Outcome Of Hematopoietic Stem Cell Transplantation Research Articles

376 - Hematopoietic Stem Cell Transplant Outcomes for Mecom-Associated Bone Marrow Failure in Infancy: A Case Series and Review of the Literature

376 - Hematopoietic Stem Cell Transplant Outcomes for Mecom-Associated Bone Marrow Failure in Infancy: A Case Series and Review of the Literature

130 - Day Zero Endothelial Activation and Stress Index (EASIX) Best Predicts Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Acute Myeloid Leukemia Patients

130 - Day Zero Endothelial Activation and Stress Index (EASIX) Best Predicts Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Acute Myeloid Leukemia Patients

134 - Hematopoietic Stem Cell Transplant Outcome in STAG2-Mutated Myeloid Neoplasms

134 - Hematopoietic Stem Cell Transplant Outcome in STAG2-Mutated Myeloid Neoplasms

A Novel Scientometrics Research on the Interaction between Oxidative Stress and Hematopoietic Stem Cell Transplantation Complications: From Graft-versus-Host Disease to Sepsis.

As major and serious complications after hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) and sepsis are the chief causes of low survival rates as well as mortality and for HSCT recipients. Although the overall treatment outcomes of HSCT have improved significantly in recent years, there is still an increased incidence rate of complications and mortality after transplantation. In the immediate past, with a deeper understanding of oxidative stress, more and more shreds of evidence have shown that it is closely related to transplantation-related sepsis. However, there is currently a precious little research on the interaction between oxidative stress and complications after HSCT, and the major mechanism has not yet been clarified. The objective of this study was to assess the internal connection between and potential mechanisms as well as visualized the scientometrics results of all important literature related to the topic. Through exhaustive scientometrics analysis, we searched and carefully screened 286 related publications from the Web of Science Core Collection (WoSCC) with "((HSCT) OR (hematopoietic stem cell transplantation)) AND (oxidative stress)" as the search strategy. Then, detailed visualization of the overall information analysis was made by scientific and rigorous bibliometrics software or website. Next, we analyzed retrieved articles extensively and then 59 publications that are relevant to this topic were selected for nuanced analysis and summary. The assessment of these studies proved the validity of the interaction between oxidative stress and complications after HSCT objectively and directly.

Levofloxacin prophylaxis and parenteral nutrition have a detrimental effect on intestinal microbial networks in pediatric patients undergoing HSCT

The gut microbiome (GM) has shown to influence hematopoietic stem cell transplantation (HSCT) outcome. Evidence on levofloxacin (LVX) prophylaxis usefulness before HSCT in pediatric patients is controversial and its impact on GM is poorly characterized. Post-HSCT parenteral nutrition (PN) is oftentimes the first-line nutritional support in the neutropenic phase, despite the emerging benefits of enteral nutrition (EN). In this exploratory work, we used a global-to-local networking approach to obtain a high-resolution longitudinal characterization of the GM in 30 pediatric HSCT patients receiving PN combined with LVX prophylaxis or PN alone or EN alone. By evaluating the network topology, we found that PN, especially preceded by LVX prophylaxis, resulted in a detrimental effect over the GM, with low modularity, poor cohesion, a shift in keystone species and the emergence of modules comprising several pathobionts, such as Klebsiella spp., [Ruminococcus] gnavus, Flavonifractor plautii and Enterococcus faecium. Our pilot findings on LVX prophylaxis and PN-related disruption of GM networks should be considered in patient management, to possibly facilitate prompt recovery/maintenance of a healthy and well-wired GM. However, the impact of LVX prophylaxis and nutritional support on short- to long-term post-HSCT clinical outcomes has yet to be elucidated.

Clinical Impact of Recipient-Derived Isoagglutinin Levels in ABO-Incompatible Hematopoietic Stem Cell Transplantation.

ABO incompatibility is not considered a contraindication for hematopoietic stem cell transplantation (HSCT). We hypothesized that recipient-derived isoagglutinin (RDI) levels could play a critical role in clinical outcomes. In this study, we compared clinical outcomes such as survival, GVHD, infection, relapse, transfusion, and engraftment, among ABO-compatible patients (ABOc), ABO-incompatible patients (ABOi) with low RDI, and ABOi patients with high RDI. The ABOi with high RDI group was defined as recipients with more than 1:16 RDI levels. We analyzed 103 recipients (ABOc, 53; ABOi with low RDI, 36; ABOi with high RDI, 14). The ABOi with high RDI group showed a decreased 1-year survival and increased acute GVHD grade IV and RBC transfusion (p = 0.017, 0.027, and 0.032, respectively). The ABOi with high RDI group was an independent risk factor for increased death, RBC transfusion, and poor platelet (PLT) engraftment (odds ratio (OR) = 3.20, p = 0.01; OR = 8.28, p = 0.02; OR = 0.18, p = 0.03, respectively). The ABOi with high RDI group showed significantly delayed PLT engraftment. In conclusion, this is the first study underscoring high RDI levels as a marker predicting unfavorable outcomes in ABOi HSCT.

