed doses and the quality assurance process as well as the safety for the irradiator operators we describe in this paper a several of physical measurements that is mandatory to support a physicist to evaluate the quality assurance during and after the irradiation process. The results obtained from this physical measurements provided a guarantee of proper radiation dose used in hemotherapy as well as methods and procedures applied to protect the patient, employees and general public due to procedure of blood irradiation accordling the Technical Regulation of Hemotherapy Procedures of the National Health Surveillance Agency (ANVISA) and safety regulations by National Nuclear Energy Commission (CNEN).