Adult Hematopoietic Cell Transplantation Research Articles

1591. The Impact of Pretransplant Respiratory Virus Infection in Pediatric Hematopoietic Cell Transplant Recipients

Abstract Background Respiratory virus infections (RVIs) in adult hematopoietic cell transplant (HCT) candidates have been shown to impact posttransplant outcomes; however, there are few studies in pediatric patients. We sought to evaluate the role of specific viruses and the location of viral infection on post HCT outcomes. Methods We evaluated allogeneic pediatric HCT recipients receiving myeloablative conditioning from 3/2010–3/2018. All patients had a multiplex PCR for RVIs prior to HCT, regardless of symptoms. Delaying HCT was recommended when feasible for RSV, parainfluenza, metapneumovirus, adenovirus, and influenza, but not routinely for human rhinovirus (HRV) and endemic coronaviruses. We utilized Cox proportional hazards models to evaluate progression to lower respiratory disease (LRD) post HCT and linear regression models to evaluated days alive and out of hospital (DAOH) by 100 days post HCT. Results Of 310 allogeneic HCT recipients receiving myeloablative conditioning, 133 (43%) were positive for a RVI before HCT. Baseline characteristics were notable for differences for age, recipient CMV serostatus, and delayed HCT (Table 1). The most common RVI was HRV (97, 73%) and 81 (61%) patients were symptomatic at the time of detection. Most patients had a URI (92%) and 11 patients had LRD (3 proven, 8 possible). In univariate analysis, HRV as virus type was associated with fewer DAOH and preHCT URI as location of viral infection (with and without symptoms) trended towards fewer DAOH (Figure 1a). When adjusted for age, preHCT lymphocyte count, cell source, and conditioning regimen, both HRV and preHCT URI showed a trend towards fewer DAOH, but no significant association was found (Figure 1b,c). Twenty patients progressed to LRD after HCT with the same preHCT RVI; no factors, including delay of transplant, were associated with reduced progression to LRD. (A) Univariable linear regression for DAOH, (B) Multivariable linear regression for DAOH by viral type, (C) Multivariable linear regression for DAOH by viral location and symptom composite. Conclusion In this single center study, HRV as virus type and URI as location of viral infection before myeloablative allogeneic HCT were associated with increased hospitalization after HCT, but not in multivariate models. Larger multicenter studies are needed to provide timely evaluation and adequate statistical power to definitively determine role of URI versus LRD and the impact of transplant delay and treatment strategies. Disclosures Yae-Jean Kim, MD, PhD, Janssen: Grant/Research Support|Korean Society of Pediatric Infectious Diseases: Grant/Research Support|Ministry of Trade, Industry and Energy: Grant/Research Support|MSD: Grant/Research Support chikara Ogimi, MD, Horiba: payment for a lecture Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support Janet A. Englund, MD, Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccine: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support|SanofiPasteur: Advisor/Consultant Alpana Waghmare, MD, Allovir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Devarra Therapeutics: DSMB|Kyorin Pharmaceutical: Advisor/Consultant|Pfizer: Grant/Research Support|Vir/GSK: Grant/Research Support.

Health-Related Quality of Life Outcomes in Older Hematopoietic Cell Transplantation Survivors

The use of hematopoietic cell transplantation (HCT) has been increasing in older patients. However, the levels if distress, psychosocial functioning, and health-related quality of life (HRQOL) among older HCT survivors remains largely unknown. In this secondary analysis using data from 2 randomized controlled trials, we analyzed baseline Cancer and Treatment Distress (CTXD) and Confidence In Survivorship Information (CSI) surveys of HCT survivors who were age ≥60 years at the time of transplantation and alive and disease-free ≥1 year post-autologous or -allogeneic HCT. We analyzed associations of these parameters with the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the 12-Item Short Form Survey (SF-12) and a healthcare adherence (HCA) scale, after adjusting for transplantation and patient demographic factors. A total of 567 patients were included. The median patient age at HCT was 65 years, and 68% of the patients underwent autologous HCT. The median CTXD score was .7 (mild), and the greatest distress was reported in the "health burden" subscale. The median CSI score was 1.4 (moderate-high), with the lowest confidence reported in the "late effects" subscale. We found negative Spearman correlations between CTXD score and SF-12 PCS (P=-.59) and MCS (P=-.54) and positive Spearman correlations between CSI score and SF-12 PCS (P=.23) and MCS (P=.30). The median HCA scale score was high at .8. Male sex, autologous HCT, increased distress level, and worse CSI score were associated with lower use of preventive care. Older survivors experienced a low level of distress and moderate-high level of CSI at ≥1 year post-HCT. As lower distress and higher CSI were associated with improved HRQOL and optimized preventive HCA, CTXD/CSI measures can be used to individualize the care of older adult HCT survivors.