Is Treosulfan-Based Conditioning Attractive as a Reduced-Intensity Conditioning Regimen in Korea?

Allogeneic hematopoietic stem cell transplantation (HSCT) was not actively performed in elderly acute myeloid leukemia (AML) or myelodysplastic syndrome patients who are at a high-risk based on hematopoietic cell transplantation-specific comorbidity index (HCT-CI). The advent of reduced-intensity conditioning (RIC) regimens has made HSCT applicable in this population. However, the selection of appropriate conditioning is a major concern for the attending physician. The benefits of combination of treosulfan and fludarabine (Treo/Flu) have been confirmed through many clinical studies. Korean data on treosulfan-based conditioning regimen are scarce. A retrospective study was conducted to compare the clinical outcomes of allogeneic HSCT using RIC between 13 patients receiving Treo/Flu and 39 receiving busulfan/fludarabine (Bu/Flu). In terms of conditioning-related complications, the frequency of ≥ grade 2 nausea or vomiting was significantly lower and the duration of symptoms was shorter in the Treo/Flu group than in the Bu/Flu group. The incidence of ≥ grade 2 mucositis tended to be lower in the Treo/Flu group. In the analysis of transplant outcomes, all events of acute graft versus host disease (GVHD) and ≥ grade 2 acute GVHD occurred more frequently in the Treo/Flu group. The frequency of Epstein-Barr virus reactivation was significantly higher in the Treo/Flu group (53.8% vs. 23.1%, P = 0.037). Non-relapse mortality (NRM) at 12 months was higher in the Treo/Flu group (30.8% vs. 7.7%, P = 0.035). Significant prognostic factors included disease type, especially secondary AML, disease status and high-risk based on HCT-CI, ≥ grade 2 acute GVHD, and cases requiring ≥ 2 immunosuppressive drugs for treating acute GVHD. In the comparison of survival outcomes according to conditioning regimen, the Bu/Flu group seemed to show better results than the Treo/Flu group (60% vs. 46.2%, P = 0.092 for overall survival; 56.4% vs. 38.5%, P = 0.193 for relapse-free survival). In additional analysis for only HCT-CI high-risk groups, there was no difference in transplant outcomes except that the Treo/Flu group tended to have a higher NRM within one year after transplantation. Survival outcomes of both groups were similar. This study suggests that Treo/Flu conditioning may be an alternative to Bu/Flu regimen in elderly patients with high-risk who are not suitable for standard conditioning.

Late Effects in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation for Nonmalignant Diseases: Proxy- and Patient-Reported Outcomes

Survival rates in pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases have improved due to advances in conditioning regimens, donor selection, and prophylaxis and treatment of infections and graft-versus-host disease. Insight into the long-term patient-reported outcomes (PROs) after pediatric HSCT for nonmalignant disease is lacking but essential for optimal shared decision making, counseling, and quality of care. The purpose of this research was to determine long-term patient-reported outcomes in allogeneic pediatric HSCT for nonmalignant diseases and to compare these results with Dutch reference data. This single-center cohort study evaluated PROs (PedsQL 4.0, PROMIS item banks), self- or proxy-reported, among patients at ≥2 years after pediatric allogeneic HSCT for nonmalignant disease. Mean scores were compared with those of the Dutch general population. Of 171 eligible patients, 119 participated, for a 70% response rate. The median patient age was 15.8 years (range, 2 to 49 years), and the median duration of follow-up was 8.7 years (range, 2 to 34 years). Indications for HSCT included inborn errors of immunity (n=41), hemoglobinopathies (n=37), and bone marrow failure (n=41). Compared with reference data, significantly lower scores were found in adolescents (age 13 to 17 years) on the Total, Physical Health, and School Functioning PedsQL subscales. Significantly more Sleep Disturbance was reported in children (age 8 to 18 years). On the other hand, significantly better scores were seen on PROMIS Fatigue (age 5 to 7 years) and Pain Interference (age 8 to 18 years) and, in adults (age 19 to 30 years), on Depressive Symptoms and Sleep Disturbance. This study showed better or comparable very long-term PROs in patients after pediatric HSCT for nonmalignant diseases compared with the reference population. Children and adolescents seem to be the most affected, indicating the need for supportive care to prevent impaired quality of life and, more importantly, to amplify their long-term well-being.

