Hematopoietic Stem Cell Transplantation Procedure Research Articles

Nutritional aspects in autoimmune diseases undergoing hematopoietic stem cell transplantation: overview and recommendations on behalf of the EBMT ADWP and Nurses Group.

Autoimmune diseases (ADs) represent a heterogeneous group of conditions affecting 5-10% of the global population. In recent decades, hematopoietic stem cell transplant (HSCT), mainly autologous, has been successfully adopted to treat patients affected by severe/refractory ADs. In this context malnutrition has a detrimental impact on relapse, mortality, infection rate, engraftment, long-term survival, and prolongation of hospitalization. However, in this population, the management of nutrition should be improved since nutritional assessment is partially performed in routine clinical practice. A panel of nurses and physicians from the European Society for Blood and Marrow Transplantation (EBMT) reviewed all available evidence based on current literature and expert practices from centers with extensive experience in HSCT for ADs, on the nutritional management of ADs patients during HSCT procedure. In this context, adequate nutritional status predicts a better response to treatment and improves quality of life. Herein, a systematic and comprehensive monitoring of nutritional status before, during and after HSCT, with adequate nutritional support in the case of ADs patients, in addition to assessing the dietary requirements associated with HSCT has been covered. Moreover, given the singularity of each AD, the underlying disease should be considered for an appropriate approach. The management and evaluation of nutritional status must be carried out by a multidisciplinary team to assess the needs, monitor the effectiveness of each intervention, and prevent complications, especially in complex situations as patients affected by ADs.

T1 Mapping in Cardiovascular Magnetic Resonance-A Marker of Diffuse Myocardial Fibrosis in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Introduction: Hematopoietic stem cell transplantation (HSCT) recipients are at increased risk of cardiovascular diseases. In our study, we aimed to find subclinical changes in myocardial tissue after HSCT with the help of cardiovascular magnetic resonance (CMR) tissue imaging techniques. Methods: The data of 44 patients undergoing autologous and allogeneic HSCT in the Hospital of Lithuanian University of Health Sciences Kaunas Clinics from October 2021 to February 2023 were analyzed. Bioethics approval for the prospective study was obtained (No BE-2-96). CMR was performed two times: before enrolling for the HSCT procedure (before starting mobilization chemotherapy for autologous HSCT and before starting the conditioning regimen for allogeneic HSCT) and 12 ± 1 months after HSCT. LV end-diastolic volume, LV end-systolic volume, LV mass and values indexed to body surface area (BSA), and LV ejection fraction were calculated. T1 and T2 mapping values were measured. Results: There was a statistically significant change in T1 mapping values. Before HSCT, mean T1 mapping was 1226.13 ± 39.74 ms, and after HSCT, it was 1248.70 ± 41.07 ms (p = 0.01). The other parameters did not differ significantly. Conclusions: Increases in T1 mapping values following HSCT can show the progress of diffuse myocardial fibrosis and may reflect subclinical injury. T2 mapping values remain the same and do not show edema and active inflammation processes at 12 months after HSCT.

Results of Levofloxacin Prophylaxis Timing in Autologous and Allogeneic Stem Cell Transplantation: A Retrospective Cohort Study.

Background Despite preventive measures and varying antibiotic recommendations, bacterial infections continue to pose a significant threat to individuals undergoing hematopoietic stem cell transplantation (HSCT).Levofloxacin prophylaxis is commonly used, but the optimal timing for initiation is debated. This study aims to assess infection outcomes based on timing of levofloxacin prophylaxis (initiation at the first day of conditioning vs. after infusion of stem cells) in autologous and allogeneic HSCT patients. Methods We compared infectious episodes, responsible pathogens, and clinical outcomes based on the implementation of levofloxacin prophylaxis in patients receiving autologous or allogeneic HSCT procedures. This retrospective single-center study involved a review of the medical records of autologous and allogeneic HSCT patients treated at our adult stem cell transplantation unit between 2018 and 2020. The study included 23 patients who underwent autologous HSCT and 12 patients who underwent allogeneic HSCT. We compared the demographic data, febrile neutropenia, proven bacterial infections, and 30-day survival among the autologous and allogeneic transplant groups, including those who received oral levofloxacin 500 mg/day prophylaxis. Results Positive blood cultures (26.1% vs. 75%; p = 0.011), mean neutrophil engraftment (10.6±1.2 vs. 14.8±1.3; p<0.001), and mean platelet engraftment (11.2±1.1 vs. 15.4±3.2; p = 0.004) were all lower in autologous transplant patients versus their allogeneic counterparts. When each type of HSCT was evaluated within the same type, there were no observed differences in infection frequency, infection type, or 30-day mortality between the patient groups with different levofloxacin initiation times. Conclusion Healthcare professionals should choose the most appropriate timing for initiating levofloxacin prophylaxis based on individual patient factors and clinical circumstances while considering the cost-effectiveness implications. Further research with a larger sample size and prospective design is needed to support our findings.