Efficacy and Safety of a Novel Non-Myeloablative Conditioning Regimen for Hematopoietic Cell Transplantation in Adults with Severe Aplastic Anemia

Introduction The distinct "age effect" that exists in severe aplastic anemia (SAA) following hematopoietic cell transplantation (HCT) favors the use of reduced intensity conditioning regimens in patients >40 years. For older adults, overall survival and disease-free survival (DFS) is reduced with increasing age and unrelated donor transplant are associated with higher rates of graft failure, Epstein-Barr virus (EBV) reactivation, and post-transplant lymphoproliferative disorders (PTLD) (Rice C, et al. BBMT 2019.). To overcome this, a novel, non-myeloablative conditioning regimen called FCR, which consists of fludarabine, cyclophosphamide, and rituximab, was designed at Vanderbilt University Medical Center (VUMC) and the associated VA Tennessee Valley Healthcare System (TVHS) for use in all SAA patients. This regimen was subsequently evaluated in the first 11 SAA patients treated at VUMC/TVHS and found to result in lower toxicity, graft-versus-host disease (GVHD), and viral reactivation with no graft failure or relapse compared to historical controls (Gatwood KS, et al. BMT 2018.). Given these initial favorable results, FCR has now been expanded as the preferred conditioning regimen for all SAA patients undergoing HCT at our center, warranting follow-up evaluation in a larger cohort. Methods Utilizing institutional registries, all SAA patients were identified who underwent first allogeneic HCT using an FCR regimen (Figure 1) between January 2016 and May 2022. VUMC and TVHS Institutional Review Boards approved this retrospective analysis. Outcomes analyzed included time to engraftment, incidence of graft failure, incidence of acute GVHD (aGVHD) and chronic GVHD (cGVHD), rate of viral reactivation, post-HCT disease status, and number of inpatient hospital days through day +100. An analysis of 1-year GVHD-free, relapse-free survival (GRFS) was conducted in evaluable patients, with differences between the curves determined using log-rank tests. Results Twenty-four SAA patients underwent HCT from January 26, 2016 to May 11, 2022, the majority of which were male with a median age of 43.5 years (range: 22-62). All patients received at least one line of therapy prior to HCT with the most common treatment being the combination of cyclosporin A with anti-thymocyte globulin with or without eltrombopag and/or corticosteroid. Median time from diagnosis to transplantation was 434.5 days (range: 84-6408). Patients received transplants from matched related (n=8), haploidentical (n=2), and matched unrelated donors (n=14) using either a peripheral blood (PB) or bone marrow (BM) stem cell source (PB=15, BM=9). Median time to neutrophil and platelet engraftment was 14 days (range: 10-25) and 18 days (range: 10-38), respectively. No patients experienced graft failure. At median follow-up of 806.5 days (range: 72-2180) post-transplant, all patients were alive and in remission. No patients developed grade III-IV aGVHD and no differences in grade I-II aGVHD rates were noted based on stem cell source. By date of last follow-up, mild to moderate cGVHD graded per 2014 NIH criteria developed in 7 and 3 patients, respectively. There were no cases of severe cGVHD. Only 2 patients experienced a viral reactivation (cytomegalovirus [CMV]=1, EBV=1) by date of last follow-up. The case of EBV reactivation did not require treatment and did not progress to PTLD. The median number of inpatient hospital days required post-engraftment through the first 100 days post-transplant was 5 days (range: 0-21). The unadjusted Kaplan-Meier estimate of 1-year GRFS was 86.3% (95% CI: 72.8%-100%) (Figure 2), with moderate cGVHD accounting for all GFRS events in the study cohort. Conclusions The use of our novel non-myeloablative conditioning regimen in SAA is well tolerated with 0% non-relapse mortality and 100% DFS with low GVHD rates at 1-year post-transplant. Despite a high-risk population with median age >40 years, using primarily matched unrelated donors, and majority peripheral blood stem cell source, there were no deaths and rates of complications remained low. This study further supports the findings of our previous study, redemonstrating low rates of toxicity, severe GVHD and viral reactivation with no graft failure, relapse, or mortality. The use of these regimens needs to be validated in a larger cohort as they have the potential to provide a new standard of care for pre-HCT conditioning in SAA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ATG-Ptcy-CSA for Gvhd Prevention in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation for Adults with Hematological Malignancies