Effect of Early Bacillus Calmette-Guerin Vaccination of Pediatric Severe Combined Immunodeficiency Patients on the Outcome of Hematopoietic Stem Cell Transplantation Using a Reduced-Intensity Conditioning Regimen

The eminence of Bacillus Calmette-Guerin (BCG) vaccine in newborn vaccination programs has been conspicuous throughout the years, especially in low-income developing countries where tuberculosis is prevalent; however, application of the BCG vaccine is not without constraints, especially in patients afflicted with immunodeficiency diseases, such as severe combined immunodeficiency (SCID). The present study aimed to evaluate whether the administration of BCG vaccine at birth could improve the outcomes of hematopoietic stem cell transplantation (HSCT) in pediatric patients with SCID. In this study, 30 SCID patients who underwent HSCT using a reduced-intensity conditioning regimen (RIC) were followed-up for 2 years post-HSCT. The outcomes of HSCT were evaluated in both non-BCG-vaccinated patients (n = 12) and BCG-vaccinated patients (n = 18). Our results show a higher incidence of acute graft-versus-host disease (aGVHD), but not of chronic GVHD, in the BCG-vaccinated patients, and a similar overall survival (OS) rate in the 2 groups. We speculate that the similar OS rate in the 2 groups, despite the risk of BGC vaccination, was because this group received an RIC conditioning regimen. There was no other difference between the 2 groups. Considering the effect of the BCG vaccine on HSCT outcome, we suggest that the administration of BCG vaccine be deferred until age 3 months so that APT testing without the interference of maternal antibodies can be performed. However, this study could benefit from a larger cohort to further validate our findings, as the possible reason for some factors not being statistically significant was our small sample size.

Effect of the COVID-19 pandemic on allogeneic stem cell transplantation in Japan.

The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018-December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.

Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes.

Mutations in the CSF1R gene are the most common cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disease with rapid progression and ominous prognosis. Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP. However, different therapy results were observed, and it was not elucidated which patient should be referred for HSCT. This study aimed to determine predictors of good and bad HSCT outcomes in CSF1R-ALSP. We retrospectively analyzed 15 patients, 14 symptomatic and 1 asymptomatic, with CSF1R-ALSP that underwent HSCT. Median age of onset was 39 years, and the median age of HSCT was 43 years. Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%). Median post-HSCT follow-up was 26 months. Good outcomes were associated with gait problems as initial (p = 0.041) and predominant (p = 0.017) manifestation and younger age at HSCT (p = 0.044). Cognitive impairment as first manifestation was a predictor of a bad outcome (p = 0.016) and worsening of cognition post-HSCT (p = 0.025). In conclusion, gait problems indicated a milder phenotype with better response to HSCT and good therapy outcomes. In contrast, patients with a higher burden of cognitive symptoms were most likely not to benefit from HSCT.

Cellular senescence marker p16INK4a and NFKB1 gene polymorphisms in lower gastro-intestinal acute graft versus host disease

BackgroundLower gastrointestinal (GI) graft versus host disease (GVHD) represents a severe complication in allogeneic hematopoietic stem cell transplant (HSCT) recipients with high rates of transplant-related mortality. Deregulated innate immunity reactions are the features of its pathogenesis. Cellular senescence has been considered a program of the innate immunity. We focused on lower GI GVHD from the perspective of cellular senescence. ObjectiveWe analyzed the impact of p16INK4a expression, a hallmark of cellular senescence, in intestinal biopsies of patients with lower GI GVHD symptoms and NFKB1 gene polymorphisms (rs3774937 C/T and rs3774959 A/G) on HSCT outcome. Study designFifty-two single-center patients who presented with symptoms of lower GI GVHD were analyzed in a retrospective manner. Two SNPs located in the NFKB1 gene regions (rs3774937 C/T and rs3774959 A/G) were genotyped from the peripheral blood samples collected before the start of the conditioning. All patients underwent proctosigmoidoscopy with biopsy of the mucosa. The expression of p16INK4a was analyzed in normal intestinal crypts and stroma. ResultsFifty-two patients (50% male) received HSCT for hematological diseases (acute leukemias in 67%) and developed lower GI symptoms. Patients with p16INK4a expression in the intestinal stroma were in lower risk of developing histological grade 3–4 aGVHD (RR 0.18 [95% CI 0.05–0.65]; p = 0.009). The multivariate linear regression confirmed the independent effect of p16INK4a expression on time of the lower GI aGVHD symptoms onset (Coef. 38.9 [95% CI 12.7–65.1]; p = 0.005). The NFKB1 rs3774937 CC and TT/TC genotype were present in 40 and 80% of patients with p16INK4a expression, respectively (p = 0.04). The rs3774959 AA and GG/AG genotype were present among 43 and 82% of patients with p16INK4a expression, respectively (p = 0.02). Expression of p16INK4a was associated with no clinical variable but NFKB1 genotype. ConclusionsOur results address possible new mechanisms that may lead to better understanding of HSCT-related immune complications. Cellular senescence may bring novel approaches in GVHD diagnostics and therapy.