Novel ABCD1 variant causes phenotype of adrenomyeloneuropathy with cerebral involvement in Ukrainian siblings: first adult hematopoietic stem cell transplantation for ALD in Ukraine: a case report

BackgroundThis article presents a case study of two white male siblings of 24 and 31 years of age of self-reported Ukrainian ethnicity diagnosed with adrenomyeloneuropathy (AMN) associated with a novel splice site mutation in the ABCD1 gene. AMN represents a form of X-linked adrenoleukodystrophy (X-ALD) characterized by demyelination of the spinal cord and peripheral nerves. The case also presents the first adult haematopoietic stem cell transplant (HSCT) for adrenomyeloneuropathy in Ukraine. The rarity of this mutation and its cerebral involvement and the treatment make this case noteworthy and underscore the significance of reporting it to contribute to the existing medical knowledge.Case presentationThe patients of 24 and 31 years initially exhibited progressive gait disturbance, lower extremity pain, and urinary incontinence, with the older sibling experiencing more advanced symptoms of speech, hearing, and vision disturbances. A comprehensive genetic analysis identified an unreported splice site mutation in exon 3 of the ABCD1 gene, leading to the manifestation of AMN. The inheritance pattern was consistent with X-linked recessive transmission. The article also outlines the clinical features, magnetic resonance imaging (MRI), and nerve conduction study (NCS) findings. Moreover, it discusses the genetic profile of the affected individuals and female carriers within the family. The younger sibling underwent HSCT, which was complicated by mediastinal lymph node and lung tuberculosis, adding to the complexity of managing adult ALD patients.ConclusionsThis report emphasizes the importance of genetic testing in diagnosing and comprehending the underlying mechanisms of rare genetic disorders, such as AMN with cerebral involvement. The identification of a novel splice site mutation expands our understanding of the genetic landscape of this condition. Additionally, the challenges and complications encountered during the hematopoietic stem cell transplant procedure underscore the need for cautious consideration and personalized approaches in adult ALD patients.

Real-World Treatment Patterns and Patient Outcomes in Relapsed/Refractory Hodgkin Lymphoma in the US

Introduction Brentuximab vedotin (BV), a CD30-directed monoclonal antibody, and programmed cell death-1 inhibitors (PD-1; e.g., nivolumab, pembrolizumab) are efficacious for the treatment of adult patients with Hodgkin lymphoma (HL) at high risk of relapse or progression post-autologous stem cell transplantation (ASCT). In this study, we investigated the real-world treatment patterns and outcomes of patients with relapsed/refractory HL (RRHL) who had received ≥1 line of therapy (LOT). Methods Patients ≥18 years old with evidence of RRHL in ≥1 inpatient or ≥2 outpatient physician medical notes or evidence of ≥1 autologous/allogeneic hematopoietic stem cell transplant (HSCT) procedure following evidence of HL in the Humedica Electronic Medical Record (EMR) database, were selected between October 1, 2016 and September 30, 2020. The earliest evidence of RRHL (medical note or HSCT procedure) was defined as the patient's index date. Patients were excluded if they had evidence of RRHL, non-Hodgkin's disease, other primary cancers, or metastatic disease in the 12 months prior to the index date (baseline period). Patient demographic and clinical characteristics were evaluated during the baseline period and the index date. Patients were followed from their index date until patient death or the end of recorded healthcare activity during which treatment patterns and outcomes were assessed. Results A total of 342 patients with ≥1 LOT post-RRHL during the follow-up period were included in the final study population. Mean age was 44.2 years, 56.7% were male, 75.7% were white, and 61.4% had commercial insurance; mean Charlson Comorbidity Index score was 3.2 (Table 1). Approximately one-third (34.5%) of patients were not eligible for HSCT based on available laboratory data and comorbidity diagnoses during the baseline period or the index date. Across the study population, the average follow-up duration was 25.6 months (median: 23.9 months). Among the overall study population, 90 (26.3%) patients received BV treatment, with most (~86%) receiving BV in LOTs 1 and 2 post-RRHL evidence (Table 2). The average time from index date to initiation of BV treatment was 2.5 months and mean duration of treatment (DOT) with BV was 4.3 months. Most patients treated with BV (n=68) had not received a HSCT. During the follow-up, among those who received BV but not a PD-1 (n=57), the progression-free survival (PFS) rate was 73.7% and overall survival (OS) was 82.5%. Among the overall study population, 56 (16.4%) patients received a PD-1, with most patients (~68%) receiving a PD-1 in LOTs 1 and 2 post-RRHL evidence. The average time from index date to initiation of PD-1 treatment was 5.5 months and mean DOT with a PD-1 was 5.3 months. Among those patients who received a PD-1 but not BV (n=23), the PFS rate was 56.5% and OS was 69.6%. One patient received post-HSCT BV+PD-1 combination maintenance therapy. Among the patients who received BV and/or a PD-1 prior- or post-HSCT, 12 (52.2%) received BV prior to the HSCT and 9 (39.1%) received BV after the HSCT. Among those who received BV and PD-1 treatments (i.e., not at the same time; n=33), the PFS rate was 60.6% and OS was 90.9%. Among the study population, a majority of patients (n=232; 67.8%) did not receive a HSCT during the follow-up period (including the index date). Of these patients without a HSCT, 68 (29.3%) received BV, 46 (19.8%) received a PD-1, and 25 (10.8%) received both BV and a PD-1 (i.e., not at the same time). Conclusions In this real-world evaluation of the treatment patterns and outcomes among patients in post-RRHL evidence setting, BV was administered more frequently in patients without HSCT. Increasing the use of BV in patients with ASCT at high risk for relapse or progression may lead to improved clinical outcomes. This study was based on EMRs from a single administrative database and has a limited sample size; these findings may not apply to all patient populations in post-RRHL evidence setting in the US.