INTRODUCTION The introduction of post-transplant cyclophosphamide (PTCY) for GVHD prevention can be considered a milestone in haploidentical hematopoietic cell transplantation (haplo-HCT). And secondary to its efficacy, the use of haplo-HCT with peripheral blood stem cell (PBSC) grafts has significantly increased in last decade. However the optimal immunosuppressive agents to combine with PTCY using peripheral blood stem cell (PBSC) sources is still a matter of debate, as in a retrospective analysis conducted by CIBMTR using PBSC grafts and PTCY-based GVHD prophylaxis in the haplo-HCT setting, was associated with higher rates of acute and chronic GVHD than with using bone marrow stem cell grafts. PTCY-based prophylaxis is considered a standard of care when haploidentical donors are selected. PTCY combined with anti-thymocyte globulin and cyclosporine (PTCY-ATG-CsA) became our institutional GVHD prophylaxis for peripheral blood (PB) haplo-HCT in 2015. The present analysis aims to share updated information about our experience using ATG-PTCY-CsA for GVHD prevention in PB haplo-HCT. METHODS Between October 2015 to December 2021, 157 consecutive adults underwent haplo-HCT at our institution and were included in the study. The GVHD prophylaxis was composed of rabbit-ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France), PTCy (50 mg/kg/day on days +3 to +4), and CsA (started on day +5 and titrated to therapeutic levels ranging between 200 and 400 ng/ml). One hundred twenty (76.4%) adults received a total dose of 4.5mg/kg of ATG (0.5 mg/kg on day -3, 2 mg/kg on day -2 and 2 mg/kg on day-1), and 37 (23.5%) received 2 mg/kg (0.5 mg/kg on day -2 and 1.5 mg/kg on day -1). T-cell replete PBSC grafts were infused on day 0 in all cases. Data was collected retrospectively and updated in March 2022. To perform regression analyses, post-transplant follow-up was censored at 2 years. RESULTS Of the 157 patients, the median age was 57 years (range: 43-66), and 67 (44%) were 60 years or older. Sixty-four (44%) patients were females. Acute myeloid leukemia was the most prevalent baseline diagnosis (n=79, 50.3%), and 38 (24.2%) patients received myeloablative conditioning (MAC) regimens. Forty-six (30%) adults had a KPS ≤80%, 46 (30%) had an HCT-CI score >3, and 34 (23.4%) had a high or very-high disease risk index (DRI). Fresh products were infused in 90 (57.32%) cases. A total of 152 patients achieved engraftment. The median time for neutrophil and platelet engraftment were 17 (IQR 19-15) and 22 days (IQR: 12-28). The cumulative incidence function (CIF) of bloodstream infection at day +28 was 51.6%. The day +180 CIF of CMV and EBV reactivations were 62.5% and 65.4%, respectively, and 5 (3.2%) patients had post-transplant lymphoproliferative disorder. The CIFs of grade II-IV and grade III-IV acute GVHD estimated at day +100 were 26.3% and 9.5%, and the CIF of moderate/severe cGVHD at 1 year was 19.9%. As reported in Table 1, the use of MAC regimens (HR 2.70), the administration of 2 mg/kg of ATG (HR 4.42, P=0.003) and the selection of donors older than 40 years (HR 3.35, P=0.011) increased the risk for grade III-IV aGVHD. The infusion of frozen products was not found to be predictor for GVHD. Nevertheless, a non-significant trend to lower grade II-IV aGVHD was documented in patients receiving frozen PBSC grafts (HR 0.54, P=0.060). The median follow-up in survivors was 32 months. Overall, 73 (46.5%) patients died, and 28 (17.3%) relapsed. The leading causes of death were infection and relapse. The median of days to discontinuation of the immunosuppression in survivors was 83 days (IQR: 69-119). As shown in Figure 1, the estimated 2-year OS, RFS, NRM, CIR, and GRFS were respectively: 49.4%, 44.6%, 36.6%, 18.8%, and 35.7%. The multivariate regression analysis reported n Table 1 showed that older patients and those with high and very-high DRI were at higher risk for worse OS and higher NRM. CONCLUSION Dual T-cell depletion using PTCy and ATG (total dose of 4.5mg/kg) combined with CsA is a safe drug combination for PB haplo-HCT. The use of this prophylaxis provided an effective GVHD prevention with acceptable relapse rates. Moreover, the selection of younger donors, and the use of a total dose of 4.5mg/kg of ATG increased the effectiveness of GVHD prevention. Further research is needed to decrease rates of NRM for patients undergoing haplo-HCT using this prophylaxis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association between Patient-Reported Social Determinant of Health Outcomes and a Social Genomics Profile in Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Introduction Patient-reported outcomes (PROs) capture the subjective experience of a patient's social and environmental context, providing a firsthand account of this and other social determinants of health (SDOH). An individual's socioenvironmental context is linked to a wide array of health outcomes, including for patients undergoing hematopoietic cell transplantation (HCT) [1, 2]. Social genomics, the study of socioenvironmental effects on human gene expression, offers a framework for understanding these complex biobehavioral relationships [3]. The conserved transcriptional response to adversity (CTRA) is a genomic biomarker characterized by increased expression of pro-inflammatory genes and decreased innate anti-viral gene expression [4]. The CTRA profile has been associated with psychosocial adversity and is predictive of clinical outcomes in HCT, and thus may be a means to map the biologic sequelae of social hardship [2, 4]. The objective of this study was to examine the association of pre-transplant CTRA profile with psychosocial PROs in allogeneic HCT recipients. Methods A cross-sectional analysis of data from a subset of participants enrolled on a prior CIBMTR study testing the feasibility of centralized collection of PROs in allogeneic HCT [5] was completed. For the present analysis, eligible patients from this larger cohort were those aged >18 years with baseline (pre-HCT) PRO measures and available pre-transplant banked biospecimens. PROs included the 36-Item Short Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). Descriptive analyses of patient-, disease-, and transplant-related characteristics were prepared. CTRA was derived from banked whole blood specimens using RNA sequencing. Transcript-per-million values of the 47 indicator genes were log2 transformed and analyzed using mixed effects linear regression models testing relative average gene expression levels to standardized PRO score controlling for age, sex, race, malignant versus non-malignant disease, and performance status. Results A total of n=140 patients representing 8 transplant centers in the United States were included. Patient characteristics are depicted in Table 1. The median age was 55 years (range 18-75y), 44% were female, and 90% identified as White. A majority (96%) of patients had a hematologic malignancy diagnosis, with acute myelogenous leukemia (AML) being most common (35%). There were statistically significant associations between lower CTRA gene expression and higher FACT-BMT total scores (β-coefficient -0.041 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.003) social well-being (β-coefficient -0.058 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.0001), physical well-being, (β-coefficient -0.031 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.031) and FACT-G scores (β-coefficient -0.042 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.003) as depicted in Figure 1. This corresponds to a 10.7%, 14.8%, 8.2%, and 11.1% difference, respectively, in CTRA gene expression per 4-SD range of variation in each PRO. Conclusions Patient reports of socioenvironmental experience were associated with the CTRA immunoregulatory pattern in adult allogeneic HCT recipients, with social well-being emerging as the most significant domain. This finding is consistent with prior literature and supports the importance of social well-being and community context in the setting of allogeneic HCT. Heightened CTRA expression could provide a potential molecular mechanism for social gradients in HCT outcomes, although this was not experimentally tested in this study. Further research and intervention that targets this pathway could support optimal multidimensional outcomes in this high-risk population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Self-Reported Experiences of Adult Hematopoietic Cell Transplantation Survivors with COVID-19 Vaccination and Infection