Second allogeneic hematopoietic stem cell transplantation in patients with inborn errors of immunity

Graft failure (GF) remains a serious issue of hematopoietic stem cell transplantation (HSCT) in inborn errors of immunity (IEI). Second HSCT is the only salvage therapy for GF. There are no uniform strategies for the second HSCTs and limited data are available on the second HSCT outcomes. 48 patients with various IEI received second allogeneic HSCT from 2013 to 2020. Different conditioning regimens were used, divided into two main groups: containing myeloablative doses of busulfan/treosulfan (n = 19) and lymphoid irradiation 2–6 Gy (n = 22). Irradiation-containing conditioning was predominantly used in suspected immune-mediated rejection of the first graft. Matched unrelated donor was used in 28 patients, mismatched related in 18, and matched related in 1. 35 patients received TCRαβ/CD19 graft depletion. The median follow-up time was 2.4 years post-HSCT. One patient died at conditioning. The OS was 0.63 (95% CI: 0.41–0.85) after busulfan/treosulfan and 0.68 (95% CI: 0.48–0.88) after irradiation-based conditioning, p = 0.66. Active infection at HSCT significantly influenced OS: 0.43 (95% CI: 0.17–0.69) versus 0.73 (95% CI: 0.58–0.88) without infection, p = 0.004. The cumulative incidence of GF was 0.15 (95% CI: 0.08–0.29). To conclude, an individualized approach is required for the second HSCT in IEI. Low-dose lymphoid irradiation in suspected immune-mediated GF may be a feasible option.

Association Between Human Leukocyte Antigens and Graft-Versus-Host Disease Occurrence in Allogeneic Hematopoietic Stem Cell Transplantation - A 10-Year Experience on Iranian Patients.

Human leukocyte antigen (HLA) molecules mediate critical roles in determining responsiveness or non-responsiveness of the immune system, especially in transplantation. Some studies have shown a possible association between certain HLA alleles and some allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes such as acute/chronic graft-versus-host disease (aGVHD/cGVHD) and overall survival (OS). In the current study, we investigated any possible association of HLA subclasses and acute/chronic GVHD occurrence as well as OS in patients receiving HLA-matched sibling allo-HSCT. We retrospectively evaluated the association of various HLA alleles with the incidence of aGVHD, cGVHD, and OS of 162 patients who received allo-HSCT from HLA-matched sibling between 2009-2018 at Taleghani hospital in Tehran. We found that the incidence of aGVHD grades II-IV was higher among patients who had HLA-B*07 (P=0.031) and HLA-DRB1*07 (P=0.052). The presence of HLA-A*01 was associated with 4.5-fold greater odds of incidence in the extensive-type of cGVHD (P=0.009). Furthermore, HLA-A*03 (P=0.089), HLA-B*13(P=0.013), HLA-B*40 (P=0.042), HLA-DRB1*02 (P=0.074), and HLA-DRB1*04 (P=0.039) were associated with a lower rate of OS. This study suggests that certain HLA alleles might influence the incidence and severity of acute or chronic GVHD in the context of HLA-matched sibling allo-HSCT. In addition, some specific HLA alleles help predict OS in allo-HSCT recipients. These results might be helpful in estimating the incidence of aGVHD, cGVHD, and OS as well as designing personalized therapy.

Two decades of stem cell transplantation in patients with Fanconi anemia: Analysis of factors affecting transplant outcomes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for the hematological complications of patients with Fanconi anemia (FA). Over the last two decades, HSCT outcomes have improved dramatically following the development of regimens tailored for FA patients. In this study, we analyzed genetic, clinical, and transplant data of 41 patients with FA who underwent HSCT at Hadassah Medical Center between November 1996 and September 2020. Overall survival (OS) was 82.9% with a median follow-up time of 2.11-years (95% CI, .48-16.56). Thirteen patients (31.7%) developed acute graft-versus-host disease (GVHD), three of them with grades 3-4. Nine patients developed chronic GVHD, five had extensive disease. Twelve patients (29.3%) developed stable mixed-chimerism with complete resolution of bone marrow failure (BMF); none of them had acute nor chronic GVHD. Significantly higher GVHD rates were observed in transplants from peripheral blood stem cell grafts as compared to other stem cell sources (p=.002 for acute and p=.004 for chronic GVHD). Outcome parameters were comparable between HSCT from matched-sibling (n=20) to other donors (n=21), including survival rates (p=.1), time to engraftment (p=.69 and p=.14 for neutrophil and platelet engraftment time, respectively), chimerism status (p=.36 and p=.83 for full-donor and mixed chimerism, respectively), and GVHD prevalence (p=1). Our results demonstrate the vast improvements in HSCT outcomes of patients with FA, narrowing the gap between matched-sibling versus alternative donor transplantations. Our data identifies factors that may significantly affect transplant outcomes such as graft source and chimerism status.

