Adult Hematopoietic Stem Cell Transplantation Patients Research Articles

Abstract 4137644: Association of Prolonged QTc with Development of Heart Failure after Hematopoietic Stem Cell Transplantation

Background: Use of hematopoietic stem cell transplantation (HSCT) continues to rise in the United States, particularly in older age groups; however, HSCT is associated with various cardiovascular complications including heart failure (HF). We sought to examine whether prolonged QTc prior to HSCT was associated with the risk of HF post-HSCT. Methods: We used data from the Cardiovascular Registry in Bone Marrow Transplantation (CARE-BMT) study, a multicenter observational study of adult patients (aged ≥18 years) who underwent autologous/allogeneic HSCT for malignant or nonmalignant bone marrow disorders at the University of Michigan Health System (UMHS) and Rush University Medical Center (RUMC) between 2008-2019. In this analysis, only patients from the UMHS site were included (n=2,435). Baseline electrocardiogram (EKG) data were recorded prior to transplant (median (IQR) 14 (3, 30) days). QTc prolongation was defined per CTCAE grading criteria as Normal (<440ms), Grade 1 (440-480ms), and Grade ≥2 (>480ms). The primary outcome was new-onset HF defined as a diagnosis documented by health care providers after the date of hospitalization for HSCT. Analyses were conducted using a Fine-Gray model adjusted for the pre-HSCT CARE-BMT cardiovascular risk score. Results: Of the 2,435 patients (mean age at HSCT 55±13.4 years; 59.7% male; 90.5% White), 534 (21.9%) had long QTc pre-HSCT. Of those, 440 were Grade 1 and 94 were Grade ≥2. In all, 138 HF events occurred over median period of 2.3 (1.0-5.3) years. The 5-year cumulative incidence of HF was 5.0% in patients with normal QTc, 8.4% in patients with Grade 1 QTc prolongation, and 19.0% in patients with Grade ≥2 QTc prolongation (Figure). Patients with Grade 1 and Grade ≥2 prolongation had a 1.57 (95% CI: 1.05, 2.33) and 2.71 (95% CI: 1.51, 4.86) times higher risk of HF, respectively, compared to those with normal QTc. Conclusions: In this contemporary cohort of adult HSCT patients, those with QTc prolongation prior to HSCT had a higher incidence of HF compared to normal QTc, with greater degree of prolongation associated with higher risk. These findings highlight the importance of accounting for the QTc as part of the pre-transplant cardiovascular evaluation

Ototoxicity associated with hematopoietic stem cell transplantation; what are the risk factors?

Background Hematopoietic stem cell transplantation (HSCT) is a critical treatment for various hematologic malignancies but can lead to complications, including ototoxicity. Aim/objectives This study aims to explore the relationship between patient-specific factors and ototoxicity in adult HSCT patients. Material and Methods We conducted a retrospective analysis of 129 adult patients who underwent HSCT between 2003 and 2020. Age, gender, transplant indications, conditioning regimens, and pre- and post-transplant audiometry thresholds data were collected from patient files. A hearing loss of 10 decibels or more at two consecutive frequencies or a hearing loss of 20 decibels or more at a single frequency was considered as significant hearing loss (SHL). Statistical analyses were performed to describe factors associated with SHL. Results SHL occurred in 16.3% of patients. Older age was significantly associated with an increased risk of SHL (p = .035). Poorer pretransplant hearing thresholds at 4000 Hz and 6000 Hz were also significant predictors of SHL (p = .039 and p = .014, respectively). There was no significant relationship between the donor type of HSCT (autologous vs. allogeneic) and ototoxicity (p = .45), and between conditioning regimens and ototoxicity (p = .860). Conclusions Age and pre-existing hearing levels are significant predictors of ototoxicity post-HSCT. Careful management and monitoring are essential to prevent and address hearing loss in HSCT patients to improve hearing-related quality of life.

Inflammation Decreases Ciclosporin Metabolism in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Graft-versus-host disease (GVHd) remains a significant challenge following allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of GVHd relies mainly on the use of calcineurin inhibitors, notably ciclosporin that exhibits complex pharmacokinetics influenced by many factors including drug-drug interactions (DDIs). Due to the downregulation of drug metabolizing enzymes and transporters, it has been postulated that inflammation may be a contributing factor to the variability observed in ciclosporin pharmacokinetics. This study aimed to assess the impact of inflammation, as indicated by C-reactive protein (CRP) levels, on the metabolism of ciclosporin in adult allogeneic HSCT recipients. A retrospective observational study was conducted at Rennes University Hospital involving 71 adult HSCT patients. The relationship between the intensity of inflammation (no-to-mild, moderate, and severe), and the metabolism of ciclosporin (estimated by the concentration/dose ratio) was assessed. Severe inflammation significantly decreased the metabolism of ciclosporin, as evidenced by higher concentration/dose ratios. Thanks to the daily dose adjustment, inflammation did not influence the blood levels of ciclosporin. Interestingly, DDIs did not emerge as a significant covariate in influencing ciclosporin metabolism. This is likely because the CYP3A4 inhibitory potential of interacting drugs may be masked in HSCT patients where metabolism is already upstream downregulated by inflammation. The study highlights the intricate relationship between inflammation and ciclosporin pharmacokinetics in HSCT patients. This underscores the necessity for therapeutic monitoring and the potential adjustment of dosage strategies based on the inflammatory status. These insights could contribute to the development of more personalized, optimized, and effective management strategies for HSCT recipients.