Hospital survival following pediatric HSCT: changes in complications, ICU therapies and outcomes over 10 years.

Hematopoietic stem cell transplantation (HSCT) is an increasingly utilized therapy for malignant and non-malignant pediatric diseases. HSCT complications, including infection, organ dysfunction, and graft-versus-host-disease (GVHD) often require intensive care unit (ICU) therapies and are associated with mortality. Our aims were to identify the HSCT characteristics, complications and ICU therapies associated with (1) survival, and (2) survival changes over a ten-year period in a national dataset. A national sample from the Health Facts (Cerner Corporation, Kansas City, MO) database from 2009 to 2018 was utilized. Inclusion criteria were age 30 days to <22 years and HSCT procedure code. For patients with >1 HSCT, the first was analyzed. Data included demographics, hospital length of stay (LOS), hospital outcome, transplant type and indication. HSCT complications included GVHD and infections. ICU therapies were positive pressure ventilation (PPV), vasoactive infusion, and dialysis. Primary outcome was survival to discharge. Statistical methods included bivariate analyses and multivariate logistic regression. 473 patients underwent HSCT with 93% survival. 62% were allogeneic (89% survival) and 38% were autologous (98% survival). GVHD occurred in 33% of allogeneic HSCT. Infections occurred in 26% of all HSCT. ICU therapies included PPV (11% of patients), vasoactive (25%), and dialysis (3%). Decreased survival was associated with allogeneic HSCT (p < 0.01), GVHD (p = 0.02), infection (p < 0.01), and ICU therapies (p < 0.01). Survival improved from 89% (2009-2013) to 96% (2014-2018) (p < 0.01). Allogeneic survival improved (82%-94%, p < 0.01) while autologous survival was unchanged. Survival improvement over time was associated with decreasing infections (33%-21%, p < 0.01) and increasing vasoactive infusions (20%-28%, p = 0.05). On multivariate analysis, later time period was associated with improved survival (p < 0.01, adjusted OR 4.28). Hospital survival for HSCT improved from 89% to 96% from 2009 to 2018. Factors associated with mortality included allogeneic HSCT, GVHD, infections and ICU therapies. Improving survival coincided with decreasing infections and increasing vasoactive use.

Health-Related Quality-of-Life Profile of Pediatric Patients with β Thalassemia after Hematopoietic Stem Cell Transplantation.

Matched hematopoietic stem cell transplantation (HSCT) is a feasible and curative treatment in pediatric patients with beta thalassemia major (β-TM). However, little data are available regarding patients and their parents' health-related quality of life (HRQoL) after the procedure. As such, we investigated the HRQoL of pediatric patients with β-TM after HSCT compared to that of patients treated with blood transfusions and iron chelation. The health-related quality of life of 43 β-TM pediatric patients and 43 parents were evaluated using the Pediatric Quality of Life Inventory (PedsQL). A total of 25 patients underwent HSCT: 15 from a sibling and 10 from an HLA-matched donor. The median follow-up time from HSCT was 5 years (range 1-13 years). The mean ages at the survey were 10.1 years (range 5-15) and 9.6 years (range 5-15) for transfused and transplanted patients, respectively. A significant reduction in HRQoL was reported in the group of transfused patients compared with that of patients transplanted in the following PedsQL domains: children's and parents' physical functions, Δ = -15.4, p = 0.009 and Δ = -11.3, p = 0.002, respectively; children's and parents' emotional functioning, Δ = -15.2, p = 0.026 and Δ = -15.2, p = 0.045, respectively; child's and parents' school functioning, Δ = -25, p = 0.005 and Δ = -22.5, p = 0.011, respectively; total child and parents scores, Δ = -14.5, p = 0.004 and Δ = -13.2, p = 0.005, respectively. The results of a multivariable analysis showed that the HSCT procedure was significantly associated with a higher total child PedsQL score (adjusted mean difference = 15.3, p = 0.001) and a higher total parent PedsQL score (adjusted mean difference = 14.1, p = 0.006). We found no significant difference in the HRQoL measured after sibling or unrelated human leukocyte antigen (HLA)-matched HSCT. Finally, a significant positive correlation across all the PedsQL domains was found between the scores reported by the children and those reported by their parents. In conclusion, our study shows that HSCT in pediatric patients with β-TM is associated with a good overall HRQoL profile. This information further supports physicians when counseling patients and their parents before the HSCT procedure.

Assessment of Bone Marrow Failure Syndrome Management Outcome in Pediatrics – Saudi Perspective

Bone Marrow Failure Syndrome (BMFS) is a rare yet severe condition affecting pediatric populations, characterized by a reduced production of hematopoietic lineages leading to pancytopenia. This article explores the multifaceted nature of BMFS in children, its diverse etiologies, treatment modalities, and outcomes, with a particular focus on the Saudi Arabian context. BMFS encompasses both inherited and acquired forms, often presenting diagnostic challenges due to its heterogeneity. Inherited BMFS accounts for 30% of cases and includes rare conditions like Fanconi Anemia and Schwachman-Diamond Syndrome, where treatment approaches vary depending on severity. Acquired BMFS, constituting 70% of cases, may exhibit complete recovery or require prolonged treatment with immunosuppressants. Hematopoietic Stem Cell Transplantation (HSCT) remains a primary treatment option, with outcomes influenced by factors such as donor type and graft success. Saudi Arabia, despite its high-income status, has faced limited data availability on BMFS outcomes, but the number of HSCT procedures performed in the country is steadily increasing. Survival rates in HSCT patients vary based on factors such as donor match and the underlying cause of BMFS. Additionally, the risk of secondary malignancies is relatively high in BMFS patients, adding complexity to long-term management. While Saudi studies indicate survival rates comparable to international standards, challenges in the assessment of BMFS outcomes persist, given the condition's rarity and diversity. This article underscores the importance of continued research and data collection to enhance our understanding and management of BMFS in the pediatric population, both in Saudi Arabia and globally.