Hematopoietic Stem Cell Transplantation in Bangladesh : Activity and Outcome Update

Background : Hematopoietic stem cell transplantation(HSCT) is a potentially life saving curative modality of treatment procedure for many hematological malignancies, bone marrow failure syndromes and thalassemia. Bangladesh started first bone marrow transplant program with autologous transplant for myeloma in 2014 with the international collaboration between Massachusetts general hospital ( MGH) and Dhaka Medical College Hospital (DMCH). Since then it is growing in both public and private sector hospitals. Method : This is a multicenter retrospective study describing the demographics, activities and outcome of HSCT in Bangladesh. HSCT related Data were collected from three eminent HSCT centres of Bangladesh ( DMCH, Evercare hospitals and Combined Military Hospital Dhaka) and were analyzed. Result : As of June 2022, total 163 HSCT have been done in Bangladesh in major three centres as DMCH(52), Evercare hospital (62)and CMH Dhaka(49). Mean age of all patients is 39.4 years( range 15-69 Y) and sex distribution is M:F 3:1. Total autologous transplants were 125(77%) for myeloma(52), Hodgkins lymphoma(27) ,non-Hodgkins lymphoma(39) and others(7). Total allogeneic transplants were 38(23%) for AML(23), ALL(6), other hematological malignancy(03), Severe aplastic anemia (04) and thalassemia (02). Donor type wise majority were from matched sibling transplant (30/78%) from mostly male donor. Eight (08) haplo transplant were also successfully done. Each center follows specific infection control protocols, conditioning chemo protocols and growth factor protocols for the best patient care. Conditioning chemo protocols that usually used are high dose melphalan for MM, BEAM( Carmustine, Etoposide, Ara-C and Melphalan) for lymphoma and Bu-Cy( Busulphan-Cyclophosphamide) based for acute leukemia. Some leukemia patients received total body irradiation( TBI), thiotepa and Fludarabine based conditioning chemotherapy. All centres use irradiated blood components as transfusion products to avoid transfusion associated GVHD. As all centre used almost similar conditioning for particular disease, mean engraftment time in all centres were almost similar. Average time for neutrophil and platelet engraftment was 10-12 and 12-16 days post transplant respectively. Major early complications following transplant were neutropenic fever (>80%) and bacteraemia (25-30%) commonly with coagulase negative Staphylococcus, Pseudomonas sp, E. Coli and Klebsiella sp. Severe sepsis, pneumonia, typhlitis, hemorrhagic cystitis and CMV reactivation were observed in few cases. Acute GVHD ( G I to GII) was observed in almost all allogeneic transplanted patients. Mucositis, vomiting and diarrhoea were mild to moderate in most patients. Almost all patients required at least 1-3 red cell and platelet transfusion during the time waiting for engraftment. Progression free survival for all patients was variable in different centres (62% to 83%) since 2014 . Relapse of primary disease is more observed in autologous than allogeneic. Transplant related mortality( TRM) was 2% for autologous transplants and 5% for allogeneic transplant. Three early deaths were due to sepsis with COVID-19 infection in autologous transplant in pandemic period. Overall cost of transplantation is much lower in Bangladesh than that of developed countries. Approximate cost of autologous stem cell transplant is about $7000 and that for allogeneic transplant is $12000 to $15,000. Conclusion : Considering total population and burden of hematological malignancy in Bangladesh, the number of transplant is very low and it needs to be grown more rapidly to provide maximum benefit to save the lives as HSCT offers a curative approach to many hematological malignancies. Financial constrain, lack of health insurance and shortage of trained human resource are the main challenges for doing transplant in Bangladesh. National transplant registry and national donor registry both are yet to be developed. Comparing the cost difference with developed countries the overall outcome of stem cell transplantation is not inferior in Bangladesh.

Clinical and Economic Outcomes in Patients with Transfusion-Dependent β-Thalassemia and Patients with Sickle Cell Disease with Recurrent Vaso-Occlusive Crises Receiving Hematopoietic Stem Cell Transplants in the United States