Safety outcomes in patients with acute myeloid leukemia receiving gemtuzumab ozogamicin and proceeding to allogeneic hematopoietic stem cell transplantation.

6516 Background: Gemtuzumab ozogamicin (GO) is a CD33-directed antibody-drug conjugate approved by the FDA in 2017 for the treatment of newly diagnosed and relapsed/refractory (R/R) CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients of 1 month and older and 2 years and older, respectively. Previous data have associated GO with adverse events (AEs) including hepatotoxicity and hepatic veno-occlusive disease (VOD). Patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) may be at greater risk of VOD with GO. This study aimed to characterize AEs after HSCT in adult patients with AML who were treated with GO. Methods: This non-interventional post-authorization safety study used de-identified healthcare data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Data were collected from 01 September 2017. Safety outcomes post-HSCT were evaluated in adult patients with newly diagnosed or R/R AML who received GO prior to first HSCT. Data cutoff was 04 July 2023. Results: We present the interim data of 157 patients from 24 centers with a median follow-up of 12.9 months (range, 3.0-49.7). At the time of HSCT, 84 patients were in first complete remission (CR1), 48 patients were in second CR (CR2) and 25 patients were in third or greater CR, relapse or primary induction failure (CR3, n=5; Rel, n=12; PIF, n=8). Most patients (n=105; 67%) received GO as first line therapy. Median lines of therapy prior to HSCT were 2, 3.5 and 5 in CR1, CR2 and CR3/Rel/PIF groups, respectively. Median age was 52.5 y (range, 18.7-74.9); 53% male. Time from diagnosis to first GO dose was <3 months for most patients (n=120; 76%). Total cumulative GO dose was 1-3 mg/m2 in 25 (16%), 4-6 mg/m2 in 28 (18%), 7-9 mg/m2 in 45 (29%) and ≥10 mg/m2 in 14 (9%) patients. The most common HSCT donor type was unrelated (n=93; 59%), and 55% of patients received myeloablative conditioning regimens. Non-fatal VOD was reported in 7 (4%) patients. Median time from HSCT to VOD was 0.9 months (range, 0.4-2.2). No VOD-related deaths occurred. Outcome probabilities for 6-month transplant-related mortality (TRM) were 8% (95% CI, 4-13) and 5% (95% CI, 2-8) for 100-day VOD. Conclusions: The use of GO appears to be safe prior to HSCT in adults with AML. Rates for 100-day VOD and TRM were comparable to those previously reported for patients with AML who received HSCT with or without prior GO. Clinical trial information: B1767034.

Safety outcomes in adult patients with AML who achieved their first complete remission with GO prior to HSCT.

e18504 Background: Gemtuzumab ozogamicin (GO) is approved in the US for the treatment of newly diagnosed and relapsed/refractory (R/R) CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients of 1 month and older and 2 years and older, respectively. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most adult patients with AML in first complete remission (CR1). Clinical studies have linked GO with hepatotoxicity and hepatic veno-occlusive disease (VOD); the risk of these events may be further elevated in patients receiving HSCT. This study aimed to characterize the toxicity after HSCT in adult patients with AML who were treated with GO prior to HSCT. These analyses look at outcomes in patients who were in CR1 at the time of HSCT. Methods: This non-interventional post-authorization safety study used de-identified healthcare data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Data were collected from adult patients in the US with newly diagnosed AML treated with GO prior to proceeding with HSCT. Data collection began on 01 September 2017, data cutoff was 04 July 2023. Results: We present data of 84 patients receiving HSCT for AML in CR1 from 19 centers with a median follow-up of 23.9 months (range, 3.0-49.7). Median age was 54.2 y (range, 18.7-74.5); 55% male. Total cumulative GO dose was 1-3 mg/m2 in 15 (18%), 4-6 mg/m2 in 15 (18%), 7-9 mg/m2 in 28 (33%) and ≥10 mg/m2 in 8 (12%) patients. Measurable residual disease (MRD) was undetectable in 50% (n=42) of patients after GO and 51% (n=43) of patients at the time of HSCT. Most patients (58%; n=49) received myeloablative conditioning and 57% (n=48) received HLA matched unrelated donor HSCT. Non-fatal VOD was reported in 6 (7%) patients, most cases were mild (n=5; 83%). Cumulative incidences of transplant-related mortality (TRM) were: 6 months, 7% (95% CI, 3-14); 2 years, 15% (95% CI, 7-25). The 2-year relapse rate was 26% (95% CI, 16-36%). Kaplan-Meier probabilities of leukemia-free survival (LFS) outcomes at 1 and 2 years were, 68% (95% CI, 57-78) and 59% (95% CI, 47-71), respectively. There were 22 deaths during the study, 10 (46%) from relapse of AML, no VOD-related deaths were observed. Conclusions: The use of GO prior to allogeneic HSCT appears to be safe with low rates of posttransplant VOD observed in patients with AML in CR1. TRM and survival outcomes are similar to historically reported rates. Clinical trial information: B1767034.