EE497 Healthcare Costs Associated with Hematopoietic Stem-Cell Transplantation in Patients with Acute Myeloid Leukemia: A Population-Based Retrospective Cohort Study in Korea

Hematopoietic stem-cell transplantation(HSCT) is considered an important treatment strategy in medically eligible acute myeloid leukemia(AML) patients, but the cost is substantial. This study aimed to estimate the hospitalization costs and follow-up costs of HSCT procedure in AML patients.

Droplet Digital PCR Development for Adenovirus Load Monitoring in Children after Hematopoietic Stem Cell Transplantation

Human adenovirus (AdV) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with life-threatening clinical manifestations. Although real-tme quantitative PCR (qPCR) has been widely used to measure AdV loads, it has not been standardized for AdV. Droplet digital PCR (ddPCR) is a novel pathogen detection technology that enables the absolute quantification of viral loads. ddPCR would enable a more accurate AdV DNA detection compared with qPCR. In this study, ddPCR was developed for AdV DNA and its performance characteristics compared with those of qPCR. AdV DNAemia incidence during the first 12 weeks after allogenic HSCT was then retrospectively examined by qPCR and ddPCR in 97 HSCT procedures using the preserved 545 DNA samples. ddPCR exhibited better reproducibility and sensitivity, as well as equivalent quantifiability, compared with qPCR. AdV DNA among HSCT patients was detected in 11 (2.0%) and 49 (9.0%) of 545 samples by qPCR and ddPCR, respectively. AdV DNA levels >1000 copies/mL were observed in five cases by qPCR and/or ddPCR. However, two patients developed fulminant hepatitis and died; other patients remained asymptomatic with subsequently undetectable AdV DNA. In conclusion, ddPCR was more sensitive and reproducible in detecting AdV DNA among pediatric HSCT recipients than qPCR. ddPCR offers the potential to provide a more accurate DNAemia detection, determine cutoff values for treatment initiation, and enable antiviral efficacy assessment.

Gonadal function in pediatric Fanconi anemia patients treated with hematopoietic stem cell transplant.

Gonadal dysfunction and reduced fertility are clinical manifestations well described in patients with Fanconi anemia (FA) and following hematopoietic stem cell transplantation (HSCT). It is difficult to differentiate gonadal dysfunction from the primary disease itself or from HSCT procedures. Therefore, it is important to manage expectations about gonadal failure and infertility for all patients with FA, regardless of the HSCT status. We performed a retrospective analysis of 98 pediatric patients with FA who were transplanted between July 1990 and June 2020 to evaluate the incidence of gonadal dysfunction in female and male patients with FA. New-onset premature ovarian insufficiency (POI) was diagnosed in a total of 30 (52.6%) patients. Follicle-stimulating hormone and luteinizing hormone levels were increased in patients diagnosed with POI. Anti- Mullerian hormone levels declined in POI patients after HSCT (r2=0.21; P=0.001). Twenty (48.8%) male patients were diagnosed with testicular failure. Follicle-stimulating hormone levels increased after HSCT even in patients without testicular failure (r2=0.17; P=0.005). Inhibin B levels decreased over time after HSCT in patients with testicular failure (r2=0.14; P=0.001). These data indicate brisk decline in already impaired gonadal function in transplanted children with FA.

Time-Series Reconstruction of CBC Profile of Pediatric Cancer Patients for Two Years after Hematopoietic Stem Cell Transplantation Using Language Programming