Background: Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are inherited blood disorders caused by mutations in the β-globin gene, resulting in abnormal, reduced, or absent expression of hemoglobin. TDT is characterized by ineffective red blood cell production that leads to chronic anemia, need for regular red blood cell transfusions (RBCTs), and organ complications. SCD is characterized by sickle-shaped red blood cells that cause vaso-occlusive crises (VOCs), hemolysis, and end-organ damage. Hematopoietic stem cell transplant (HSCT) is currently the only curative option for patients with TDT and patients with SCD. There is limited research on the frequency and outcomes of HSCT in these two patient populations. This study describes the economic and clinical outcomes for a combined population of patients with TDT and patients with SCD with recurrent VOCs who received HSCTs in the United States. Methods: This retrospective cohort study used administrative claims from the MerativeTM Commercial, Medicare, and Multi-State Medicaid Databases to identify patients with ≥1 inpatient or ≥2 outpatient claims for β-thalassemia or SCD between March 1, 2010, and March 1, 2019. Eligible patients with TDT were required to have ≥8 discrete RBCTs in any 12-month period on or after the date of the earliest qualifying β-thalassemia claim. At least 3 days between service dates of RBCT claims were required to be considered discrete RBCTs. Patients with TDT were required to have 1 year of continuous enrollment after their first transfusion to be included. Eligible patients with SCD with recurrent VOCs were required to have ≥2 diagnosed VOCs per year in any 2 consecutive years after and including the first qualifying SCD claim. A VOC was defined as inpatient or outpatient claim of acute chest syndrome, priapism, SCD crisis, or splenic sequestration; at least 3 days between VOC claims were required to be considered discrete VOCs. Eligible patients with SCD with recurrent VOCs were required to have 24 months of continuous enrollment before the second VOC in the second consecutive year and 12 months of continuous enrollment after. Patients with TDT and patients with SCD who met the above criteria and received an HSCT were included in the analysis set. Patients receiving HSCT were identified utilizing relevant procedure codes. The index date was the date of transplant. Patients were followed from the index date to the earliest of end of enrollment, death, or end of study period (March 1, 2020). Demographics were assessed at the index date, and clinical complications, healthcare resource utilization, and costs were descriptively summarized in the post-index period. Costs were based on paid amounts of adjudicated claims and patient cost-sharing and included costs in the 10 days before the index date to account for pre-transplant healthcare services associated with the transplant. Results: Two hundred thirty-four and 3500 patients met the criteria for TDT and SCD with recurrent VOCs, respectively, for a total of 3734 patients. Of that total, 62 patients (1.66%) underwent a transplant and were therefore included in the analysis cohort. Mean patient age at the index date was 12.6 years, and 46.8% were female. A proportion of transplant patients experienced graft versus host disease (GvHD) (37/62; 59.7%), unspecified HSCT complications (33/62; 53.2%), or bone marrow transplant rejection or failure (6/62; 9.7%) post-transplant. Average length of stay for the index HSCT admission was 42 days; in the first year post-transplant, patients averaged 58.3 days in the hospital. Total costs in the first 100 days and 1 year post-transplant were $442,752 and $623,301, respectively. Inpatient costs accounted for 93.7% and 88.7% of costs at 100 days and 1 year, respectively. Conclusions: This retrospective cohort study suggests that only a small proportion of patients with TDT and patients with SCD with recurrent VOCs receive HSCTs. Many patients who undergo transplants experience clinical complications, including graft failure and GvHD, and substantial economic burden. Given the limited utilization and potential safety risks of HSCT, additional curative treatment approaches are needed for patients with TDT and patients with SCD with recurrent VOCs.

Allogeneic Hematopoietic Stem Cell Transplant Outcomes in Adults with Inherited Myeloid Malignancies

Recognition of hereditary hematopoietic malignancies (HHMs) has accelerated in recent years, with deleterious germline variants in more than 20 genes recognized as drivers of myeloid malignancies. Individuals with HHMs generally receive similar treatment plans as those with de novo disease. Hematopoietic stem cell transplantation (HSCT) is often employed as a curative approach for myeloid malignancies, and in those with germline pathogenic (P)/likely pathogenic (LP) predisposition variants, there is a preference for use of related donors who lack the familial variant. However, there are limited data on the outcomes of patients with HHMs who are treated in this manner. In this study, we used comprehensive clinical and genomic data to investigate the allogeneic transplant-related outcomes in the largest international myeloid HHM cohort reported to date. We performed a retrospective analysis of all patients with myeloid malignancies who underwent germline predisposition testing at The University of Chicago (UofC) or the Central Adelaide Health Network between 2010 and 2021; or were known to have deleterious germline DDX41 variants from the University of Pennsylvania and Moffitt Cancer Center. We studied 472 patients, of whom 28% (80/289) in the UofC cohort and 20% (35/175) in the Adelaide cohort had a deleterious germline variant causative of HHMs. In the UofC cohort, P/LP CHEK2 variants were the most common, whereas P/LP DDX41 variants were most common in the Adelaide cohort (Fig. 1). A total of 161 patients (34% of the entire cohort) underwent allogeneic HSCT for their myeloid neoplasm (Table 1). There were no differences in the distribution of diagnoses, donor types, disease status at the time of HSCT (remission vs active disease), conditioning regimens, or conditioning intensity. All donor cells were mobilized from peripheral blood. Almost all donors lacked the deleterious germline causative variant, with one donor sharing a deleterious familial DDX41 variant with the relative/HSCT recipient. The median time to engraftment was similar between those who had vs lacked germline HHM variants. Patients with P/LP germline DDX41 variants had higher rates of severe (stage 3-4) acute graft versus host disease (GVHD) when compared to patients with P/LP CHEK2, those with other germline variants, or those without P/LP germline variants (38% vs 0, 12%, and 9%, respectively; p=0.002). Notably, severe gastrointestinal GVHD was seen in a third of patients with P/LP germline DDX41 variants as opposed to <10% incidence in other groups (p<0.001, Table 1). Similarly, 33% of patients with P/LP germline DDX41 variants experienced moderate to severe chronic GVHD, whereas this incidence was 29% for patients with P/LP germline CHEK2 variants, 4% for patients with other P/LP germline variants, and 10% for patients without a P/LP inherited variant (p=0.008). Patients with P/LP germline DDX41 variants who received post-HSCT cyclophosphamide had lower rates of severe acute GVHD compared to those who received other forms of GVHD prophylaxis (0% vs 53%, p=0.03). To adjust for the effects of known GVHD risk factors, we performed a multivariable logistic regression analysis. Germline DDX41 status remained an independent predictor of both acute GVHD (OR: 4.76, range 1.27-17.9; p=0.01) and chronic GVHD (OR: 3.39, range 1.09-10.5; p=0.03). Importantly, post-HSCT cyclophosphamide use was associated with a reduced risk of acute GHVD when adjusted for other variables (OR: 0.10, range 0.01-0.71; p=0.008). Our data establish severe GVHD as a clinically relevant post-transplant phenomenon in germline DDX41-associated HHMs and suggest that donor-derived wild-type T-cells may become activated by a pro-inflammatory milieu conferred by P/LP germline DDX41 variants. Moreover, our observations suggest that post-HSCT cyclophosphamide is an effective strategy for GVHD prevention in these individuals. Broader confirmation of our results in other heterogeneous patient cohorts will serve to expand the spectrum of known pathogenic variants implicated in HHMs and support the development of targeted interventions for those with deleterious germline HHM alleles. Finally, these results argue for germline genetic testing in patients prior to allogeneic HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Breadth of the Human Leukocyte Antigens Class I Immunopeptidome in Allogenic Hematopoietic Stem Cell Transplantation Outcomes for Myeloid Malignancy