Incidence and outcomes of subsequent malignancy after allogeneic hematopoietic stem cell transplantation in adult patients with severe aplastic anemia

The allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed for the curative treatment of severe aplastic anemia (SAA). After HSCT, the long-term survival rates of SAA patients have substantially improved, with reported over 80%. However, as the post-HSCT survival period extends, there is a risk of exposure to long-term complications associated with HSCT. One such complication is the development of subsequent malignancies (SNs), which has observed to occur 2-5 times more frequently in HSCT recipients compared to age-matched controls. Although SN can have a critical impact on the survival of patients with SAA post-HSCT, there has been a lack of large-scale, long-term observational studies on the occurrence of SNs after HSCT in a disease of SAA. In this background, we investigated the incidence of SNs after HSCT in adult patients with SAA. This study is a single-center retrospective cohort study conducted on adult patients with SAA who received HSCT from 2002 to 2021. We analyzed the frequency of SN that occurred after HSCT, and the SN types were denominated according to the Surveillance, Epidemiology, and End Results (SEER) database classification. In addition, the cumulative incidence of SNs were analyzed considering death as a competing risk, and the risk factors influencing the occurrence of SN after HSCT were examined using the Fine-Gray model. Total 376 patients were included, and their median age at the time of HSCT was 35 (interquartile range, IQR: 27-46). Of them, 52.9% had received immunosuppressive treatment (ATG+CsA or CsA) before HSCT. HLA-matched sibling, unrelated, haplo-identical donors compromised of 48.7%, 31.6%, and 19.7%, respectively. During the observation period, 30 cases (7.2%) of SN were observed. one patient diagnosed with primary malignancies three times, and another patient having two primary malignancies. Among subsequent malignancies, 33.3% were hematologic malignancies, and 66.7% were solid malignancies. The frequencies of hematologic malignancies were as follows: Post-transplant lymphoproliferative disorder (23.3%), myelodysplastic neoplasm (6.7%), and acute myeloid leukemia (3.3%). The most common solid malignancies were thyroid cancer (26.7%), followed by stomach cancer (13.3%), oral cavity & pharyngeal cancer (10.0%), esophageal cancer (6.7%), bladder cancer, skin cancer, and cervical cancer (3.3% of each). The 15-year cumulative incidence of all malignancies was 13.4% (95% confidence interval [CI]: 7.3%-23.9%) (Figure A). After SN diagnosis, the overall survival rate from the diagnosis of SN (n=27) was 72.3% (95% CI: 55.0%-95.2%) at 12 years (Figure B). The 15-year post-HSCT survival rate for SN patients from the date of HSCT was 74.6% (95% CI: 85.6%-94.9%), which was significantly lower than the survival rate of patients who did not develop SN (n=334, 92.4% [95% CI: 89.6-95.2]) (Log-rank test p = 0.03). Factors identified to have significant impact to the occurrence of SN were the use of Total body irradiation (HR 7.58 [95% CI: 1.07-53.83]) and ATG usage of more than 5mg/kg (HR 7.97 [95% CI: 1.22-52.23]) during HSCT (Table A). We observed occurrences of SN in a considerable proportion of SAA patients after HSCT. Our finding highlights that SN adversely affects survival, and the use of TBI and high dose of ATG were found to be significantly associated with SN occurrence. Therefore, SAA patients having these factors during conditioning regimen should be carefully monitored after HSCT.

Impact of self-directed exercise intervention in a minority rich, hematopoietic stem cell transplant (HSCT) inpatient population at high risk for sarcopenia and falls.

390 Background: Extended hospitalizations in the adult HSCT population increase patients’ risk for deconditioning and sarcopenia. Sarcopenia negatively impacts overall survival in adult HSCT patients (Armenian et al, 2019) and is strongly associated with falls among older adults (Yeung et al, 2019; Marques A & Queirós C., 2018; Wheatley et al, 2021). Methods: In a safety net, minority rich, academic medical center in suburban NYC, stationary pedals were placed inside patient rooms in a 31-bedded inpatient HSCT unit starting Q4 2020. Intentional, inpatient room placement prevented additional risk of infectious exposures to COVID-19 in late 2020-2021, allowed for safe access to pedals from a seated position in chairs inside patient rooms, and provided insight into self-directed exercise participation. Attending MDs, PAs and RNs encourage HSCT patients to utilize stationary pedals up to 3 times daily, while usage remains self-directed. Direct observation of patient pedal usage and patient-verbalized interest in participation reflects positive acceptance and consistent usage since implementation. Results: 2019-2023 Midas Event Reporting data was reviewed by the author. Total numbers of Weak/Impaired Gait patient falls decreased in the post-implementation period: 19 falls at baseline versus 13 falls in 2021, 11 falls in 2022, and 3 falls in Q1 2023. Pre-intervention 2019 data indicates 63.3% of falls are among Weak/Impaired Gait patients. (2020 falls data is not included due to unit closures during the COVID-19 pandemic). Post-intervention 2021-2023 data reveals a mean of 51.2% of falls are in Weak/Impaired Gait patients, indicating a 12.1% decline in falls in the post-intervention period of 2.25 years. Conclusions: Sarcopenia and inpatient falls impact patient outcomes (i.e., injuries, extended hospitalizations, and survival) and are financially burdensome. Each inpatient fall, whether injurious or not, costs hospitals approximately 35,000 (Dykes et al, 2023). Reductions in numbers of inpatient falls at this institution are potentially associated with the following hospital cost savings: 210K in 2021, 280K in 2022 and a projected 245K in 2023. Reduction in sarcopenia during extended hospitalizations, when reviewed alongside the financial impact of inpatient falls, supports the ongoing implementation of self-directed exercises in this population. Next steps include self-directed use of resistance bands, chair-based and bed-based stretches, and utilizing self-tracking devices to record exercise duration. (Full references available upon request).

COVID-19 in hematopoietic stem-cell transplant recipients: A systematic review and meta-analysis of clinical characteristics and outcomes.

Patients who undergo hematopoietic stem-cell transplantation (HSCT) are more susceptible to developing severe forms of COVID-19 with an increased risk of mortality. The aim of this study was to analyze, by performing a systematic review and meta-analysis, all studies that evaluated COVID-19 in HSCT adult recipients and present clinical characteristics and outcomes. Studies were eligible for inclusion if they: (I) described the clinical characteristics of COVID-19 in adult (aged 18years old or above) HSCT recipients; (II) described outcomes of COVID-19 in this population, mainly lethality; (III) were full-text articles. We searched MedLine, Embase, SCOPUS, LILACS and Web of Science for full-text studies that evaluated COVID-19 in adult HSCT patients until 26 Apr 2023. Two independent reviewers screened the articles and extracted the data. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Studies Reporting Prevalence Data was used to assess quality of the included studies. Meta-analysis was performed and the pooled prevalence of severe/critical disease and of death with a 95% CI was calculated with the random-effects model. Sixteen studies were included; seven (43.7%) were multicenter. Most of the studies were from Europe (37.5%). All of them had a low risk of bias using the JBI Checklist. A total of 1186 patients were included. Allogeneic HSCT patients were the majority in most studies, with a total of 861 patients (72.5%). The symptomatic rate was 79.4%. The pooled prevalence of severe/critical COVID-19 was 24.0% (95% CI 0.13-0.36; I2 =94%; n=334/990). The pooled prevalence of death for the entire population was 17% (95% CI 0.13-0.22; I2 =76%; n=221/1117), 17% (95% CI 0.12-0.23; I2 =67%; n=152/822) for allogeneic-HSCT and 14% (95% CI 0.08-0.22; I4 =65%; n=48/293) for autologous-HSCT. In conclusion, frequently the infection of SARS-CoV-2 in HSCT was symptomatic and lethality is higher than in general population. Thus, it is essential to focus on the implementation of measures to mitigate the risk of SARS-CoV-2 infection in this population, as well as to carefully assess HSCT recipients who develop COVID-19.

Adenovirus F41 infection and liver cytolysis in adult hematopoietic stem cell transplant recipients.

Human adenoviruses (HAdVs) of the F species are commonly responsible for acute gastroenteritis. A few cases of systemic infections have been described in adults or children who have received a hematopoietic stem cell transplant (HSCT), but with no report of liver cytolysis. Since January 2022, several countries have reported an increase in cases of acute hepatitis of unknown cause in children. Adenovirus species F type 41 (HAdV-F41)infection was predominantly identified. The objective of this study is to describe HAdV-F41 infections diagnosed since January 2022 in adult HSCT recipients in two French hospitals. All four patients had diarrhea and liver cytolysis at the time of diagnosis of infection. HAdV viremia was observed in three patients (#1, #3, and #4), but no disseminated disease was reported. HAdV whole genome sequencing and metagenomics characterization were performed on stool and blood samples. The complete HAdV-F41 genome sequence was obtained for three patients and phylogenetic analysis showed that the strains consisted of similar lineage (2b). We did not identify any new HAdV-F41 strains. Metagenomics analysis found adeno-associated virus 2 and torque-teno virus infection in patient #1 and Epstein-Barr virus in patient #4. This is the first case series reporting liver cytolysis during HAdV-F41 infection in adult HSCT patients.

Utility of Urine Cultures During Febrile Neutropenia Workup in Hematopoietic Stem Cell Transplantation Recipients Without Urinary Symptoms.

The utility of obtaining screening urine cultures for febrile neutropenia (FN) during hematopoietic stem cell transplant (HCT) is unknown. In 667 adult HCT patients with FN, only 40 (6%) were found with bacteriuria. Antibiotics were modified in 3 patients (0.4%) based on urine cultures and none developed urinary-associated infectious complications.

Third BNT162b2 mRNA SARS-CoV-2 Vaccine Dose Significantly Enhances Immunogenicity in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

COVID-19-related mortality among hematopoietic stem cell transplantation (HSCT) recipients in the pre-vaccine era ranged between 22 and 33%. The Pfizer/BioNTech BNT162b2 vaccine demonstrated significant immunogenicity and efficacy in the healthy population; however, its long-term effects on allogeneic HSCT recipients remained unclear. Our study longitudinally evaluated humoral and cellular responses to the BNT162b2 vaccine in adult allogeneic HSCT patients. A positive response was defined as antibody titers ≥ 150 AU/mL post-second vaccination. Among 77 included patients, 51 (66.2%) responded to vaccination. Response-associated factors were female gender, recent anti-CD20 therapy, and a longer interval between transplant and vaccination. Response rates reached 83.7% in patients vaccinated >12 months post-transplant. At 6 months post-second vaccination, antibody titers dropped, but were significantly increased with the booster dose. Moreover, 43% (6/14) of non-responders to the second vaccination acquired sufficient antibody titers after booster administration, resulting in an overall response rate of 79.5% for the entire cohort. The BNT162b2 vaccine was effective in allogeneic transplant recipients. Although antibody titers decreased with time, the third vaccination led to their significant elevation, with 93% of third-dose responders maintaining titers above 150 AU/mL at 3 months post-administration.

Abstract 13185: Incidence and Risk Factors of Acute Cardiovascular Complications After Hematopoietic Stem Cell Transplantation

Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with various cardiovascular (CV) complications. Due to the lack of recent large cohort studies, the incidence and clinical determinants of acute HSCT-related CV events are ill-defined. Methods: We conducted a multi-center observational study (University of Michigan and Rush University) of adult (≥18 years) patients who underwent autologous or allogeneic HSCT for malignant or non-malignant bone marrow disorders from 2005-2021. Data on demographics, pre-HSCT clinical characteristics, imaging, laboratory findings, and acute (<100 days post-HSCT) CV outcomes were collected through manual chart review. The primary outcome was defined as a composite of death from CV cause, non-fatal myocardial infarction, need for revascularization, new-onset heart failure (HF), new diagnosis of atrial fibrillation/flutter, or sustained ventricular tachycardia. Results: Of 4,262 included patients (mean age at HSCT 56±14 years; 59% male; 82% White), 161 (3.8%) patients experienced an acute CV event (153 events/1,000 person-years). Compared to patients without a CV event, those who developed a CV event were older, had greater burden of CV comorbidities including HF, more likely to be on antihypertensives, statins, and aspirin, and had higher B-type natriuretic peptide and lower high-density lipoprotein pre-HSCT (Table). Pre-HSCT ejection fraction and prior anthracycline exposure were not associated with acute CV events. Conclusions: In the largest cotemporary cohort of adult HSCT patients to date, acute CV events occurred in <5% of patients. Events were more common in older patients with CV comorbidities. highlighting the potential need for improving the pre-HSCT CV risk stratification. The major limitation of this study is the retrospective nature and accompanying selection bias. Future prospective studies should assess evidence-based strategies for risk-stratifying HSCT patients.

Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients

Simple SummaryImmunotherapies are promising approaches to curing different acute leukemias. Natural killer (NK) cells are lymphocytes that are efficient in the elimination of leukemic cells. NK-cell-based immunotherapies are particularly attractive, but the landscape of the heterogeneity of NK cells must be deciphered. This review provides an overview of the polymorphic KIR and HLA class I genes that modulate the NK cell repertoire and how these markers can improve the outcomes of patients with acute leukemia. A better knowledge of these genetic markers that are linked to NK cell subsets that are efficient against hematological diseases will optimize hematopoietic stem-cell donor selection and NK immunotherapy design.Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR+ NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.

Malyglycemia Is Associated with Increased Infection in Pediatric Hematopoietic Stem Cell Transplant Recipients