BACKGROUND Hematopoietic cell transplantation (HCT) survivors are at an increased risk of COVID-19 infection and complications. There are scant data for HCT recipients regarding compliance and experiences with COVID-19 vaccination or uptake of other prevention strategies. COVID infection rate data by vaccination status are also lacking in this population. We surveyed a long-term HCT survivor population to characterize the use of COVID-19 vaccination, other precautionary measures, and COVID-19 outcomes. METHODS As part of Fred Hutchinson Cancer Center's follow up of HCT recipients, we administer an annual survey regarding health status, HCT follow up, and chronic GVHD (cGVHD) status including immunosuppressive treatment. We analyzed surveys sent to adults between 7/1/21 and 5/31/22 that included additional questions about COVID-19 infection, prevention measures, and vaccinations. Comparisons by response and vaccination status were performed using the Chi-square test and Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous variables. RESULTS Of 4758 survivors who underwent HCT from 1971-2020 and consented to receive annual surveys, 1939 (42%) answered the survey and 1572 (33%) answered the COVID-19 questions. Among 1559 respondents who reported their vaccination status, 1456 (93%) received ≥1 dose of COVID vaccine, the majority of whom (1358/1456, 93%) received only mRNA vaccine. Of 1442 patients who received ≥1 dose of vaccine and who provided vaccination information, 1363 (95%) received 2 doses, 808 (56%) received 3 doses, and 115 (8%) received 4 doses. In univariate analysis, older age (p < 0.001), work status (p = 0.005), and current cancer (p = 0.01) were significantly associated with being vaccinated (Table 1). 1254/1344 (93%) non-Hispanic White patients, 107/108 (99%) non-Hispanic/non-White patients, and 31/37 (84%) of Hispanic/Latino patients reported receipt of ≥1 dose of vaccine. Presence of cGVHD, chronic medical conditions, autologous vs. allogeneic transplant, sex, and time since transplant were not associated with vaccination status. Severe adverse effects after vaccination were reported by 66 (4%) respondents (Figure 1). Among 108 vaccinated patients with cGVHD, 96 (89%) did not report any changes in their cGVHD symptoms after vaccination; 12 (11%) reported worsening symptoms. The most common reasons for declining vaccination in unvaccinated patients (n = 103) were the rapidity of vaccine development (70%), side effects (70%), and lack of testing in HCT recipients (53%) as the most common reasons for declining vaccination. Among survey respondents, 212/1564 (14%) reported having a COVID infection, with 55% (114/206) reporting moderate or severe symptoms and 10% (21/204) requiring hospitalization; 10% (20/204) reported "long-COVID." Of 142 vaccinated patients who developed a COVID infection and whose vaccination and infection dates were available, 56% (n = 79) received their first doses of COVID vaccine after COVID infection. Vaccinated patients (5% vs. 68%, p < 0.001) and their household members (10% vs. 45%, p < 0.001) were significantly less likely to have contracted COVID. Higher number of vaccination doses was significantly associated with reduced risk of COVID infection (p < 0.001) but not disease severity. Among the patients who had COVID, there were no significant differences in disease severity, duration, or hospitalization between those who were and were not vaccinated prior to COVID infection. Vaccinated patients took significantly more precautions against COVID than unvaccinated patients (n = 103) both during (7/1/21-2/28/22: median of 5 vs. 2, p < 0.001) and after (3/1/22-5/31/22: median of 4 vs. 1, p < 0.001) the CDC mask mandate was in effect. Vaccination of household contacts was more frequently reported by vaccinated than unvaccinated patients (82% vs. 45%, p < 0.001). CONCLUSION The majority of survey respondents received ≥1 dose of COVID vaccine, and most reported minimal to no adverse effects. The majority of patients with cGVHD did not experience any worsening symptoms. COVID infection was reported by 14% of respondents and was more common in unvaccinated recipient households than vaccinated households. Vaccinated patients reported greater use of precautionary measures, including household vaccination. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cytomegalovirus Therapy: Role of Letermovir in Prophylaxis and Treatment in Transplant Recipients.

Cytomegalovirus (CMV) is a common viral pathogen in the transplant population and is associated with significant morbidity and mortality. CMV prevention is paramount; however, selecting the best preventive strategy depends on many factors including donor-recipient CMV serostatus, transplant-specific risks, antiviral toxicities and cost. Novel CMV therapeutics such as letermovir (LTV) are desperately needed to optimize CMV management. Uniquely among CMV antiviral therapies, LTV inhibits the viral terminase complex in the CMV DNA synthesis pathway and disrupts viral genome packaging. Further, it lacks side effects frequently associated with other CMV antiviral therapies and evades common mechanisms of resistance. LTV is approved by the US Food and Drug Administration for CMV prevention in adult CMV-seropositive hematopoietic cell transplant recipients but is increasingly applied off-label for prophylaxis and treatment. This review summarizes important concepts of CMV management in transplantation, with a specific focus on LTV pharmacology and clinical experience to date alongside future prospects for its application.

Prevalence and Determinants of Return to Work as a Patient-Centered Outcome in Survivors of Hematopoietic Cell Transplantation.

Employment is an important indicator of health and functional recovery for hematopoietic cell transplantation (HCT) survivors and has significant social and economic impacts. Cancer survivors treated with conventional non-HCT therapy are known to be at a higher risk of unemployment or not returning to work after completion of therapy compared with the control population. However, the literature on return-to-work challenges among HCT survivors remains limited. Here we summarize the evidence on prevalence and determinants of return-to-work challenges among HCT survivors using previously published literature. Findings from previously published research show that return to work or unemployment is a major concern among HCT survivors, especially for allogeneic HCT recipients, and prior studies have identified several modifiable risk factors associated with it. Survivors' post-HCT employment status is significantly associated with quality of life, impacting physical, emotional, social, and financial aspects of their lives. We also highlight the gaps in current knowledge such as limited information on employment outcomes of childhood, adolescent, and young adult HCT survivors; work-related challenges among employed HCT survivors; consequences of work-related challenges; and interventions to improve return to work among HCT survivors. Findings highlighted in this review make a strong case of a multidisciplinary return-to-work support for HCT survivors to properly address their needs.

Comparison of Dose Adjustment Strategies for Obesity in High-dose Cyclophosphamide Among Adult Hematopoietic Cell Transplantation Recipients: Pharmacokinetic Analysis

Cyclophosphamide (CY) is an alkylating agent widely used in the field of oncology and hematopoietic cell transplantation (HCT). It is recommended to use an adjusted body weight with an adjustment factor of 0.25 (ABW25) for dosing of CY in obese patients undergoing HCT. However, evidence based on the pharmacokinetics (PK) of CY to support this recommendation is lacking. We aimed to identify a dosing strategy of CY that achieves equivalent exposures among obese and nonobese patients. The present study is a secondary analysis of a previously conducted observational PK study of phosphoramide mustard (PM), the final cytotoxic metabolite of CY. Data were collected from 85 adults with hematologic malignancy who received a single infusion of CY 50 mg/kg, fludarabine, ± anti-thymocyte globulin, and a single fraction of total body irradiation as HCT conditioning therapy. A previously developed population PK model in these patients was used for simulations. Using individualized PK parameters from that analysis, simulations were performed to assess cumulative exposures of PM (i.e., area-under-the-curve [AUC]) resulting from 8 different dosing strategies according to various measures of body size: (1) “mg/kg” by total body weight (TBW); (2) “mg/kg” by ideal body weight (IBW); (3) “mg/kg” by fat free mass; (4) “mg/m2” by body surface area (BSA); (5) “mg/kg” by TBW combined with ABW25 (TBW-ABW25); (6) “mg/kg” by IBW combined with ABW25 (IBW-ABW25); (7) “mg/kg” by TBW combined with ABW by adjustment factor of 0.50 (TBW-ABW50); and (8) “mg” by fixed-dose. We defined equivalent exposure as the effect of obesity on PM AUC within ±20% from the PM AUC in the nonobese group, where obesity is defined based on TBW/IBW ratio (i.e., nonobese, <1.2; mildly obese, 1.2-1.5; and moderately/severely obese, >1.5). Primary and secondary outcomes were PM AUC0-8hours and PM AUC0-infinity, respectively. In the 85 patients, with the median age of 63 years (range 21-75), 46% were classified as mildly and 25% were moderately/severely obese based on the TBW/IBW ratio. Negative correlations (i.e., higher the extent of obesity, lower the PM AUC) were shown when dosing simulations were based on IBW, TBW-ABW25, and fixed dosing (P < .05). Positive correlations were shown when dosing was simulated by TBW (P < .05). None of the 8 dosing strategies attained equivalent PM AUC0-8hours between patients with versus without obesity, whereas dosing by BSA and TBW-ABW50 attained equivalent PM AUC0-infinity (P < .05). Our study predicted that the recommended ABW25 dose adjustment may result in lower exposure of CY therapy in obese patients than in nonobese. A CY dosing strategy that would result in similar PM concentrations between obese and nonobese was not identified for early exposure (i.e., PM AUC0-8hours). The data suggest though that CY dosing based on “mg/m2” by BSA or “mg/kg” by TBW-ABW50 would result in similar total exposure (i.e., PM AUC0-infinity) and may minimize exposure differences in obese and nonobese patients.

Experimental and clinical progress of in utero hematopoietic cell transplantation therapy for congenital disorders.

In utero hematopoietic cell transplantation (IUHCT) is considered a potentially efficient therapeutic approach with relatively few side effects, compared to adult hematopoietic cell transplantation, for various hematological genetic disorders. The principle of IUHCT has been extensively studied in rodent models and in some large animals with close evolutionary similarities to human beings. However, IUHCT has only been used to rebuild human T cell immunity in certain patients with inherent immunodeficiencies. This review will first summarize the animal models utilized for IUHCT investigations and describe the associated outcomes. Recent advances and potential barriers for successful IUHCT are discussed, followed by possible strategies to overcome these barriers experimentally. Lastly, we will outline the progress made towards utilizing IUHCT to treat inherent disorders for patients, list out associated limitations and propose feasible means to promote the efficacy of IUHCT clinically.

Exercise training and NR supplementation to improve muscle mass and fitness in adolescent and young adult hematopoietic cell transplant survivors: a randomized controlled trial {1}

BackgroundAdvances in hematopoietic cell transplantation (HCT) have led to marked improvements in survival. However, adolescents and young adults (AYAs) who undergo HCT are at high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the developing musculoskeletal system. HCT survivors who have sarcopenia also have excess lifetime risk of non-relapse mortality. Therefore, interventions that increase skeletal muscle mass, metabolism, strength, and function are needed to improve health in AYA HCT survivors. Skeletal muscle is highly reliant on mitochondrial energy production, as reflected by oxidative phosphorylation (OXPHOS) capacity. Exercise is one approach to target skeletal muscle mitochondrial OXPHOS, and in turn improve muscle function and strength. Another approach is to use “exercise enhancers”, such as nicotinamide riboside (NR), a safe and well-tolerated precursor of nicotinamide adenine dinucleotide (NAD+), a cofactor that in turn impacts muscle energy production. Interventions combining exercise with exercise enhancers like NR hold promise, but have not yet been rigorously tested in AYA HCT survivors.Methods/designWe will perform a randomized controlled trial testing 16 weeks of in-home aerobic and resistance exercise and NR in AYA HCT survivors, with a primary outcome of muscle strength via dynamometry and a key secondary outcome of cardiovascular fitness via cardiopulmonary exercise testing. We will also test the effects of these interventions on i) muscle mass via dual energy x-ray absorptiometry; ii) muscle mitochondrial OXPHOS via an innovative non-invasive MRI-based technique, and iii) circulating correlates of NAD+ metabolism via metabolomics. Eighty AYAs (ages 15-30y) will be recruited 6–24 months post-HCT and randomized to 1 of 4 arms: exercise + NR, exercise alone, NR alone, or control. Outcomes will be collected at baseline and after the 16-week intervention.DiscussionWe expect that exercise with NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. We will apply the insights gained from this trial to develop individualized, evidence-supported precision initiatives that will reduce chronic disease burden in high-risk cancer survivors.Trial registrationClinicalTrials.gov, NCT05194397. Registered January 18, 2022, https://clinicaltrials.gov/ct2/show/NCT05194397 {2a}.

Outcomes of allogeneic hematopoietic cell transplantation in adults with fusions associated with Ph-like ALL

AbstractAllogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for acute lymphoblastic leukemia (ALL), yet large amounts of data describing alloHCT outcomes in Philadelphia (Ph)-like ALL are lacking. We retrospectively analyzed archived DNA samples from consecutive adults with B-cell Ph-negative ALL who underwent alloHCT in complete remission (CR) (n = 127) at our center between 2006 and 2020. Identification of fusions associated with Ph-like ALL was performed using cumulative results from RNA-seq, conventional cytogenetics, fluorescence in situ hybridization, and whole genome array studies. Fusions associated with Ph-like ALL were detected in 56 (44%) patients, of whom 38 were carrying CRLF2r. Compared with other non–Ph-like ALL (n = 71), patients with fusions associated with Ph-like ALL were more frequently Hispanic (P = .008), were less likely to carry high-risk cytogenetics (P < .001), and were more likely to receive blinatumomab prior to HCT (P = .019). With the median followup of 3.5 years, patients with Ph-like ALL fusions had comparable posttransplant outcomes compared with other B-cell ALL: 3-year relapse-free survival (RFS) (41% vs 44%; P = .36), overall survival (OS) (51% vs 50%; P = .59), and relapse (37% vs 31%; P = .47). In multivariable analysis, age (P = .023), disease status at the time of transplant (P < .001), and donor type (P = .015) influenced OS. RFS (primary endpoint) was significantly influenced by disease status (P < .001) and conditioning regimen intensity (P = .014). In conclusion, our data suggest that alloHCT consolidation results in similarly favorable survival outcomes in adult patients with Ph-like fusions and other high-risk B-cell ALL.

Immunogenicity and safety of the meningococcal B recombinant (4CMenB) vaccine in allogeneic hematopoietic cell transplantation recipients

ObjectivesDespite a high risk of invasive meningococcal (Men) disease, there is no published data on any MenB vaccine after hematopoietic cell transplantation (HCT). We investigated the immunogenicity and safety of the 4CMenB recombinant vaccine (Bexsero) in adult HCT recipients. MethodsPatients were eligible from 6 months post-HCT to receive 2 4CMenB doses at 2-month intervals. Sera were collected at baseline, 1 month after the second dose, and 12 months after enrolment. The serum bactericidal activity (SBA) using human complement (hSBA) was assessed against fHbp, NadA, PorAP1.4, and NHBA antigens. The vaccine response was defined by one criterion for one vaccine antigen: (1) in patients with a hSBA titer <4 at baseline: a titer ≥4; (2) in patients with a hSBA titer ≥4 at baseline: at least a 4 time increase. ResultsForty (40) patients were included at a median of 2.14 (0.57–13.03) years posttransplant. At baseline, most patients (32/40, 80%) had hSBA titers <4 for all vaccine antigens. After 2 vaccine doses, the proportion of patients with a titer ≥4 was significantly increased for fHbp (23/40, 57.5%), NadA (25/40, 62.5%), and PorA (31/40, 77.5%) but not for NHBA for which only 6 of 40 (15%) patients responded. Of patients, 36 out of 0 (90%) were responders to ≥1 antigen. However, 9 months later, only 23 out of 37 (62.2%) patients were still seroprotected. No severe adverse event was observed. DiscussionThe response rate of 90% for ≥1 vaccine antigen and our safety data supports the 4CMenB vaccination of HCT recipients from 6 months after transplant with 2 doses.

Correlation of initial upper respiratory tract viral burden with progression to lower tract disease in adult allogeneic hematopoietic cell transplant recipients.

Some respiratory viruses have been evaluated for the association between viral burden and respiratory disease progression in hematopoietic cell transplant (HCT) recipients, and no significant association has been reported. To assess whether initial viral burden of respiratory viruses predicts risk of progression to lower respiratory tract infection (LRTI) among adult allogeneic HCT recipients who presented with upper respiratory tract infection (URTI) with 12 viruses in the PCR era. We reviewed adult allogeneic HCT recipients (4/2008-9/2018) who presented with their first symptomatic respiratory viral infection following transplantation at the Fred Hutchinson Cancer Center. Cox proportional hazards models were used to investigate whether viral burden as measured by initial Ct values at the diagnosis of URTI is associated with progression to LRTI within 90 days for each virus, treating death as a competing risk. Among 2,148 adult HCT recipients during the study periods, 1,102 episodes of URTI met the study inclusion criteria. Higher viral burden (lower Ct value) were associated with an increased risk of progression to LRTI for influenza after adjusting for immunodeficiency scoring index and initiation of antiviral therapy, respectively. The association between viral burden and progression to LRTI was not found for other viruses. Our findings suggest that routine reporting of viral burden in current molecular diagnostic platforms may be beneficial. Further studies are needed to investigate the impact of viral burden on LRTI in other populations including pediatric HCT recipients.

Voriconazole in Hematopoietic Stem Cell Transplantation and Cellular Therapies: Real-World Usage and Therapeutic Level Attainment at a Major Transplantation Center

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.

Long-term patient-reported neurocognitive outcomes in adult survivors of hematopoietic cell transplant

AbstractSurvivors of hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can negatively affect quality of life. Given limited studies, we aimed to describe the neurocognitive outcomes in a cohort of long-term adult HCT survivors. Eligible survivors (age ≥21 years at HCT and alive ≥2 years following HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL) and the Childhood Cancer Survivor Study Neurocognitive Questionnaire (NCQ). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Survivors (n = 1861, 47.7% female, 65.6% allogeneic HCT) were surveyed at a median age of 64.2 years (interquartile range [IQR], 56.8-70.5) and a median 12.0 years (IQR, 6.0-21.0) from HCT. Survivors reported average Neuro-QoL scores (50.0 allogeneic; 49.2 autologous survivors) compared with an expected mean of 50 in the general population. On the NCQ, 17.4% to 31.2% of survivors reported impairments (Z-score >1.28) in task efficiency, memory, emotional regulation, or organization, compared with an expected 10% in the general population (all P < .01). In multivariable regression analyses, impaired Neuro-QoL (T-score <40) was independently associated with hearing issues (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.46-3.10) and sleep impairment (OR, 4.41; 95% CI, 2.80-6.94) among allogeneic survivors, with comparable associations in autologous survivors. Overall, long-term adult HCT survivors reported average cognitive quality of life compared with the general population. Subsets of survivors with hearing issues and sleep impairments were more likely to report lower quality of life and impaired neurocognitive function, which may facilitate targeted monitoring or interventions following HCT.

Male-specific late effects in adult hematopoietic cell transplantation recipients: a systematic review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. We provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. The systematic review summarizes incidence, risk factors, screening, prevention and treatment of these complications and provides consensus evidence-based recommendations for clinical practice and future research.

Reduced Enterohepatic Recirculation of Mycophenolate and Lower Blood Concentrations Are Associated with the Stool Bacterial Microbiome after Hematopoietic Cell Transplantation

Mycophenolate mofetil (MMF) is an important immunosuppressant used after allogeneic hematopoietic cell transplantation (HCT). MMF has a narrow therapeutic index, and blood concentrations of mycophenolic acid (MPA), the active component of MMF, are highly variable. Low MPA concentrations are associated with the risk of graft-versus-host disease (GVHD), whereas high concentrations are associated with toxicity. Reasons for variability are not well known and may include the presence of β-glucuronidase-producing bacteria in the gastrointestinal tract, which enhance MPA enterohepatic recirculation (EHR) by transforming MPA metabolites formed in the liver back to MPA. This study was conducted to determine whether individuals with high MPA EHR have a greater abundance of β-glucuronidase-producing bacteria in their stool and higher MPA concentrations compared with those with low EHR. We conducted a pharmacomicrobiomics study in 20 adult HCT recipients receiving a myeloablative or reduced-intensity preparative regimen. Participants received MMF 1 g i.v. every 8 hours with tacrolimus. Intensive pharmacokinetic sampling of MMF was conducted before hospital discharge; total MPA, MPA glucuronide (MPAG), and acyl-glucuronide metabolite (acylMPAG) were measured. EHR was defined as the ratio of MPA area under the concentration-versus-time curve (AUC)4-8 to MPA AUC0-8. Differences in stool microbiome diversity and composition, determined by shotgun metagenomic sequencing, were compared above and below the median EHR (22%; range, 5% to 44%). The median EHR was 12% in the low EHR group and 29% in the high EHR group. MPA troughs, MPA AUC4-8, and acyl-glucuronide metabolite (acylMPAG) AUC4-8/AUC0-8 ratio were greater in the high EHR group compared with the low EHR group (1.53 μg/mL versus .28 μg/mL [P=.0001], 7.33 hour·μg/mL versus 1.79 hour·μg/mL [P=.0003], and .33 hour·μg/mL versus .24 hour·μg/mL [P=.0007], respectively). MPA AUC0-8 was greater in the high EHR group than in the low EHR group, and the difference trended toward significance (22.8 hour·μg/mL versus 15.3 hour·μg/mL; P=.06). Bacteroides vulgatus, Bacteroides stercoris, and Bacteroides thetaiotaomicron were 1.2- to 2.4-fold more abundant (P=.039, .024, and .046, respectively) in the high EHR group. MPA EHR was positively correlated with B. vulgatus (⍴=.58; P ≤ .01) and B. thetaiotaomicron (⍴=.46; P < .05) and negatively correlated with Blautia hydrogenotrophica (⍴=-.53; P < .05). Therapeutic MPA troughs were achieved in 80% of patients in the high EHR group but in no patients in the low EHR group. There was a trend toward differences in MPA AUC0-8 and MPA concentration at steady-state (μg/mL) between the high EHR group versus the low EHR group (P=.06). MPA EHR was variable. Patients with high MPA EHR had greater abundance of Bacteroides species in stool and higher MPA exposure compared with patients with low MPA EHR. Therefore, Bacteroides may be protective against poor outcomes, such as graft-versus-host disease, in some patients but may increase the risk of MPA adverse effects in others. These data need to be confirmed and studied after oral MMF therapy.

Respiratory viruses in hematopoietic cell transplant candidates: impact of preexisting lower tract disease on outcomes

AbstractPretransplant respiratory virus infections (RVIs) have been shown to negatively affect hematopoietic cell transplantation (HCT) outcomes. The impact of and need for delay of HCT for pretransplant infection with human rhinovirus (HRV) or endemic human coronavirus (HCoV; 229E, OC43, NL63, and HKU1) remain controversial. We analyzed the impact of symptomatic RVI within ≤90 days before HCT on overall mortality, posttransplant lower respiratory tract disease (LRD), and days alive and out of hospital (DAOH) by day 100 post-HCT in multivariable models. Among 1,643 adult HCT recipients (58% allogeneic recipients), 704 (43%) were tested for RVI before HCT, and 307 (44%) tested positive. HRV was most commonly detected (56%). Forty-five (15%) of 307 HCT recipients had LRD with the same virus early after HCT. Pretransplant upper respiratory tract infection (URI) with influenza, respiratory syncytial virus, adenovirus, human metapneumovirus, parainfluenza virus, HRV, or endemic HCoV was not associated with increased overall mortality or fewer DAOH. However, in allogeneic recipients who received myeloablative conditioning, LRD due to any respiratory virus, including HRV alone, was associated with increased overall mortality (adjusted hazard ratio, 10.8 [95% confidence interval, 3.29-35.1] for HRV and 3.21 [95% confidence interval, 1.15-9.01] for all other viruses). HRV LRD was also associated with fewer DAOH. Thus, the presence of LRD due to common respiratory viruses, including HRV, before myeloablative allogeneic HCT was associated with increased mortality and hospitalization. Pretransplant URI due to HRV and endemic HCoV was not associated with these outcomes. Improved management strategies for pretransplant LRD are warranted.

Effects of cyclophosphamide related genetic variants on clinical outcomes of adult hematopoietic cell transplant patients.

Genetic variants may influence the pharmacokinetics and pharmacodynamics (PKPD) of cyclophosphamide (CY). CY plays a critical role in conditioning chemotherapy for hematopoietic cell transplantation (HCT), but its use is limited by toxicity. We explored the effect of genetic variants, potentially affecting PKPD of CY, and outcomes after HCT. This observational pharmacogenomic study included 85 adults with hematologic malignancies who received reduced intensity conditioning with CY, fludarabine, and total body irradiation. We collected recipient DNA prior to HCT and evaluated 97 candidate variants in 66 genes and 3 metabolism phenotypes potentially involved in PKPD pathways of CY. In multivariable analysis we investigated the association between the genotypes and four clinical outcomes: Day 180 non-relapse mortality (NRM) and day 180 overall survival (OS), acute graft-versus-host-disease(aGVHD) grades 2-4, and engraftment. p values were not adjusted for multiple testing. The median recipient age was 63years (range 21-75). Acute myeloid leukemia was the most common diagnosis (34%; n = 29). In multivariable analysis adjusted for exposure to phosphoramide mustard, the final active metabolite of CY, we identified 6 variants in 6 genes associated with at least one of theclinical outcomes. An ABCC4 variant (rs9561778) was associated with poor Day 180 NRM (p < 0.01), MUTYH variant (rs3219484) with higher Day 180 NRM and aGVHD (both p < 0.01), and SYNE1 variant (rs4331993) with better Day 180 OS and engraftment (both p ≤ 0.01). The present study suggests that genetic variants influencing the PKPD of CY may help identify patients at risk for inferior outcomes after HCT using CY-based reduced-intensity conditioning.