Introduction Expected graft-versus-leukemia (GVL) effect, allogeneic hematopoietic stem cell transplantation (allo-HCT) is performed for myeloid malignancies. GVL is modulated by alloreactive T cells that recognize cancer cell antigens, but not all the mechanisms of GVL have been elucidated. Alloreactive T cells can also cause a harmful immune response, graft-versus-host disease (GVHD). Human leukocyte antigens (HLA) are the key molecules presenting antigens to T cells. They are highly polymorphic and vary widely among individuals. HLA allelic diversity causes differences in the immunopeptidome breadth. Recent reports suggest that a smaller immunopeptidome breadth may result in autoimmune disease such as aplastic anemia or type I diabetes, and that larger differences may enhance the antitumor effects of immune checkpoint inhibitors. This suggests that understanding the impact of the HLA immunopeptidome on allo-HCT, which may also be relevant to GVL and GVHD, might improve outcomes. Aim To examine the association between HLA class I immunopeptide diversity and outcomes in patients undergoing allo-HCT. Methods From 2006 to 2021, 145 patients with myeloid malignancies underwent initial allo-HCT at our institution. Of the 109 patients with evaluable allele data, 53 who received 8/8 allele-matched donors (acute myeloid leukemia, n = 40; myelodysplastic syndrome, n = 13) were analyzed. Graft sources were bone marrow (n = 31) and peripheral blood stem cells (n = 23). Donors were related (n = 23) and unrelated (n = 30). The conditioning regimens were myeloablative (n = 31) and non-myeloablative (n = 21). The disease status pre-transplantation was standard risk (n = 30) and advanced stage (n = 23). Differences in the immunopeptidome breadth between individuals were quantified as HLA evolutionary divergence (HED). HED was calculated using Grantham distance, which predicts amino acids from HLA allelic information and attempts to measure evolutionary distance based on the chemistry of the two amino acids. HLA allele data were drawn from clinical records and analyzed in the HLA laboratory (Kyoto, Japan) or SRL, Inc. (Japan). The calculator program was produced by Tobias Lenz et al. (https://hladiv.net/). The HED of each HLA class I: HLA-A, HLA-B, and HLA-C was calculated. Based on HED degree, overall survival (OS), cumulative relapse rate (CIR), acute/chronic GVHD, and non-relapse mortality (NRM) were evaluated. Result The median HED (range) was HLA-A, 10.34 (0.00-13.70); HLA-B, 7.50 (0.00-14.33); and HLA-C 4.66, (0.00-7.60), respectively. Based on their median HED, patients were divided into HED high or HED low groups for HLA-A, HLA-B, and HLA-C. On univariate analysis, patients with HED low for HLA-A had better 2-year OS compared to HED high for HLA-A (80.4%; 95%CI, 55.6%-92.2% vs. 42.0%; 95%CI, 23.9%-59.1%; p = 0.025) and better 2-year CIR (14.3%; 95%CI, 3.4%-46.1% vs. 59.5%, 42.2%-77.5%; p = 0.0027) (Figure 1). HED levels of HLA-B and HLA-C were not related to OS (p = 0.501, and p = 0.972, respectively) or CIR (p = 0.257 and 0.796, respectively). NRM was not associated with HED levels for any of the HLA. Multivariate analysis found HED low for HLA-A to be a favorable risk factor for OS (HR, 0.46; 95%CI, 0.22-0.95; p = 0.035) and CIR (HR, 0.22; 95%CI, 0.07-0.69; p = 0.0092) when adjusted for HLA-B, HLA-C, donor, graft, conditioning, and disease status. Next, the association between the HED level of each HLA class I and GVHD was analyzed. In acute GVHD, grades 2-4, after adjusting for graft, donor, and conditioning, HED high of HLA-B (HR, 4.66; 95%CI, 1.23-17.7; p = 0.024) and HED low of HLA-C (HR, 3.98; 95%CI, 1.16-13.6; p = 0.028) were risk factors but not for HLA-A. In chronic GVHD, multivariate analysis found HED high for HLA-C was a risk factor (HR, 4.77; 95%CI, 1.13-20.2; p = 0.034). Also, HED low for HLA-A tended to increase chronic GVHD ((HR, 2.61; 95%CI, 0.95-7.14; p = 0.063) (Table 1). Conclusion HED low for HLA-A was a favorable risk factor for OS and CIR, possibly because chronic GVHD tended to increase with HED low of HLA-A. HED levels for HLA-B and HLA-C did not contribute to OS and CIR but did influence acute and chronic GVHD. Since immunopeptidome significance may differ for each HLA class I, consideration of HED level during the donor selection may improve the safety and efficacy of allo-HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gilteritinib Maintenance Therapy Post-Allogenic Stem-Cell Transplantation Improves the Prognosis of Patients with FLT3-Mutated AML