▪Background: Malglycemia, defined as hypoglycemia, hyperglycemia, or glycemic variability is common in adult hematopoietic stem cell transplant (HSCT) recipients. It is associated with increased rates of infection, acute graft-versus-host disease (GVHD), organ dysfunction, time to engraftment, and mortality. Malglycemia in pediatric HSCT has not been well studied and may have unique incidence, risk factors and clinical implications. Therefore, this study aimed to identify the incidence of and risk factors for malglycemia inpediatric, adolescent and young adult (AYA) HSCT patients, and to characterize associated impacts on outcomes.Methods: Medical records for 351 pediatric/AYA patients, age 0-26 years (average 8.0 years, interquartiles 3.0, 15.0; 59.3% male), who underwent first HSCT from 2007-2016 at Children's Hospital Colorado were retrospectively reviewed. Patients with pre-existing diabetes mellitus (n=5) and patients with inadequate blood glucose data (n=2) were excluded, resulting in a final cohort of 344 patients. The goal was to identify risk factors for malglycemia and to determine its association with clinically significant infection in the first 100 days after HSCT. Malglycemia was defined as presence of mean blood glucose ≥126 mg/dL and/or standard deviation ≥29 mg/dL for each patient, assessed for the following intervals: pre-HSCT (days -14 to 0), days 0-30, days 0-100, and overall (days -14 to +100).Results: Malglycemia occurred in 43.9% of patients, with 22.3% experiencing malglycemia in the two weeks prior to HSCT, 22.3% in the first 30 days post-HSCT, and 22.6% in the first 100 days post-HSCT. In univariate analysis, the rate of malglycemia was higher among patients who underwent allogeneic than autologous transplant (pre-HSCT 35.6% vs 8.4%, p<0.001; days 0-30 25.8% vs 16.1%, p=0.056; days 0-100 27.6% vs 13.6%, p=0.004). In multivariate analysis, age ≥12 years was a risk factor for pre-HSCT malglycemia (p<0.0001), and post-HSCT steroids and treatment with tacrolimus were risk factors for post-HSCT (day 0-100) malglycemia (p<0.0001, p=0.034). Additional factors that did not have an association with malglycemia in multivariate analysis included body mass index, underlying diagnosis category (malignant vs non-malignant), pre-HSCT treatment with insulin, asparaginase, steroids, or radiation, HSCT type (autologous vs allogeneic), preparative regimen, post-HSCT treatment with total parenteral nutrition or radiation. Malglycemia at any time was associated with increased infection (p=0.008-0.042). After adjusting for age, pre-HSCT radiation, HSCT type, GVHD diagnosis (grades II-IV and/or chronic) and post-HSCT steroids, for each 10 mg/dL increase in pre-HSCT glucose, there was a 29.3% increase in any post-HSCT infection (p=0.007) and specifically a 28.8% increase in serious bacterial infection (SBI) (p<0.0001) and a 29.7% increase in viremia/viruria (p=0.002); similar findings existed at other time intervals analyzed (Table 1). Additionally, after adjusting for HSCT type and presence of GVHD, for every 10 mg/dL increase in mean glucose over days 0-100, the average number of hospitalized days from 0-100 increased by 2.7 days (p<0.0001) and days in the intensive care unit (ICU) increased by 1 day (p<0.0001). Similarly, patients with malglycemia during days 0-100 averaged 12.9 more hospital days (p<0.0001) and 3.9 more ICU days (p<0.0001) in the first 100 days post-HSCT than patients without malglycemia, regardless of HSCT type or GVHD diagnosis.Conclusion : Malglycemia occurs frequently in the pediatric/AYA HSCT population and is more common in adolescent patients. When controlling for HSCT type, presence of GVHD and treatment with steroids, malglycemia is an independent risk factor leading to increased rates of serious bacterial infections and viremia/viruria. Mechanistically, the temporal relationship between pre-HSCT mean glucose increases and higher rates of infection support a causal link. The underlying pathophysiology by which malglycemia may influence outcomes such as infection is likely multifactorial, but data suggests that hyperglycemia drives immune system impairment and supports a pro-inflammatory state. Understanding the morbidities associated with malglycemia, and the underlying pathophysiology, should inform future studies evaluating the utility of intensive glucose control in improving pediatric/AYA HSCT outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Busulfan Pharmacogenetics and Drug Exposure in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction: Busulfan, a bifunctional alkylating agent widely used in conditioning regimens before hematopoietic stem cell transplantation (HSCT), is metabolized via glutathione-S-transferases (GSTs) and cytochrome P450 (CYP) enzymes. Busulfan demonstrates wide interpatient variability in pharmacokinetics (PK); high drug exposure is associated with increased risk of toxicities (e.g. veno-occlusive disease) and low drug exposure is associated with increased risk of relapse and graft failure. Drug exposure within a narrow therapeutic range yields optimal results. PK-guided dosing is used in many patients to achieve optimal drug exposure; however, better methods to select the initial dose would improve consistency of busulfan exposure and the likelihood of achieving the target area under the concentration-time curve (AUC). Previous pharmacogenomic (PGx) studies have identified GST polymorphisms as predictors of drug exposure, however, these were primarily performed in pediatric populations and/or Asians. We performed a PGx study in adult HSCT patients to identify polymorphisms in candidate genes associated with busulfan AUC and clearance.Methods: Buccal swabs were collected from HSCT patients scheduled to receive busulfan as part of their conditioning regimen on the day of admission (one day prior to initiating busulfan) between 04/28/14 and 06/06/2017. DNA was extracted using the GenElute™ Mammalian Genomic DNA Kit. A custom Ion AmpliSeq™ PGx Panel and various orthogonal methods were used to genotype the samples for polymorphisms in GSTA1 (135T>C), GSTM1 (null/present), GSTP1 (Ile105Val, Ala114Val), CYP2B6 (*2, *4, *5, *6, *18, *22), CYP2C8 (*2, *3), CYP2C9 (*2, *3, *8, *11), CYP2C19 (*2, *3, *17), and MTHFR (A1298C, C677T). Phenotypes were inferred according to established guidelines or literature. IV busulfan was administered once daily over 3 hours at 2.8 mg/kg (for autos) or 3.2 mg/kg (for allos) for a total of 4 doses. PK samples were obtained at 15 mins, 1 hr, 2 hrs, 3 hrs, and 5 hrs after the end of the first infusion. Non-compartmental analysis was performed to estimate PK parameters and doses 3 and 4 were adjusted to target an AUC of either 4500 or 5000 uM*min/L, depending on transplant type and conditioning regimen. The primary objective was to investigate the impact of polymorphisms on busulfan AUC, which was measured using univariate linear regression analysis adjusting for dose. Secondary objectives included a comparison of mean AUCs between phenotypes, which was measured using ANOVA, and to determine the association between SNPs and busulfan clearance using univariate linear regression adjusting for dose.Results: A total of 36 patients were evaluable for the primary endpoint. The median age was 47 (22-73) years, 56% were male, 75% received busulfan/cyclophosphamide/etoposide, 22% received busulfan/cyclophosphamide with post-transplant cyclophosphamide, and 3% received thiotepa/busulfan/cyclophosphamide. The genotype and inferred phenotype frequencies are summarized in Table 1. The mean AUC across all patients was 4255 µM*min/L (range 2834-5989). Results from the univariate linear regression analysis identified that CYP2B6 polymorphisms were significantly associated with busulfan AUC (intermediate [IM] vs. poor metabolizer [PM], p = 0.05; normal/rapid metabolizer [NM/RM] vs. PM, p = 0.02) (Table 2). The mean AUC in CYP2B6 PMs, IMs, NM/RMs was 5242, 4277, and 4134 µM*min/L, respectively (p = 0.03 by ANOVA test). There was no association of polymorphisms in GSTA1, GSTM1, GSTP1, CYP2C8, CYP2C9, CYP2C19 and MTHFR with AUC. CYP2B6 polymorphisms were also associated with busulfan clearance (IM vs. PM, p = 0.07; NM/RM vs. PM, p = 0.03).Conclusion: CYP2B6 polymorphisms were significantly associated with busulfan AUC and clearance; these appear to be an important determinant of drug exposure, however, GST polymorphisms did not replicate as significant, possibly due to differences in patient populations. PGx testing for CYP2B6 may provide an important tool to individualize up front dosing and improve the likelihood of achieving the target AUC earlier or to achieve target AUC in a higher proportion of the many patients who do not receive PK-guided dosing; however, our findings require further validation in larger cohorts of patients. We plan to enroll more patients and assess the relationship between PK, PGx and clinical outcomes, including toxicity and response. [Display omitted] DisclosuresTrivedi:Pharmacyclics: Consultancy, Honoraria. Grunwald:Pfizer: Consultancy; Alexion: Consultancy; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; ARIAD: Consultancy; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Janssen: Research Funding. Ghosh:AbbVie: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jassen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding.

Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients.

e19027 Background: Clostridiodes difficile infection (CDI) is reported to occur up to 9-fold higher in allogenic hematopoietic stem cell transplant (HSCT) recipients compared to the general population of hospitalized patients. This is attributed to disruption of gut microbiome by antibiotics, myeloablative regimens, neutropenia, prolonged hospitalization, and immunosuppressive regimens administered to prevent acute graft-versus-host disease (aGVHD). CDI by disruption of the intestinal microbiome may trigger gastrointestinal aGVHD. Previous studies from HSCT centers have reported conflicting data on the relationship between CDI and subsequent development of aGVHD. Methods: The Nationwide Readmissions Database was queried for admissions of adult allogenic HSCT patients between 2016 and 2018. Those with and without CDI during index admission were compared. Multivariable logistic regression was used to evaluate the primary outcome of risk of aGVHD in the index admission or within 100 days post-engraftment. Results: A total of 13518 allogenic HSCT patients were included in the study. Mean age was 52.4 years. 57.2% of patients were female. The most common underlying diagnoses were acute myeloid leukemia (38%), myelodysplastic syndrome (17%) and acute lymphoblastic leukemia (14%). 11.1% of the index admissions were complicated by CDI. Rates of aGVHD during the index admission or 100 days post-engraftment were similar between CDI and non-CDI groups: 13.8% vs. 12.1%, p=0.19 during index admission and 29.2% vs. 26.1%, p=0.09 during 100 days post-engraftment. Nonetheless, patients with CDI had longer length of hospital stay (34.6 vs 29.8 days, p&lt;0.0001), higher hospitalization costs ($608K vs $506K USD) and greater rate of inpatient mortality (7.3% vs 4.6%, p&lt;0.001). In the multivariate regression analysis, CDI during index admission was not associated with risk of development of aGVHD (Adjusted Odds Ratio 1.14, 95% Confidence Interval 0.87-1.48, p=0.34). Age and unrelated donor HSCT were predictive of risk of aGVHD. Conclusions: CDI during index admission was not predictive of aGVHD during the first 100 days post-allogenic HSCT. HSCT patients are frequency colonized with C.difficile. Diarrhea secondary to CDI may resemble gastrointestinal aGVHD. Therefore, overdiagnosis of CDI in this population is a concern. Antimicrobial stewardship and use of clinical decision support tools have been advocated recently to decrease testing of HSCT patients with C.difficile colonization. Multivariable analysis of risk factors of aGVHD.[Table: see text]

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Using a machine learning algorithm to predict acute graft-versus-host disease following allogeneic transplantation

AbstractAcute graft-versus-host disease (aGVHD) is 1 of the critical complications that often occurs following allogeneic hematopoietic stem cell transplantation (HSCT). Thus far, various types of prediction scores have been created using statistical calculations. The primary objective of this study was to establish and validate the machine learning–dependent index for predicting aGVHD. This was a retrospective cohort study that involved analyzing databases of adult HSCT patients in Japan. The alternating decision tree (ADTree) machine learning algorithm was applied to develop models using the training cohort (70%). The ADTree algorithm was confirmed using the hazard model on data from the validation cohort (30%). Data from 26 695 HSCT patients transplanted from allogeneic donors between 1992 and 2016 were included in this study. The cumulative incidence of aGVHD was 42.8%. Of >40 variables considered, 15 were adapted into a model for aGVHD prediction. The model was tested in the validation cohort, and the incidence of aGVHD was clearly stratified according to the categorized ADTree scores; the cumulative incidence of aGVHD was 29.0% for low risk and 58.7% for high risk (hazard ratio, 2.57). Predicting scores for aGVHD also demonstrated the link between the risk of development aGVHD and overall survival after HSCT. The machine learning algorithms produced clinically reasonable and robust risk stratification scores. The relatively high reproducibility and low impacts from the interactions among the variables indicate that the ADTree algorithm, along with the other data-mining approaches, may provide tools for establishing risk score.

Vitamin D Deficiency and Oral Mucositis in Hematopoietic Stem Cell Transplantation: A Cross-Sectional Observation

Backgrounds: One of the most frequent complications of high-dose chemotherapy regimen before hematopoietic stem cell transplantation (HSCT) is oral mucositis (OM). Vitamin D (VD) has well-known immunoregulatory, anti-inflammatory, and antioxidant properties.This study aimed to evaluate the association of pre-HSCT VD levels with OM as well as neutrophil and platelet engraftments in patients with multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma after autologous HSCT. Methods: A sample of 71 patients was enrolled after obtaining informed consent. Serum samples were collected in the morning prior to the administration of conditioning regimen to measure the 25-OH-D. OM was examined daily during hospital stay. The World Health Organization (WHO) scale was used for scoring the OM. Absolute neutrophil count and platelet count were determined daily from transplantation until engraftment. Results: Patients aged 18-65 years. Mean length of hospital stay was 15.8±5.7 days. OM was detected in 44/71 (62.0%) of patients. Mean time to the engraftment of neutrophils and platelets were 11.8±4.0 and 17.2±7.3 days, respectively. Mean level of 25-OH-D was 17.5±14.0 ng/ml. VD deficiency (&lt;20 ng/ml) was diagnosed in 51/71 (71.8%) of patients. No association between the 25-OH-D levels and incidence of OM (P=0.69) or OM grade 3-4 (P=0.46) was found. No significant correlations were detected between the 25-OH-D and engraftment time of neutrophils (P=0.46) or platelets (P=0.17). Conclusions: The prevalence of VD deficiency was high among adult HSCT patients at the time of transplantation. No association was found between the pre-HSCT VD level and OM or engraftment time.

2694. Incidence of Pneumocytis jiroveci (PJP) Infection with 3-Month Prophylaxis of Aerosolized Pentamidine (AP) in Autologous Hematopoietic Stem Cell Transplantation (HSCT)

BackgroundHSCT patients are at an increased risk of developing PJP after transplant due to treatment induced immunosuppression. Given the risk of cytopenias with co-trimoxazole, AP is utilized as an alternative for PJP prophylaxis. A prior study revealed a 0% (0/19 patients) incidence when AP prophylaxis was given for one year post autologous HSCT. Current guidelines recommend a duration of 3 – 6 months for PJP prophylaxis in autologous HSCT. The primary endpoint of this study was to assess the incidence of PJP infection within one year post autologous HSCT in patients who received 3 months of AP. Secondary endpoint was a cost comparison of 3 months compared with 6 months of AP.MethodsA single-center, retrospective study of adult autologous HSCT patients at Yale New Haven Hospital between February 2013 and December 2017 was performed. Patients were excluded if: <18 years of age, received < or >3 months of AP, changed to alternative PJP prophylactic agent or received no PJP prophylaxis, received tandem HSCT, deceased prior to one year post-transplant from a non PJP-related infection, HIV positive, or lost to follow-up. Pentamidine was given as a 300 mg inhalation monthly for 3 months starting Day +15 after autologous HSCT.ResultsA total of 288 patients were analyzed, no PJP infections occurred within one year post HSCT. Additionally, 187 (65%) patients received treatment post HSCT with 135/215 (63%) receiving maintenance immunomodulatory drugs for myeloma and 40/288 (14%) patients developing relapsed disease. 43% of the chemotherapy regimens for relapsed disease included high dose corticosteroids. The cost difference of using 3 months vs. 6 months of AP is $790, reflecting the cost of drug and its administration. Applying our incidence of 0%, potential cost savings of 3 months vs. 6 months of AP would be $330,000 over 5 years or $66,000 per year.ConclusionThree months of AP for PJP prophylaxis in autologous HSCT patients is safe and effective as well as cost-effective compared with a 6 month regimen.Disclosures All authors: No reported disclosures.