In this single center and retrospective study, we analyzed every single patient totaling 249 patients who was admitted and undergone hematopoietic stem cell transplantation (HSCT) at our institution from year 2013 to 2019. Twenty three patients were excluded mainly due to returning home country after HSCT without further follow up at our institution. We re-analyzed the remaining 226 patients (169 alive patients and 57 expired patients) and re-constructed time-series laboratory data of white blood cell (WBC) count (Figure 1), hemoglobin, platelet, absolute neutrophil count (ANC), monocytes number, blood urea nitrogen, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), cyclosporine level, and/or tacrolimus level for up to two years since their last HSCT. These large sets of data were visualized by custom-written codes using language programming. We performed subgroup analysis of these patients' laboratory data according to the tumor type, which was grouped into acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), other types of leukemia not aforementioned, lymphoma, solid tumor, aplastic anemia and other diseases including neurologic disease or immunodeficiency. We also compared these patients' laboratory data according to immunosuppressant used (cyclosporine versus tacrolimus), and hematopoietic stem cell transplantation procedures employed (allogeneic peripheral blood stem cell transplantation (PBSCT), autologous PBSCT or bone-marrow transplantation). In all patients analyzed who remain alive after HSCT (male 100 patients (59%), female 69 patients (41%), the median WBC engraftment time was 13 days with interquartile range (IQR) of 11-15 days). Both WBC and ANC steadily increased after engraftment up to 400 days since HSCT and reached plateau level at 7,000cells/uL for WBC and 3,000cells/uL for ANC. Hemoglobin and platelet showed faster recovery time since HSCT as hemoglobin level of 12 g/dL and platelet count of 200x10^9/L both reached at 300 days since HSCT. Patients underwent HSCT due to the occurrence of solid tumor generally showed shorter WBC engraftment time of 11 days with IQR of 10-12 days while those with hematologic malignancy showed relatively longer WBC engraftment time of 14 days with IQR of 12-16 days. In subgroup analysis of hematologic malignancy categorized into ALL, AML, other leukemia not aforementioned and lymphoma, no significant differences in engraftment time or general trend over two-year time-course of WBC, ANC, hemoglobin and platelet. In sharp contrast, 57 patients who have expired since HSCT showed WBC recovery after engraftment - the median WBC engraftment time was 13 days with IQR of 11-16 days - up to 3,000cells/uL but the WBC count did not increase thereafter in the following two years. The hemoglobin and platelet plateau for these expired patients were markedly lower than those alive as hemoglobin level was maintained around 9 g/dL (Figure 2) and platelet count ranged from 50 to 90x10^9/L since HSCT. HSCT is not the end but the beginning of return to normal daily activities for many patients and vigilant long-term care of these patients is crucial not only for the patients but also for their families. As analogous to Fenton growth chart being used for premature babies and their parents to visually aid their growth progression at outpatient clinic, we aimed at constructing time-series laboratory data of HSCT patients since transplantation to serve as reference curves for HSCT patients at our institution with hope that these reference curves as a visual aid may better assist and assure those patients and their families with successful recovery and for those without successful course, early intervention and further treatment may be better understood and accepted by the patients and their families. Figure 1. Time course of white blood cell count for each patient after HSCT. Each line is color-coded differently and represents a single patient. Red curve is the median of all patients with error bars denoting interquartile range. Shaded area also represents interquartile range. Figure 2. Time course of hemoglobin trend for two years after HSCT. Median average of 169 alive patients' data (red) was compared with that of 57 expired patients (blue). Error bars represent interquartile ranges. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pediatric Age at Hematopoietic Stem Cell Transplant: Associations with Non-Malignant Genetic Disease and Race

Introduction: Increasingly, hematopoietic stem cell transplant (HSCT) is used in pediatrics to treat both malignant and nonmalignant conditions. Many of the nonmalignant disorders for which HSCT is curative are genetic, and it has long been recognized that the diagnostic odyssey for patients with genetic disorders is frequently quite long. Notably, the diagnostic odyssey is longer for non-white patients with genetic diseases than for white patients with genetic diseases. We hypothesized that this disparity would also manifest as older age at time of HSCT, which could be associated with greater co-morbidities and worse outcomes. While previous studies have analyzed the association between race and pediatric HSCT access and survival, (PMID:32497418; 35071585; 34900869)we sought to determine if the diagnostic odyssey is longer for racial minorities compared to Caucasians. Methods: To test this hypothesis, we utilized the 2019 version of the Kids’ Inpatient Database (KID), developed by the Healthcare Cost and Utilization Project (HCUP), sponsored by the Agency for Healthcare Research and Quality (AHRQ). The HSCT sample was identified using ICD-10-PCS Procedure Codes for transfusion of hematopoietic/cord blood stem cells: Allogenic: 30243X3, 30243Y3, 30243X4, 30233X4, 30243Y2; Autologous: 30243Y0. A variable for pediatric genetic disease (PGD) was generated using 348 ICD-10-CM diagnostic codes corresponding to 283 pediatric genetic diseases for which the carrier frequency is greater than 1 in 500 in the general population or in an at-risk subpopulation (e.g., sickle cell anemia in AA). We controlled for malignant disease leading to HSCT using ICD-10-CM diagnostic codes to identify lymphomas, leukemias, myelodysplastic syndrome, myeloproliferative neoplasms, neuroblastomas, and brain tumors. Multiple linear regression was used to test if age of HSCT procedure was significantly associated with race, known non-malignant PGD, malignant disease, payer status, and location (rural vs. urban). Results: We identified 1,178 pediatric aged patients (age 20 and younger) who received HSCT in 2019 (Allogenic N=618; autologous N=560). The clinical characteristics of these patients are described in Table 1. The average age for Caucasian pediatric patients treated with HSCT is 6.8 years (82 months). Comparing PGD vs. all other diagnoses related to HSCT, patients with known PGD are transplanted on average 1.9 years (22 months) earlier than matched controls (P<0.001). This difference persists after controlling for race, disease severity, transplant type, Medicaid status, and rural health system location. African American and Asian pediatric patients are treated with HSCT on average 1.6 years (18 months) older than matched Caucasian controls (P=0.003 and 0.032, respectively). The effect of race persists even after controlling for thalassemias and sickle cell disease, associated with non-European ancestry. Conclusions: Age at transplant may be a useful surrogate for ongoing health disparities and to inform real-world research. African American and Asian ancestries are associated with HSCT at an older age, suggesting a prolonged diagnostic or therapeutic odyssey. This effect persists after controlling for factors such as non-malignant and malignant conditions, payer status, rural location, and genetic diseases that are over-represented in racial groups. More work is required to determine if this delay in treatment is due to differences in the spectrum of genetic diseases treated by HSCT in children of different ancestries, and if these delays in therapy may be associated with increased comorbidities and worse HSCT outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Role of Cell Blood Count in Chronic Myeloid Neoplasm and Acute Myeloid Leukemia and Its Possible Implications in Hematopoietic Stem Cell Transplantation.

Numerous prognostic indexes have been developed in hematological diseases based on patient characteristics and genetic or molecular assessment. However, less attention was paid to more accessible parameters, such as neutrophils, lymphocytes, monocytes, and platelet counts. Although many studies have defined the role of neutrophil-to-lymphocyte or platelet-to-lymphocyte in lymphoid malignancies, few applications exist for myeloid neoplasm or hematopoietic stem cell transplantation procedures. In this review, we synthesized literature data on the prognostic value of count blood cells in myeloid malignancies and hematopoietic stem cell transplantation in the context of classical prognostic factors and clinical outcomes.

HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE BRAZILIAN SUPPLEMENTARY HEALTH SYSTEM: A RETROSPECTIVE COHORT ANALYSIS

To analyze resource usage and costs of patients who underwent Hematopoietic Stem Cell Transplantation (HSCT) in the Brazilian Supplementary Health System (SHS). Data from a longitudinal retrospective dynamic cohort study (from January/2014 to December/2019) were analyzed. The population consisted of SHS patients who underwent HSCT (regardless of being autologous, allogeneic related or unrelated), and were beneficiaries of one of the 15 main health maintenance organizations that use Orizon billing system (25% of total Brazilian private market). The follow-up period ranged from six months prior to HSCT, to identify the total costs of hospitalization and preparatory exams for the procedure, up to one year after HSCT, or until censored/death. 1,265 HSCT procedures were analyzed (1,132 patients). Sex and age were missing data in 40% of the patients’ records, however from the data that were possible to collect, 33.0% were males, and 42.75% were between 30 and 70 years old. The most common causes for transplant were Multiple Myeloma (ICD-10 C90.0) and Acute Myeloid Leukemia (C92.0). During the six months that precede transplant, each patient cost an average of BRL 303,500 (total cohort cost of BRL 383.6 million, 55% of this total consisting of hospitalization expenses). During hospitalization for HSCT procedure, 41.2% of patients were admitted to the ICU, with a median length of stay of 21 days. Total hospitalization costs for transplant in this cohort was BRL 503.4 million (average of BRL 398,000 per patient). Additionally, 4.24% of patients presented an immediate adverse event after HSCT. Graft-Failure (T86.0) was the most common event (26,19%). Of the 1,132 patients followed, 26% had new admissions within one month after transplant; Acute Myeloid Leukemia and Multiple Myeloma relapse were the most common causes for re-hospitalization, followed by other transplanted organs and tissues (Z94.8), Acute Lymphoblastic Leukemia (C91.0), unspecified medical care (Z51.9), Cytomegalovirus unspecified disease (B25.9) and unspecified fever (R50.9). The highest costs after discharge from transplant were associated to hospitalizations (BRL 231 million in total, average of BRL 67,300 per hospitalization). HSCT is a growing procedure in the SHS in Brazil, and is associated with high costs, especially those with repeated hospitalizations, either caused by diseases that were the primary cause for HSCT indication or by infections after the procedure. The comprehension on HSCT-related costs in Brazilian SHS setting can help to define actions oriented to a improve patients’ quality of life and treatment strategies, thus achieving better patients’ outcomes. This study was sponsored by Novartis Pharmaceuticals Corporation. Dr. Funke and Dr. Schmidt-Filho have participated on this study for the sole purpose of scientific exchange and report no conflicts of interest.

Two cases of Chronic Neutrophilic Leukemia were successfully treated with Allogeneic Stem Cell Transplantation

Objective: Chronic Neutrophilic Leukemia (CNL) is a rarely seen myeloproliferative neoplasia (MPN) in which the BCR-ABL1 gene mutation is negative, and is characterized by persistent neutrophilic proliferation in the bloodstream and granulocytic hyperplasia in the bone marrow. CNL is usually diagnosed incidentally in asymptomatic individuals with persistent neutrophilic leukocytosis. When genetically examined, BCR-ABL1 fusion gene, JAK-2 V617F, and exon12 mutations, CALR mutations, PDGFRA-B, FGRF1 mutations are all not detected, while CSF3R mutation is observed in most of the cases. The WHO-2016 classification determined the presence of CSF3R T618I and other activating CSF3R mutations as diagnostic criteria. While the prognosis is poor in CNL cases with the CSF3R T618I mutation, it is more moderate in the presence of other CSF3R mutations. The average life expectancy is 21-30 months, and 5-year survival rates are around 28%. Although no treatment modality provides an average survival advantage other than hematopoietic stem cell transplantation (HSCT), there is no accepted 'standard of care' consensus. HSCT procedures performed in CNL cases are limited in the literature. Case: In this study, we presented two cases of CNL who were successfully treated with allogeneic stem cell transplantation and cured.

Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation.

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations.

Blinatumomab as a Bridge Therapy for Hematopoietic Stem Cell Transplantation in Pediatric Refractory/Relapsed Acute Lymphoblastic Leukemia.

Simple SummaryImmunotherapies are modern treatment modalities, giving hope for improvements of frozen cure rates in many childhood malignancies. More intensive cytotoxic chemotherapy cycles didn’t improve cure rates, only increase number of adverse events. Blinatumomab, a bispecific CD3/CD19 antibody construct, has been successfully used in relapsed/refractory r/r B-cell precursor ALL (BCP-ALL) as a bridge to hematopoietic stem cell transplantation (HSCT). We retrospectively assessed the efficacy and toxicity of blinatumomab in 13 children with r/r BCP-ALL. The response rate in our cohort of patients was 85%, with subsequent feasible HSCT in 11 out of 13 children. Although our study had some limitations with regard to its retrospective design and limited patient population, it clearly showed blinatumomab as not only a feasible but also an effective therapeutic option in pretreated children with r/r BCP-ALL, with a tolerable toxicity profile, paving the way for an HSCT procedure. To date, this is the first retrospective study from Poland on efficacy and toxicity of blinatumomab therapy in children with r/r ALL.Despite the progress that has been made in recent decades in the treatment of pediatric acute leukemias, e.g., converting acute lymphoblastic leukemia (ALL) from a fatal to a highly curable disease, 15–20% of children still relapse. Blinatumomab, a bispecific CD3/CD19 antibody construct, has been successfully used in relapsed/refractory r/r B-cell precursor ALL (BCP-ALL) as a bridge to hematopoietic stem cell transplantation (HSCT). We retrospectively assessed the efficacy and toxicity of blinatumomab in 13 children with r/r BCP-ALL. Between 2017 and 2021, thirteen children, aged 1–18 years, with r/r BCP-ALL were treated with blinatumomab. Two patients were administered blinatumomab for refractory relapse without complete remission (CR), one due to primary refractory disease, and ten patients were in CR with minimal residual disease (MRD) ≥ 10−3. The response rate in our cohort of patients was 85%, with subsequent feasible HSCT in 11 out of 13 children. Ten children reached MRD negativity after the first blinatumomab administration. The three-year OS for the study patients was 85% (Mantel–Cox, p < 0.001) and median follow-up was 24.5 (range: 1–47). All responders proceeded to HSCT and are alive in CR, and MRD negative. Although our study had some limitations with regard to its retrospective design and limited patient population, it clearly showed blinatumomab as not only a feasible but also an effective therapeutic option in pretreated children with r/r BCP-ALL, with a tolerable toxicity profile, paving the way for an HSCT procedure.

Acute GvHD after HLA-Haploidentical Hematopoietic Cell Transplantation with Regulatory and Conventional T Cell Immunotherapy Does Not Adversely Affect Transplantation Outcomes

IntroductionAdoptive immunotherapy with CD4+CD25+FOXP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) has been employed after allogeneic hematopoietic stem cell transplantation (HSCT) to prevent Graft-versus-Host Disease (GvHD) while mantaining Graft-versus-Leukemia effect in the absence of any further immune suppressive GvHD prophylaxis (Di Ianni, Blood 2011; Martelli, Blood 2014). A recent study of age-adapted haploidentical HSCT with Treg/Tcon adoptive immunotherapy (Treg/Tcon haplo-HSCT) resulted in an unprecedented 75% chronic GvHD (cGvHD)/leukemia-free survival (CRFS) in acute myeloid leukemia patients. Acute GvHD (aGvHD) occured in 33% of patients and was the most frequent complication of the procedure (Pierini, Blood Advances 2021). Here, we analyzed clinical and histological characteristics of aGvHD and evaluated its impact on outcomes in patients who received Treg/Tcon haplo-HSCT.MethodsWe retrieved data of patients who underwent Treg/Tcon haplo-HSCT at Perugia University Hospital and who were evaluable for aGvHD from January 2015 until June 2021 (clinicaltrials.gov: NCT03977103). Histological features and lymphoid infiltration by immunohistochemistry were analyzed in gut samples of patients who received diagnostic colonscopy and biopsy for gastrointestinal symptoms.ResultsA total of 105 patients engrafted after Treg/Tcon haplo-HSCT. Mean age at transplant was 48 years (range 18-70). Acute leukemia was the most frequent diagnosis (78/105 myeloid, 23/105 lymphoblastic), 4 patients had myelodisplastic syndrome and 2 multiple myeloma. Twenty-seven (26%) patients had active disease at the time of HSCT. Fourteen (13%) patients received Treg/Tcon haplo-HSCT as a second HSCT procedure. Thirty-one (29%) patients developed grade II-IV aGvHD. Four patients had grade II aGvHD, 23 grade III, and 4 grade IV. Almost all patients (90%) presented gut involvement, while skin was involved in 64% of them and liver in 35%. To explain why gut symptoms such as diarrhea and abdominal pain were more frequently present than symptoms of skin or liver involvement, we evaluated 40 histological samples from 34 patients who received colonoscopy for suspected aGvHD. Twenty-two of them (65%) received a clinical diagnosis of aGvHD and pharmacological immune suppression was promptly started. Clinical diagnosis did not always match histological findings: biopsies were suggestive of aGvHD in 20/22 patients who required treatment, but also in 8/12 patients who did not. We found no difference in median CD3+ cell infiltration among patients who did not need immune suppressive treatments and patients with aGvHD (460 cells/mmq vs 446 cells/mmq). However, FOXP3+ Tregs preferentially infiltrated gut mucosa of patients who resolved clinical symptoms with no need of immune suppressive treatments (120 cells/mmq vs 59 cells/mmq, p = 0.008; FOXP3/CD3 ratio: 0.27 vs 0.18, p = 0.004). This observation suggested Treg defective homing to gut mucosa of aGvHD patients. Indeed, we found infused Tregs expressed lower levels of gut homing receptor α4β7 in comparison with Tcons (p< .001).Despite severe presentation at diagnosis, aGvHD resolved in the majority of patients (71%), and immune suppressive therapy could be completely withdrawn after a relatively short-course (median: 98 days, range 48-404). Sixteen/31 patients (52%) were steroid refractory and required further treatments after first-line (e.g. Ruxolitinib). Only two of them developed moderate/severe cGvHD and one is alive and off-therapy.Indeed, aGvHD diagnosis did not result in higher incidence of non-relapse mortality (cumulative incidence of 29% in aGvHD patients vs 27% in controls; p=non significant, ns, Fig.1A), relapse (13% vs 20%; p=ns, Fig.1B), or cGvHD (6.5% vs 3%; p=ns, Fig.1C). In fact, CRFS of aGvHD patients was similar to CRFS of patients that did not develop aGvHD (Fig. 1D, p=ns, median follow up of live patients: 1246 days).ConclusionsTreg/Tcon haplo-HSCT is followed by low rates of relapse and cGvHD and results in good CRFS in high risk leukemia patients. aGvHD after Treg/Tcon haplo-HSCT preferentially involves the gut where Treg homing is defective. Strategies that enhance Treg homing in the gut (e.g. low-dose IL-2) may help reduce aGvHD after Treg/Tcon haplo-HSCT. In conclusion, despite aGvHD occurred in 29% of patients, it was responsive to treatments and it did not result in disease relapse or cGvHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Negative MRD at Day 100 after Allogenic Hematopoietic Stem Cell Transplant (HSCT): The Grail to Reach in Acute Myeloid Leukemia (AML)

INTRODUCTIONHSCT remains the best curative treatment in eligible AML patients with adverse or intermediate cytogenetics according to the ELN classification, and for those with unfavorable molecular markers at diagnostic or with a positive measurable residual disease (MRD) after intensive chemotherapy. MRD-positivity after HSCT confers an inferior outcome and a recently published study demonstrated that the evaluation of WT1 MRD before HSCT or 3 months after HSCT is highly predictive of post-transplant relapse. Besides, the impact and the kinetics of MRD positivity on prognosis are still unclear. Here we assess the impact of both pre- and post-transplant MRD on long term survival and incidence of relapse among a real-life cohort of 117 AML patients who underwent HSCT. PATIENTS AND METHODFrom November 7, 2012 to December 17, 2019, 117 patients diagnosed with AML and aged over 18 years underwent HSCT in Amiens University Hospital Center. MRD status was assessed using RQ-PCR (sensitivity 10 -4 to 10 -5) or multiparametric flow cytometry (sensitivity 10 -3 to 10 -4) before HSCT, depending on the markers available at diagnosis, at day 30, day 100 and a year after HSCT. Overall survival (OS) and cumulative incidence of relapse (CIR) were evaluated at the same time-points in landmark analysis for patients surviving beyond d100 to reduce the impact of early death on CIR. Statistical analyses were performed with SPSS Statistics 20 (IBM). RESULTSMedian age was 55 years (range 18-72) with 67/117 males. 85% patients had de novo AML. Cytogenetic ELN risk stratification was favorable for 15 (13%), intermediate for 72 (62%) and adverse for 28 (25%). At the time of HSCT, 76% were in complete remission (CR) after intensive chemotherapy. 30 patients (25%) had myeloablative conditioning (MAC) or toxicities-reduced regimens (TRC), 34 patients (30%) had reduced-intensity regimens (RIC) and 53 patients (45%) underwent sequential-based conditioning regimens (Seq). For the 100 patients who survived beyond d100, median time follow-up was 23.5 months (3.0-85.0). OS at 1 and 3 years was respectively 80% (75.9-84.1) and 61.7% (56.1-67.3) and CIR at same time-points was 19,3% (15.2-23.4) and 29,8% (24.6-35.0). No OS and CIR differences were observed according to the conditioning regimen, stem cell source and ELN score. A progressive disease before HSCT increased the risk of relapse but didn't worsen the OS. Before HSCT, MRD was positive in 48 patients (58.5%) with analyzable markers, either at molecular or flow cytometry level. OS and CIR were not impacted by the pre-HSCT MRD. Strikingly, performing HSCT resulted in MRD negativation at day 100 for 85.4% of patients with previous positive MRD, significantly improving OS and CIR (p<.001 for both, Figure 1A and B). Beyond day 100, achieving a negative MRD limited the 5-year CIR to 20%. In multivariate analysis, OS was significantly inferior, in patients with acute GVHD > grade 2 (HR=5.4, 95CI=1.8-16.1; p=.002) and positive MRD at day 100 (HR=19.2, 95CI=6.0-61.1; p<.001). Positive MRD at day 100 was the only significant predictor of adverse CIR (HR=17.5, 95CI=5.6-55.3; p<.001).DISCUSSION/CONCLUSIONIn this real-life cohort of patients diagnosed with AML, we show that HSCT procedure consistently allows MRD negativation, subsequently improving the outcome of patients surviving beyond d100. Persistence of positive MRD after HSCT was the main predictor of long-term adverse outcome after transplant. Our data highlight the importance of MRD negativation at day 100 regardless of pre-transplant status, conditioning regimen or initial ELN classification. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.