Introduction FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) and -tyrosine kinase domain (TKD) mutation were common mutations in acute myeloid leukemia (AML). FLT3-ITD mutation adversely affected the outcome of hematopoietic stem-cell transplantation (SCT). While sorafenib and midostaurin as maintenance therapy after SCT prolonged relapse-free and overall survival (OS), there are very few reports of post-transplant gilteritinib maintenance therapy outside of clinical trials. Hence, to explore the efficacy of the gilteritinib maintenance therapy post-SCT, we here report the prognostic impact of post-SCT gilteritinib maintenance in a clinical setting. Methods We retrospectively analyzed 25 FLT3-mutated relapsed or refractory AML patients who received allogeneic SCT at our center from January 1, 2011 to April 30, 2022. FLT3 mutation was analyzed by a commonly used polymerase chain reaction (PCR)-based assay. Measurable residual disease (MRD) was assessed by Wilms tumor 1 (WT1) mRNA expression in peripheral blood, and MRD positivity was defined as WT-1 >50 copies/μg in this study. Relapse was defined as an increase of 5% blasts or more. Non-relapse mortality (NRM) was defined as death without relapse. Leukemia-free survival (LFS) was defined as the time from transplantation to leukemia relapse or death from any cause, which comes first. OS was defined as the time from transplantation to death from any cause. Results The median age was 52 years. Twenty-two patients had ITD mutation and 5 had TKD mutation (2 had both ITD and TKD mutation). At the time of the transplant, 20 patients were in remission (6 were MRD-negative and 14 were MRD-positive) and five were in non-remission. All patients achieved hematologic complete remission (CR) after SCT and no patients relapsed within 30 days post-SCT. After hematological engraftment, 14 patients started to receive gilteritinib as maintenance therapy and 11 patients did not. Between the two groups, the patients' characteristics including disease status at transplant, SCT procedures, and donor sources were well balanced except for the administration of FLT3-inhibitor prior to SCT (100% in patients with gilteritinib maintenance and 45.5% in those without gilteritinib maintenance, p = 0.003). Eleven patients (78.6%) in the gilteritinib group and eight (72.7%) patients in the non-gilteritinib group had residual MRD in hematological CR or were non-CR prior to SCT. The median time from SCT to the initiation of gilteritinib was 36 days. The median dose at gilteritinib initiation was 40mg (range 20-120 mg). One patient developed grade 2 skin acute graft-versus-host disease (GVHD) after gilteritinib administration and 4/14 patients (28.6%) developed moderate-severe chronic GVHD (cGVHD, two developed pulmonary cGVHD, one eye and mouse, and one skin) with a median onset of 10.5 months (range 3.1-30.5 months), while only one patient temporary discontinued gilteritinib until the improvement of cGVHD. Late engraftment failure during gilteritinib maintenance was not observed. In terms of survival benefit, patients with gilteritinib maintenance showed significantly longer LFS and OS than those without gilteritinib (1-y LFS; 100% vs. 36.4%, 95% CI; 100-100% vs. 11.2-62.7%, p = 0.0028, Figure A, and 1-y OS; 100% vs. 45.5%, 95% CI; 100-100% vs. 16.7-70.7%, p = 0.0075, Figure B). The cumulative incidence of AML relapse at one-year in patients with gilteritinib maintenance group was significantly lower than those without (0% vs. 51.5%, 95% CI; 0-0% vs. 24.9-86.0%, p = 0.005). Especially, among patients with MRD positive or non-CR prior to SCT (n=19), patients who received gilteritinib maintenance showed a lower cumulative incidence of AML relapse at one-year than those without gilteritinib maintenance (0% vs. 68.8%, 95% CI; 0-0% vs. 35.9-95.2%, p = 0.0028, Figure C). Patients without MRD prior to SCT did not relapse with or without gilteritinib maintenance. These results suggest that gilteritinib maintenance therapy contributes to preventing post-transplant relapse in patients who remain MRD positive at the time of SCT. Conclusion Gilteritinib maintenance therapy post-SCT showed survival benefit in a clinical setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal