Adult Allogeneic Hematopoietic Cell Transplantation Research Articles

A retrospective study of intravenous pentamidine for Pneumocystis jirovecii pneumonia prophylaxis in adult patients with hematologic malignancies—its utility during respiratory virus pandemics

ObjectivesIn hematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematologic malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent; however, its use is not straightforward. Inhaled pentamidine is the recommended second-line agent; however, aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic hematopoietic stem cell transplantation recipients and patients with hematologic malignancies during COVID-19. ResultsA total of 202 unique patients who received 239 courses of IV pentamidine, with a median of three doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The most common reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients developed an infusion reaction or experienced adverse effects from IV pentamidine. ConclusionsPentamidine administered IV monthly is safe and effective.

Letermovir safety and efficacy for cytomegalovirus prophylaxis in adult Japanese kidney transplant recipients: a multicenter, open-label, noncomparative Phase 3 study.

Letermovir is approved for cytomegalovirus (CMV) prophylaxis in adult allogeneic hematopoietic cell transplantation recipients worldwide and is also approved in the United States for CMV prophylaxis in adult high-risk (D+/R-) kidney transplant recipients (KTRs). The safety and efficacy of letermovir for CMV prophylaxis in adult Japanese KTRs are reported here. In this Phase 3, single-arm, open-label study, adult Japanese KTRs with CMV serostatuses D+/R-, D+/R+, and D-/R+ received letermovir 480mg daily orally within 7days post-transplant through Week 28. Participants were followed through Week 52. The primary objective was to evaluate letermovir safety and tolerability. Efficacy was a secondary objective, measured by CMV disease, CMV disease or infection requiring intervention, and quantifiable CMV DNAemia. All CMV disease cases were confirmed by an independent adjudication committee. Among 22 participants (12 were D+/R-) who received letermovir prophylaxis, 20 (90.9%) experienced ≥ 1 AE through Week 28. Most AEs were mild to moderate in severity; no deaths were reported. During the prophylaxis period through Week 28, one transient case of quantifiable CMV DNAemia was detected, but no CMV disease or infection requiring intervention was reported. Through Week 52, four D+/R- participants met the endpoint of CMV disease or infection requiring intervention, of whom two had committee-confirmed CMV syndrome; all recovered with CMV therapy. A total of 5 participants had quantifiable CMV DNAemia through Week 52. Letermovir was generally well tolerated, and the data support its use for the prevention of CMV disease/infection in adult Japanese KTRs. ClinicalTrials.gov NCT04129398.

Feasibility of Optimizing Older Adult Allogeneic Hematopoietic Cell Transplant (Allo-HCT) Candidates: Results from a Pilot Study of Geriatric Assessment (GA)-Directed Intervention

Feasibility of Optimizing Older Adult Allogeneic Hematopoietic Cell Transplant (Allo-HCT) Candidates: Results from a Pilot Study of Geriatric Assessment (GA)-Directed Intervention

Incidence and Nature of BK and Adenovirus Infections in Post-Transplant Cyclophosphamide-Based Adult Allogeneic Hematopoietic Cell Transplant

Incidence and Nature of BK and Adenovirus Infections in Post-Transplant Cyclophosphamide-Based Adult Allogeneic Hematopoietic Cell Transplant

Trends in underlying causes of death in allogeneic hematopoietic cell transplant recipients over the last decade.

Improved survival after hematopoietic cell transplantation (HCT) and an increasingly comorbid transplant population may give rise to new trends in the causes of death. This study includes all adult allogeneic HCT recipients transplanted at Rigshospitalet between January 1, 2010 and December 31, 2019. Underlying causes of death were determined using the Classification of Death Causes after Transplantation (CLASS) method. Among 802 HCT recipients, 289 died during the study period. The main causes of death were relapse (N = 133, 46.0%), graft-versus-host disease (GvHD) (N = 64, 22.1%) and infections (N = 35, 12.1%). Multivariable analyses showed that with increasing transplant calendar year, a decreased risk of all-cause mortality (HR 0.92, 95% CI 0.87-0.97) and death from GvHD (HR 0.87, 95% CI 0.78-0.97) was identified, but not for other specific causes. Standardized mortality ratios (SMRs) for all-cause mortality decreased from 23.8 (95% CI 19.1-28.5) to 18.4 (95% CI 15.0-21.9) for patients transplanted in 2010-2014 versus 2015-2019, while SMR for patients who died from GvHD decreased from 8.19 (95% CI 5.43-10.94) to 3.65 (95% CI 2.13-5.18). As risk of all-cause mortality and death from GvHD decreases, death from relapse remains the greatest obstacle in further improvement of survival after HCT.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment.

Help for Ukrainian Hematology Patients (HUP) - a Global Initiative Supporting the Establishment of Hematology Centers and Hematopoietic Cell Transplantation Programs in a Time of War

Background In 2021 most of the Ukrainian patients with hematological diseases and in need of allogeneic hematopoietic cell transplantation (HCT) were treated outside the country with governmental funding or not treated. Only 147 autologous and 6 allogeneic HCT in adults (75 and 33 in children, respectively) in a country of 44 million population were reported to the Worldwide Network for Blood ad Marrow Transplantation (WBMT). In the same year, the European Leukemia Net (ELN) and the WBMT were approached to support or establish sustainable HCT programs for adults in the country. Methods After a site visit at different Ukrainian hospitals in November 2021, daily supervisory telemedicine was initiated in January 2022, immediately before the war in February affected daily life and the existing healthcare in the country. With the mission to establish sustainable care for hematology patients, representatives from major international hematology (ASH, ASCO, EHA, DGHO, ECO), transplant organizations (WBMT, EBMT, ASTCT) and physicians from multiple Ukrainian institutions formed the HUP (Help for Ukrainian Hematology Patients) network with the participation of the Ministry of Health and the World Health Organization (WHO). On weekly video conference meetings, the need and solutions were discussed starting with a list of patients in need for treatment. Results Patients were allocated according to their wishes in Ukrainian Hospitals or abroad with the help of EBMT, WBMT, EHA and ECO. In the same time, the daily grand rounds were pursued to help Ukrainian physicians to treat patients with blood disorders remaining in the country. While many drugs were already available, a list of drugs not available and not registered in the Ukraine was created. Medicines were donated from different sources including sister cities, governments and EU commission. In parallel, standard operating procedures were provided to the institutions. Despite war and during bombing, autologous HCT activities continued and allogeneic HCT programs for adults initiated. To ensure highest quality, the EBMT instituted a routine tumor board with global experts to discuss the indication for treatments and, if this was not possible in the country (e.g. CAR-T cell, bispecific antibody treatment), transfer to transplant centers abroad was organized. In order to identify unrelated transplant donors, the Ukrainian unrelated donor search and registry was supported. The cooperation of the Ukrainian institutions with regard to exchange of drugs and other needs was impressive and a transplant society (UABMT) for adult and pediatric patients with the participation of all Ukrainian centers was founded. The volume of allogeneic HCT in adult patients increased rapidly to 45 patients from related, unrelated and haploidentical donors at the BMT center in Kyiv, in the Cherkhasy Regional Hospital in Cherkhasy, and in the Children Hospital “Ohmatdyt” in Kyiv (Table 1) in the same year 2022. Autologous HSCT also increased in these and other hospitals in Lviv and Kyiv. The activities are now continuously increasing and will reach an even higher number in 2023. It rapidly became apparent that with HCT also the other hematological infrastructure had to be improved. While basic hematological diagnostics were available in the Ukraine, a possibility to have the most sophisticated diagnostics was created with the help of ASH and ASTCT. Blood or marrow samples from the whole country are now transferred weekly to the Munich Leukemia Lab (MLL) laboratory to be tested for cytological, cytogenetical, immunophenotyping, and molecular analyses and results made available to Ukrainian hospitals within a few days free of charge. Up to now samples from 341 patients from all Ukraine have been analyzed at diagnosis and at different time points during their treatment. Conclusion Despite the hostile environment, intense cooperation and support by international societies, private institutions, WHO, together with the personal involvement of the committed local physicians and the Ministry of Health were able to provide an example on how to establish a sustainable healthcare system for hematological patients in a low resource country in extreme distress. This effort represents a model that by using solidarity and new technologies may greatly impact other countries affected by socio-economic, or conflict challenges. SK, IK and MA, TH, AG, AS, DR, DN contributed equally

Slow and Steady Wins the Race: Optimization of Older Adult Allogeneic Hematopoietic Cell Transplant (Allo-HCT) Candidates

Background: Allo-HCT is the only potentially curative therapy available for many hematologic malignancies, but due to its intensity and associated toxicities, is infrequently offered to older adults. This study explored the feasibility and efficacy of individualized, geriatric assessment (GA)-guided intervention among older adult candidates for allo-HCT. Methods: Patients ≥ 60 years old that were candidates for allo-HCT were recruited between June 11, 2021 and July 1, 2022. Exclusion criteria included inability to speak English, diagnosis of dementia, and planned allo-HCT in < 1 month or > 6 months. Baseline GA was completed at time of enrollment. Subjects were prescribed multi-domain personalized geriatric intervention based on results of their individual GA. Patients were continued on geriatric intervention for up to 6 months or until transplant. A post-intervention GA was conducted after 6 months or at time of admission for allo-HCT, whichever occurred first. Metrics included in GA are defined in table 1. Subjects were provided wearable accelerometer device for activity tracking. Primary outcome of interest was change in 6-minute walk test (6MWT) and secondary outcomes included improved or maintained short physical performance battery (SPPB), receipt of allo-HCT, and overall survival (OS). Wilcoxon signed rank test was used to compare GA metrics pre- and post-intervention, and OS was estimated using the Kaplan-Meier method. Exploratory analyses included univariable modeling of association of baseline GA metrics with receipt of allo-HCT and OS. Results: A total of 63 allo-HCT eligible patients were approached, 30 consented and were evaluable. Of 33 not enrolled, 17 declined (7 due to requirement to wear accelerometer device), 7 were planned for allo-HCT in < 1 month, 4 were not interested in allo-HCT, 3 had virtual appointments with incomplete GA, 1 had dementia and 1 with anticipated allo-HCT date > 6 months. The majority of enrolled subjects were male (80%) and all were non-Hispanic, white. Median age at enrollment was 68.9 years (range: 60.8-79.2). Half (n=15) were diagnosed with acute myeloid leukemia, 40% (n=12) with myelodysplastic syndrome, and one each with chronic myelomonocytic leukemia, myelofibrosis, and non-Hodgkin lymphoma. The median time from allo-HCT-eligible diagnosis to baseline GA was 4.1 months (range: 1.2-118.9). More than half (n=16, 53.3%) of subjects received allo-HCT. Median time to allo-HCT from diagnosis was 13.8 months (range: 3.3-122.1) and from baseline GA was 4.6 months (range: 0.5-10.8). No one baseline GA metric was associated with receipt of allo-HCT (table 2). Median OS from study enrollment for all subjects was not reached (95% CI: 9.8 month-NR) with median follow-up of 14.8 months (range: 10.7-19.3). At baseline, better gait speed on 6MWT (HR: 0.72; 95% CI: 0.59-0.89, p=0.0018), SPPB (HR: 0.76; 95% CI: 0.60-0.97; p=0.02), and Montreal Cognitive Assessment (MOCA; HR: 0.72; 95% CI: 0.55-0.95; p = 0.02) scores were all associated with improved OS in univariable analysis (table 2). Pre and post-intervention GA metrics are presented in table 1. Only 14 subjects completed at least partial post-intervention GA, 12 of whom received allo-HCT. Reasons for not completing post-intervention GA included subjects declining to schedule (n=6), issues of care coordination (e.g.: frequent or prolonged hospital admissions, changes to allo-HCT admission plan; n=6), and death (n=4). Twelve subjects had both pre and post-intervention 6MWT data, 83.3% (n=10) improved by at least 50 feet. Ten subjects had both pre and post-intervention SPPB and all improved by at least 1 point or maintained a normal score (>9). Discussion: Improvement in or maintenance of 6MWT and SPPB were demonstrated in the majority of subjects with measured pre and post-intervention GA. Unfortunately, attrition was a major limitation of the study. Patterns of loss to follow-up, as well as reasons for screen failure, will be important areas for further exploration and potential targets for intervention at institutional and provider levels. Importantly, age was not associated with OS. Early education about allo-HCT paired with patient-centered goals of care conversations may be useful in identifying older adults most motivated and likely to benefit from GA-guided intervention.

Racial and Socioeconomic Disparities in Long-Term Outcomes in ≥1 Year Allogeneic Hematopoietic Cell Transplantation Survivors: A CIBMTR Analysis

Racial/ethnic minorities have demonstrated a worse survival after allogeneic hematopoietic cell transplantation (HCT) compared to Whites. Whether the racial disparity in HCT outcomes persists in long-term survivors, and possibly may even be exacerbated in this population that frequently transitions back from the transplant center to their local healthcare providers, is unknown. In the current study we compared long-term outcomes among one-year allogeneic HCT survivors by race/ethnicity and socioeconomic status (SES). The Center for International Blood and Marrow Transplant (CIBMTR) database was used to identify 5,473 patients with acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, or myelodysplastic syndromes who received first allogeneic HCT between 2007-2017 and were alive and in remission for at least 1 year after transplantation. Study was restricted to patients transplanted in the United States. SES was defined using patient neighborhood poverty level estimated from the recipient's ZIP code of residence; a ZIP code with ≥20% of persons below the federal poverty level was considered a high poverty area. The primary outcome was to evaluate the association of race/ethnicity and neighborhood poverty level with overall survival (OS), relapse, and non-relapse mortality (NRM). Cox regression models were used to determine associations of ethnicity/race and SES with (OS), relapse, and (NRM). Standardized mortality ratios (SMR) were calculated to compare mortality rates of the study patients to their general population peers matched on race/ethnicity, age and sex. Patients were reported to be Non-Hispanic White (n=4,385), Non-Hispanic Black (n=338), Hispanic (n=516), and Asian (n=234). Overall, 729 (13%) patients resided in areas with high poverty level. We found that a significantly larger proportion of non-Hispanic Black (37%) and Hispanic (26%) patients lived in areas with higher poverty levels compared to Non-Hispanic Whites (10%) and Asians (10%) (p<0.01). In multivariable analysis, we observed no significant association between OS, PFS, relapse, or NRM and race/ethnicity or poverty level when adjusted for patient-, disease- and transplant-related covariates. Our retrospective cohort registry study highlights that among adult allogeneic HCT recipients who survived at least 1-year in remission, there was no observed association between race/ethnicity, neighborhood poverty level, and long-term outcomes.

Epidemiology, treatment patterns, and disease burden of cytomegalovirus in hematopoietic cell transplant recipients in selected countries outside of Europe and North America: A systematic review.

Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America. The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011-17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden. Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%-61.2% (23 studies) and 2.9%-15.7% (10 studies), respectively. Recurrence occurred in 19.8%-37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%-10% of recipients (five studies). Patient-reported outcomes and economic data were scarce. The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.

Long-term health outcomes of allogeneic hematopoietic stem cell transplantation.

Fifty years of hematopoietic cell transplantation (HCT) has ushered in an exciting era of cellular therapy and has led to enormous progress in improving the outcomes of patients with both malignant and non-malignant hematologic disease. As the survival of transplanted patients has increased, so has the recognition of long-term complications related to this therapy. The goal of this review is to highlight some of the most common long-term complications of HCT. To this end, we have conducted a review of the published literature on the long-term complications of HCT encompassing the past 50 years. We have endeavored to include long-term complications reported in research articles, case series and case reports, reviews, and abstracts. We have focused primarily on adult allogeneic HCT, but have included some data from studies of pediatric allogeneic HCT as well. We have also prioritized the literature published in the last 15 years. Key data supporting the onset and prevalence of the most common long-term complications was extracted. While the list of long-term complications extracted and reported was comprehensive, it was not exhaustive. We have endeavored to highlight some of the most common long-term complications of HCT, the recognition and management of which constitutes an important part of HCT survivorship care.

Cost Effectiveness of Letermovir for Cytomegalovirus Prophylaxis Compared with Pre-Emptive Therapy in Allogeneic Hematopoietic Stem Cell Transplant Recipients in the United States.

The aim of this study was to assess the cost effectiveness of letermovir prophylaxis with the option for subsequent pre-emptive therapy (PET) for the prevention of cytomegalovirus (CMV) infection compared with a PET-only scenario in adult allogeneic hematopoietic stem cell transplant (allo-HCT) recipients in the United States over a 10-year time horizon. A publicly available decision tree model was constructed using a commercial third-party payer perspective to simulate an allo-HCT recipient's clinical trajectory in the first-year post-transplant, followed by entry to a Markov model to simulate years 2 through 10. Clinical inputs and utility estimates were derived from published literature. Costs were derived from published literature and US Department of Veterans Affairs Federal Supply Schedule drug pricing. Outcomes assessed included life expectancy, quality-adjusted life-years (QALYs), direct medical costs, and the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the findings. Compared with PET alone, letermovir prophylaxis was projected to increase life-years per person (4.99 vs. 4.70 life-years), and increase QALYs (3.29 vs. 3.08) and costs (US$83.411 vs. US$70,698), yielding an ICER of US$59,356 per QALY gained. One-way sensitivity analyses indicated our model was sensitive to mortality (ICER: $164,771/QALY) and utility (letermovir ICER: $117,447/QALY; PET ICER: $107,290/QALY) in the first-year post-transplant. In 57.1% of the PSA simulations, letermovir was a cost-effective option using a willingness-to-pay threshold of US$100,000 per QALY. Letermovir prophylaxis is cost effective compared with PET alone with a willingness-to-pay threshold of US$100,000 per QALY gained. Sensitivity analysis results indicate future research is required to understand the impact of mortality and quality of life in the first-year post-transplant to arrive at a conclusive decision on letermovir adoption.

Real-World Outcomes Associated With Letermovir Use for Cytomegalovirus Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: A Systematic Review and Meta-analysis of Observational Studies.

A systematic review and meta-analysis of real-world observational studies was conducted to summarize the impact of letermovir cytomegalovirus (CMV) primary prophylaxis (PP) among adult allogeneic hematopoietic cell transplant (allo-HCT) recipients. Systematic searches in Medline/PubMed, Embase, and conferences (from database inception to October 2021) were conducted to identify studies for inclusion. Random-effects models were used to derive pooled estimates on the relative effectiveness of letermovir PP compared to controls. Forty-eight unique studies (N = 7104 patients) were included, most of which were comparative, single-center, and conducted in the United States. Letermovir PP was associated with statistically significant reduction in odds of CMV reactivation (pooled odds ratio [pOR], 0.13 and 0.24; P < .05), clinically significant CMV infection (pOR, 0.09 and 0.19; P < .05), and CMV disease (pOR, 0.31 and 0.35; P < .05) by day +100 and day +200 after allo-HCT, respectively. Letermovir PP was associated with significantly lower odds of all-cause (pOR, 0.73; P < .01) and nonrelapse mortality (pOR, 0.65; P = .01) beyond day 200 after allo-HCT. Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.

Letermovir and tacrolimus interaction effects in hematopoietic cell transplantation recipients receiving moderate cytochrome P450 3A4 inhibitors for antifungal prophylaxis.

Letermovir inhibits cytomegalovirus replication and is approved for the prevention of cytomegalovirus infection in cytomegalovirus seropositive hematopoietic cell transplantation recipients. Studies have found that letermovir coadministration has minimal effect on tacrolimus levels prior to the start of voriconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor. However, data are lacking for hematopoietic cell transplantation recipients receiving letermovir and tacrolimus with moderate CYP 3A4 inhibitors as antifungal prophylaxis. In this retrospective single-center analysis, we reviewed the charts of 92 consecutive adult allogeneic hematopoietic cell transplantation recipients receiving letermovir, tacrolimus, and moderate CYP3A4 inhibitors for antifungal prophylaxis. Tacrolimus concentration/dose (C/D) ratios were evaluated for the first 7 days pre-letermovir and for the first and second 7-day periods after letermovir. The tacrolimus mean C/D ratios [(ng/mL)/(mg/kg/day)] increased significantly with the addition of letermovir: 172.99 (95% confidence interval (CI): 158.2-187.78) pre-letermovir, 268.66 (95% CI: 244.34-292.98) first-week letermovir, and 312.19 (95% CI: 279.39-344.99) second-week letermovir (P < 0.001). The average dosages (mg/kg) of tacrolimus also decreased significantly across the three-time intervals (P < 0.001). Only four patients experienced clinically significant cytomegalovirus reactivation which required systemic treatment. These results demonstrate a reduction in tacrolimus dosing requirements for patients receiving tacrolimus and letermovir with concomitant moderate CYP3A4 inhibitors. The results of this interaction suggest that frequent monitoring of tacrolimus trough levels is warranted when starting letermovir and that empiric reduction of tacrolimus dosing upon letermovir initiation should be considered.

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

Pneumocystis jirovecii Pneumonia Prophylaxis with Intravenous Pentamidine in Adult Allogeneic Hematopoietic Stem Cell Transplant Patients.

The purpose of this single-center retrospective case series was to evaluate the efficacy and safety of 300-mg once-monthly intravenous (IV) pentamidine prophylaxis in 702 adult allogeneic hematopoietic stem cell transplant (HSCT) patients. We observed no cases of Pneumocystis jirovecii pneumonia (PJP) following IV pentamidine administration. Breakthrough Nocardia and Toxoplasma infections were observed in 7 (1%) and 5 (0.7%) patients, respectively. The most commonly reported adverse event was nausea. Monthly IV pentamidine is a reasonable alternative to trimethoprim-sulfamethoxazole (TMP-SMX).

T cell receptor excision circles are potential predictors of survival in adult allogeneic hematopoietic stem cell transplantation recipients with acute myeloid leukemia.

BackgroundLymphocyte neogenesis from primary lymphoid organs is essential for a successful reconstitution of immunity after allogeneic hematopoietic stem cell transplantation (HSCT). This single-center retrospective study aimed to evaluate T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) as surrogate markers for T and B cell recovery, as predictors for transplantation-related outcomes in adult acute myeloid leukemia (AML) patients.MethodsNinety adult patients diagnosed with AML and treated with HSCT between 2010 and 2015 were included in the study. TREC and KREC levels were measured by quantitative PCR at 1, 3, 6, and 12 months after transplantation.ResultsOverall, excision circle levels increased between 3 and 6 months post-HSCT for TREC (p = 0.005) and 1 and 3 months for KREC (p = 0.0007). In a landmark survival analysis at 12 months post-HSCT, TREC levels were associated with superior overall survival (HR: 0.52, 95% CI: 0.34 - 0.81, p = 0.004). The incidence of viral infections within the first 100 days after transplantation was associated with lower TREC levels at 6 months (p = 0.0002). CMV reactivation was likewise associated with lower TREC levels at 6 months (p = 0.02) post-HSCT. KREC levels were not associated with clinical outcomes in statistical analyzes.ConclusionsResults from the present study indicate that TREC measurement could be considered as part of the post-HSCT monitoring to identify AML patients with inferior survival after transplantation. Further prospective studies are warranted to validate these findings.

When and how do we stop antifungal treatment for an invasive mould infection in allogeneic haematopoietic cell transplant recipients?

Limited data exist to describe end-of-treatment (EOT) parameters of antifungal therapy for invasive mould infections (IMI). In a 10-year cohort of consecutive adult allogeneic haematopoietic cell transplant recipients with proven/probable IMI, we describe treatment duration and patient profile at EOT. There were 61 patients with 66 proven/probable IMI identified: 47/66 (71%) invasive aspergillosis (IA), 11/66 (17%) mucormycosis, and 8/66 (12%) other-IMI. Excluding 5 (8%) patients lost to follow-up, treatment was prematurely discontinued due to death or palliative care in 29/56 (51.8%) patients. Antifungal treatment was completed in 27 (48.2%) patients, for a median duration of 280 days (IQR: 110, 809): 258 (IQR: 110, 1905) and 307.5 (99, 809) days in IA and non-IA IMI, respectively. Treatment was continued after 90 and 180 days in 43/56 (76.8%) and 30/56 (53.6%) patients, respectively. At EOT, most patients were not neutropenic (ANC: 2.12 G/L, IQR: 0.04, 5.3), with CD4+ counts at 99 cells/μl (IQR: 0, 759) and immunoglobulins at 5.6 g/L (IQR: 2.3, 10.6). Most patients (16/27, 59.3%) were not receiving steroids at EOT, while 14/27 (53.9%) were on another type of immunosuppression. Amongst 15 patients with imaging at EOT, 12 (80%) had complete/partial radiologic response. Any chart documentation or an infectious disease consultation on treatment discontinuation was observed in 12/56 (21%) and 11/56 (20%) patients, respectively. Long treatment courses are observed in patients with IMI, due to prolonged immunosuppression. Although immune reconstitution and radiological response were frequently observed at EOT, consistent documentation of treatment discontinuation based on well-defined parameters is lacking.

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.

Addition of plerixafor in poorly mobilized allogeneic stem cell donors.

BackgroundPeripheral blood stem cells (PBSCs) are the predominant graft source for adult allogeneic hematopoietic stem cell transplantation (HSCT). In poorly mobilized autologous donors, plerixafor improves collection outcomes. We examine plerixafor use in allogeneic donors who mobilize poorly with granulocyte colony‐stimulating factor (G‐CSF) in those who are healthy and those with pre‐existing medical conditions, and determine the optimal threshold to add plerixafor.Study Design/MethodsWe retrospectively examined all allogeneic PBSC collections from January 2013 to October 2020 at our center. Donors received G‐CSF 10 mcg/kg daily for 4 days before undergoing apheresis collection on day 5. Plerixafor was added based on poor CD34+ cell collection yield after the first or second collection day.ResultsOf the 1008 allogeneic donors, 41 (4.1%) received one dose of plerixafor in addition to G‐CSF due to poor collection yield. After starting plerixafor there was a 0.75‐ to 7.74‐fold (median 2.94) increase in CD34+ yield from the previous day. No donors with G‐CSF‐only mobilization who collected <2.0 × 106 CD34+ cells/kg recipient weight on day one achieved the goal of ≥4.0 × 106 CD34+ cells/kg recipient weight total over 2 days but 59.2% of donors who used rescue plerixafor did.ConclusionDonors both healthy and those with pre‐existing disease responded well to plerixafor with minimal side effects. If the first‐day collection yield is less than ~63% of the collection goal, addition of plerixafor may be necessary to reach the collection goal and limit the number of collection days in allogeneic donors.