Autologous Recipients Research Articles

Fatigue in Hematopoietic Cell Transplantation Survivors: Correlates, Care Team Communication, and Patient-Identified Mitigation Strategies

With improved survival after hematopoietic cell transplantation (HCT), the number of individuals at risk for persistent or late effects is increasing. The importance of optimizing HCT survivor health and well-being is mounting. Fatigue is a common post-transplantation symptom that impairs quality of life, yet it remains poorly understood and inadequately addressed. Multiple challenges to addressing fatigue exist, including its multidimensional presentation, multiple (often concomitant) causes, patient-clinician communication barriers, and few highly effective, evidence-based interventions that can be readily implemented. To address these challenges, we sought to better describe the impact and potential causes of fatigue in the post-transplantation setting, fatigue-related communication with clinicians, and the most effective patient-identified mitigation strategies (PIMS) for fatigue. A total of 1703 adult HCT recipients from a single center completed a survey including the Medical Outcomes Survey Short Form-36 (SF-36), PROMIS Fatigue, and other fatigue-related items between July 2017-June 2018. The survey was offered to recipients at their post-transplantation anniversary occurring during this interval. Two independent raters categorized free-text responses about fatigue PIMS. PROMIS Fatigue scores were dichotomized into low (≤55) or high (>55). Associations between high fatigue and participant characteristics and health outcomes were evaluated using the Fisher exact test for categorical variables and the Student 2-sample t test for continuous variables. Among the 1660 respondents with evaluable fatigue scores, 67% underwent allogeneic HCT. The majority of these (n=1588; 96%) had a malignancy, with hematologic malignancy the most common diagnostic category (n=1555; 94%). The median time post-transplantation was 11 years (interquartile range, 4 to 20 years). PROMIS item responses indicate that 44% of patients were at least somewhat fatigued and 37% were at least somewhat bothered by it. The mean fatigue score was 50.2 ± 11; 591 patients (36%) had high fatigue, which was associated with worse SF-36 scores across all domains (General Health, Physical Functioning, Emotional Well-being/Mental Health, Social Functioning, Role Limitation due to Physical Health, Role Limitation due to Emotional Health, Vitality [eg, energy], and Bodily Pain). High fatigue also was associated with self-reported chronic graft-versus-host disease, anxiety, depression and sleep problems. Diagnosis of plasma cell disorder and receipt of an autologous transplant were associated with high fatigue (P=.001). Among the 553 individuals who received an autologous transplant, 226 (41%) had multiple myeloma. Compared with the autologous transplant recipients without myeloma group, those with multiple myeloma were significantly more likely to have high fatigue (109 of 226 [48%] versus 118 of 325 [36%]; P < .01). Twenty percent of the patients with high fatigue did not discuss it with their care team. Among the 89 different reasons provided for not discussing it, the most common was "thought they already knew the answer" (n=21). The 370 survivors with high fatigue who identified at least 1 most effective PIMS generated a total of 639 PIMS. Although the PIMS for fatigue spanned a wide array of strategies, most PIMS were related to sleep/rest (n=192; 30%) or exercise (n=139; 22%). Although fatigue is associated with worse HCT survivor-reported outcomes, it is only sometimes discussed with care teams. Survivors identify specific strategies that are most effective. Given its prevalence and impact, clinicians should promote communication about fatigue, treat underlying causes, and recommend sleep/rest and exercise, recognizing that individualized approaches also may be beneficial.

Impact of Benzodiazepine Use on Length of Stay and 30-Day ED Visits among Hospitalized Hematopoietic Stem Cell Transplant Recipients.

This study assesses the impact of benzodiazepine (BNZ) use on length of stay (LOS) and 30-day emergency department (ED) visits after hematopoietic stem cell transplant (HSCT). Adult patients (18 years and older) who underwent an allogeneic or an autologous HSCT from 2015 to 2018 at the study site were included. Five multivariable models were used for both allogeneic and autologous HSCT: BNZ-naïve status, diazepam equivalent daily dosage (DEDD; 0 vs any), DEDD (excluding 0), ED visits, and LOS. BNZ-naïve autologous HSCT recipients were less likely to use any BNZs in the hospital (odds ratio [OR] 0.07, P < 0.001). If prescribed BNZs, then they used a lesser amount (incidence rate ratio 0.39, P < 0.001). BNZ-naïve autologous HSCT recipients were less likely to experience a 30-day ED visit (OR 0.17, P = 0.009). BNZ-naïve allogeneic HSCT recipients were also less likely to use any BNZ than previous users (OR 0.11, P = 0.014). Patient characteristics influenced BNZ naïvety, DEDD usage, LOS for autologous patients, and BNZ naïvety and DEDD for allogeneic patients. BNZ use resulted in increased 30-day ED visits after autologous HSCT. BNZ-naïve recipients were less likely to use BNZs during hospital stays; if they required BNZs, then it was in lower dosages.

Latent tuberculosis in adult hematopoietic stem cell transplantation recipients: Clinical experience from a previously endemic population.

Hematopoietic stem cell transplantation (HSCT) recipients may be at an elevated risk of developing active tuberculosis infection due to suppression in the cellular immune system. Herein, we aimed to evaluate the prevalence of latent tuberculosis and active tuberculosis in patients with allogeneic and autologous HSCT. In this cohort, data were obtained retrospectively from patients' records. The patients who were followed up in the bone marrow transplantation unit of the University of Health Sciences Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital between January 2016 and December 2019 were screened for the study. And the HSCT recipients who had tuberculin skin test and/or QuantiFERON-TB gold (QFT-GIT) test results were included in the study. A total of 361 patients were included in the study, 227 patients had autologous HSCT, and 134 patients had allogeneic HSCT. QFT-GIT was performed in 10 patients with allogeneic HSCT, and it was found positive in only 1 patient. Tuberculin skin test ≥5 mm was accepted as positive and was accepted to have latent tuberculosis, and it was positive in 18.2% (41) of the patients with autologous HSCT and was positive in 21.6% (29) of the patients with allogeneic HSCT. There was no significant difference between the 2 groups (P = .429). Isoniazid (INH) prophylaxis was started in 16.7% of patients with autologous HSCT and 22.4% of patients with allogeneic HSCT. During follow-up, active tuberculosis did not develop in any patients in both groups. There was no statistically significant difference found between allogeneic and autologous HSCT recipients regarding the prevalence of latent tuberculosis. Active tuberculosis infection did not develop in any of the patients who started INH prophylaxis. INH prophylaxis seems to be very efficient in preventing the reactivation of latent tuberculosis in patients going through allogeneic HSCT and/or autologous HSCT.

Epidemiology, Risk Factors and Outcome of Bacterial, Fungal, and Viral Infections in Pediatric Allogeneic and Autologous Hematopoietic Stem Cell Transplantation Recipients

Objectives Infection remains a major cause of morbidity and mortality after hematopoietic stem cell transplant (HSCT). With recent changes in transplant practices, such as the increasing use of alternative donors and T-cell depletion, how various risk factors interplay and affect the timeline of infections have not been well elucidated in children. While the epidemiology and risk factors for viral infections post-HSCT were well described for cytomegalovirus (CMV) and Epstein-Barr virus (EBV), the corresponding information on human herpes virus 6 (HHV-6), adenovirus (ADV) and BK virus (BKV) infection in children is limited. This study aims to review comprehensively the epidemiology, risk factors and outcome of bacterial, viral and fungal infections after contemporary HSCT to inform future infection prophylaxis strategies. Method We retrospectively reviewed the first 100 consecutive HSCT for malignant and non-malignant diseases from April 2019 to October 2021 in the only pediatric HSCT center in Hong Kong. The incidences were recorded and risk factors were analyzed for bacterial, viral and fungal infections and infection-related mortality. Results The vast majority of the allogeneic transplant recipients (69/74, 93.2%) had infections after HSCT, amongst which bacterial, viral and fungal infection rate was 35.1%, 90.5% and 9.5% respectively. In contrast, only 30.8% (8/26) of autologous transplant recipients had infections, and their respective rate of bacterial, viral and fungal infection was 19.2%, 15.4% and 3.8%. HHV-6 and BKV typically occurred early after HSCT, ADV and varicella zoster virus (VZV) thereafter, and CMV and EBV throughout the entire 2.5-year observation period. The cumulative incidences of HHV-6 and BKV were significantly higher in patients receiving umbilical cord blood (UCB) or haploidentical stem cell transplant (p = 0.0001; p <0.0001, respectively) when compared with matched sibling (MSD) or matched unrelated donor (MUD) transplant (Figure 1 and 2). Ex vivo T-cell depletion was a general risk factor for viral infection with HHV-6 (HR = 3.03), BKV (HR = 3.36), CMV (HR = 4.45) and EBV (HR = 7.15); all p < 0.02. Cancer in second- compared with first-complete remission was a risk factor for bacterial infection in multivariate analyses (OR = 6.0, 95% CI = 1.12-32.2, p = 0.037). Patients with gut graft-versus-host disease were at risk for fungal infections (OR = 12.3, 95% CI = 1.33-114.4, p = 0.027). The infection-related mortality (IRM) rate was 10%, which occurred only in allogeneic HSCT patients with hematological malignancies receiving cord blood (n = 4) or haploidentical HSCT (n = 6). History of bacterial infection after HSCT was associated with an increased risk of IRM (HR = 4.13, 95% CI = 1.05-16.3, p = 0.042). Conclusion Not all HSCT recipients are of equal risk to infections and IRM. Our findings in pediatric patients after contemporary HSCT support both time-dependent and risk-adapted measures against infective complications to improve transplant outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outpatient Treatment with Anti-Sars-Cov-2 Monoclonal Antibodies and Remdesivir for COVID19 Infections Demonstrates Encouraging Outcomes in Hematopoietic Stem Cell Transplant Recipients: A Single-Center Experience

Introduction: Patients with hematologic malignancies are at high risk of severe illness and increased mortality from SARS-CoV-2 infection. Autologous (auto) and allogeneic (allo) hematopoietic stem cell transplant (HCT) recipients also have a higher likelihood of developing severe COVID-19 with increased risk of mortality as described in registry analysis (Sharma et al, Lancet Haematol 2021, Ljungman et al, Leukemia 2021). Several monoclonal antibody (MOAB) combinations, as well as the antiviral remdesivir (Rem) have been approved under an emergency use authorization (EUA) and for outpatients with mild to moderate COVID-19 at risk of progression. There is limited data on HCT patient outcomes in the era of novel COVID-19 directed treatments. The aim of this study is to describe the effectiveness of outpatient (OP) MOABs and Rem in HCT recipients at our institution. Methods: We conducted a retrospective analysis of HCT patients treated at H. Lee Moffitt Cancer Center who were COVID-19 PCR positive between June 2020 and February 2022. The primary endpoint was hospitalization related to severe SARS-CoV-2 infection. We used Fisher's exact test, the Wilcoxon test and the Chi-squared test to compare the characteristics of patients who progressed to severe COVID-19 requiring hospitalization and those who did not. Results: 150 HCT patients were PCR positive for COVID-19 thus were included in this analysis. Patient characteristics are described in Table 1. The mean age was 60 years old (interquartile range [IQR], 48-68 years old) with 61% males. The majority of patients (65%) were recipients of alloHCT, while 35% had autoHCT. Median time from cell therapy to COVID-19 diagnosis was 548 days (IQR 167-1368 days). Data on COVID-19 vaccinations was missing in the majority of patients and was not included in this analysis. At the time of diagnosis, 82% of alloHCT patients were on immunosuppressive therapy (IST) and 25% had received chemotherapy within the past 30 days prior to diagnosis. With a median follow up of 132 days (range 1-875 days), 32 patients (21%) required hospitalization with moderate to severe COVID-19 as primary diagnosis. A total of 89 subjects (59%) received MOABs active against circulating variants and/or Rem. Sixty-two (70%) were treated with only MOAB and 27 (30%) with Rem. Of those requiring hospitalization, eight (25%) had received OP treatment with MOAB or Rem in comparison to twenty-four patients (75%) who did not receive OP therapy (p-value<0.01). Hospitalized patients who received OP treatment were more likely to be older (median age 64 years [IQR 57-70] vs 56 years [IQR 47-64]; p-value=0.05), male (75% vs 44%; p-value = 0.45) and to have received chemotherapy in the preceding 30 days (50% vs 9%; p-value < 0.01). No differences in race, body mass index (BMI), type of transplant or conditioning were noted (Table 2). Overall, rates of COVID-19 related death were significantly lower in patients who had received OP therapy (N=2 [2.3%]) compared to those who had not (N=8 [13.1%]; p-value = 0.02). Of those admitted, 22 (69%) received inpatient Rem for five days with 59% and 27% receiving concurrent dexamethasone or tocilizumab respectively. Ten hospitalized patients died of COVID-19-related complications resulting in a mortality rate of 31.2% in patients requiring hospitalization. Conclusions: Treatment with anti-SARS-CoV-2 MOABs and Rem in 89 HCT patients at our institution demonstrated encouraging safety and efficacy in a high-risk population with an overall COVID-19 mortality rate of 2.3% which compares favorably to published data. Despite novel therapies for the treatment of COVID19, further studies are needed in HCT recipients as nearly one third of patients with severe disease requiring hospitalization died. While the study is limited by retrospective design and the presence of confounders, our findings support continued vigilance against COVID-19 in HCT recipients with early testing via PCR swabs and prompt outpatient therapy in mildly symptomatic patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Subsequent Solid Neoplasms Following Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies: Comparing Center for International Blood and Marrow Transplant Research (CIBMTR) and California Cancer Registry (CCR) Data

Introduction: Subsequent neoplasms (SN) represent a leading cause of non-relapse mortality among hematopoietic cell transplantation (HCT) survivors. Treatment advances and expanded access for older patients have resulted in a growing population of HCT survivors. Changes in the clinical approaches to HCT, including the introduction of reduced-intensity conditioning regimens, have changed the landscape of potential SN risk factors. The Center for International Blood and Marrow Transplant Research (CIBMTR) collects extensive patient, procedure, and outcome data from HCT centers in the United States and abroad and serves as a key resource for quantifying SN incidence and identifying risk factors. The completeness of SN and other late effects reported to the CIBMTR is uncertain because patients may not continue follow-up care, particularly long-term care, at HCT centers. The California Cancer Registry (CCR) is a statewide population-based cancer registry which is estimated to capture 99% of all cancer diagnoses occurring among state residents. We compared the distribution and cumulative incidence of solid SNs within a cohort of individuals who underwent HCT for hematologic malignancy reported to the CIBMTR and linked to the California Cancer Registry (CCR). Methods: The study population included 18,450 California residents from the CIBMTR (8,232 allogeneic and 10,218 autologous HCT recipients) who were diagnosed with a hematologic malignancy between 1991-2016, linked to the CCR, and had known dates of first HCT, death (if deceased), or last known date alive. Patients were followed from the date of first HCT until the earliest of a second HCT, death, or date last known alive according to either source. ICD-O-3 histology and topography codes were used to identify and classify solid tumors in the CCR according to 10 broad types available from CIBMTR (see Table 1 below). We excluded non-melanoma skin cancers, as cutaneous basal and squamous cell carcinomas are not reportable to the CCR. We matched reports of solid SNs from the two sources according to type and diagnosis date. Cumulative incidence of developing a solid SN, accounting for the competing risk of death, was estimated from CCR and CIBMTR separately and using both data sources. Results: During a median time since HCT of 2.4 years (range: 0.003 to 27.4 years), CIBMTR and CCR reported solid SNs among 518 and 641 HCT survivors, respectively. In CCR, 7.5% of patients with an SN (48/641) had more than one type of SN; in CIBMTR the corresponding estimate was 4.1% (21/518). Among 775 unique patients with at least one solid SN from either source, 384 (49.6%) had an SN reported from both sources, 257 (33.2%) from CCR only and 134 (17.3%) from CIBMTR only. As patients could have multiple SN types, the combined dataset included 871 solid SNs, of which 38.0% were found in CCR only, 20.6% in CIBMTR only, 38.1% were found in both sources and had diagnosis dates within 90 days, and the remaining 3.3% were found in both sources but had discrepant dates (Table 1). The proportion of SNs found in both sources varied by HCT type, SN type, calendar year of SN diagnosis, and time since first HCT. Specifically, the proportion identified in both sources was higher after autologous than allogeneic HCT. By SN type, >50% of SNs of the lung, thyroid, GU system, and breast were found in both sources; a majority of sarcomas and SNs of the oral cavity/pharynx and CNS tumors were found in CCR only; and other/poorly specified SN types were more likely to be found in CIBMTR only, driven by poorly specified SNs. The proportion of cases found in both sources and concordant on diagnosis date was lower for SNs diagnosed in earlier calendar years (<2010) and those occurring >10 years since HCT. The cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.4% (95% cumulative incidence [CI] 3.9%-4.8%) based on CIBMTR information, 5.6% (95% CI] 5.1% to 6.1%) based on CCR information, and 6.6% (95% CI 6.1%-7.2%) based on both sources combined (Figure 1). Conclusion: In this linkage of CIBMTR data with population-based cancer registry data, 38.0% of solid SNs were found in CCR only, 20.6% in CIBMTR only, and 41.4% in both sources. These analyses suggest that linkage of these high-quality data sources can offer a more complete assessment of the burden of solid SNs among HCT survivors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Late Morbidity and Mortality after Autologous Blood or Marrow Transplantation (BMT) for Lymphoma in Children, Adolescents and Young Adults - a Report from the BMT Survivor Study (BMTSS)

Introduction: Autologous BMT is an integral part of consolidation and/or salvage therapy for children, adolescents and young adults with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). However, there is paucity of information regarding the long-term outcome after autologous BMT for lymphoma performed in this age group. We address this gap by leveraging the BMTSS to determine the magnitude of risk of chronic health conditions as well as cause-specific late mortality in patients undergoing autologous BMT for lymphoma between 1980 and 2014 at City of Hope, University of Minnesota or University of Alabama at Birmingham. Methods: To be included in this analysis, patients had to have received a single or tandem autologous BMT before age 40y and survived ≥2y after transplantation. BMT recipients (n=583 [HL: 59.7%; NHL: 40.3%]) and a sibling comparison group (n=330) completed a 255-item survey, and self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Vital status and cause of death information was ascertained using the National Death Index (NDI), medical records and Accurint databases. Logistic regression estimated the odds of grade 3-4 conditions in BMT recipients alive at study participation compared to siblings. Fine-Gray regression estimated the hazard of grades 3-5 chronic health conditions among BMT recipients (alive and deceased), treating death as a competing risk. Results: Median age at BMT was 30.0y (range: 2.0-39.0); median length of follow-up was 9.6y (2.0-32.1) and median age at study participation was 41.1y (13.7-67.1). Severe/life-threatening chronic health conditions in BMT survivors compared with siblings: By age 45y, the cumulative incidence of a grade 3-4 chronic health condition was 31.2% (95%CI; 25.5-37.0) among the BMT survivors and 12.9% (95%CI; 8.8-17.7) among the siblings (p<0.0001) (Figure 1). BMT survivors were at a 3.2-fold greater odds of a grade 3-4 condition (aOR=3.2, 95%CI=2.2-4.8) compared to siblings. Greater odds were observed among BMT survivors vs. siblings for the following conditions: joint replacement (OR=4.9, 95%CI=1.7-13.7), cataract (OR=4.2; 95%CI=1.4-13.0), cardiovascular disease (OR=2.2, 95%CI=1.2-4.0), and multiple conditions (OR=4.9; 95%CI=2.6-9.5). Severe/life-threatening/fatal chronic health conditions among BMT recipients: The 20y cumulative incidence of grade 3-5 conditions for the entire cohort was 46.8% (95%CI=41.6-51.7%). The 20y cumulative incidence was 42.1% (95%CI=34.2-49.7%) for patients with NHL and 49.6% (95%CI=42.9-56.0%) for patients with HL, placing HL patients at a 1.4-fold higher adjusted hazard of grade 3-5 conditions (95%CI=1.0-1.8, p=0.0232). Late mortality in BMT survivors: Conditional on surviving the first 2y after BMT, the all-cause mortality rate was 54.3% (95%CI=48.8-59.4%) at 25y from BMT (HL: 62.6%; NHL: 42.3%). The adjusted hazards of all-cause mortality were higher in HL patients (HR=1.8, 95%CI, 1.3-2.4; reference: NHL), and among Black patients (HR=3.0, 95%CI, 1.9-4.6; reference: non-Hispanic white). Causes of death were available for 84% of the cohort, and included primary disease (35%), subsequent neoplasm (16%), infection (13%), cardiac disease (8%), pulmonary disease (3%), and homicide/suicide/accident (3%). As shown in Figure 2, relapse-related mortality (RRM) plateaued after 20y from BMT, whereas the non-relapse-related mortality (NRM) continued to climb, crossing RRM at 20y from BMT. The 25y cumulative incidence of RRM was 28% (95%CI=22-34%), while that for NRM was 37% (95%CI=31-44%). Patients with HL were at increased risk for RRM (HR=2.3, 95%CI=1.3-3.8, p=0.0029; reference: NHL). The hazard of NRM was greater among HL patients (HR=1.7, 95%CI=1.1-2.7), and Black patients (HR=3.1, 1.5-6.4; reference: non-Hispanic white). Conclusions: The burden of severe/life-threatening chronic health conditions was 3-fold higher in autologous BMT recipients for lymphoma when compared with a non-BMT sibling comparison group. Patients with HL were at increased risk of a severe/life-threatening/fatal conditions as well as late mortality, when compared to patients with NHL. Finally, Black patients were at a higher risk for non-relapse-related mortality. These findings suggest a need for long-term surveillance among the vulnerable sub-populations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk Factors, Prevalence, and Outcomes of Invasive Fungal Disease Post Cellular Therapies: A Real-World Analysis

Objective: Cellular therapies, including CAR-T cell, gene therapy, autologous and allogeneic hematopoietic cell transplantation (HCT), remain a cornerstone in management of various benign and malignant disorders. Despite intensified efforts to improve strategies, invasive fungal infections (IFD) remain an important cause of morbidity and mortality. Therefore, we investigated risk factors, prevalence, and outcome of IFD in the era of novel anti-fungal prophylaxis. Methods: We retrospectively enrolled consecutive adult patients that underwent cellular therapies at our JACIE-accredited center according to standard operating procedures (2013-2022). We defined IFD according to current consensus (2020) and guidance on imaging (2021, EORTC). We analyzed the following factors: age, disease, donor, HLA matching, conditioning, graft, severe acute and moderate/severe chronic GVHD, antifungal prophylaxis, immunosuppressants, IFD type (according to current consensus), galactomannan/β-D-glucan, cultures, imaging, bacterial/viral infections, IFD treatment, relapse, and overall survival (OS). Results: We studied 950 recipients of cellular therapies (19 CAR-T cell and 2 gene therapies, 456 autologous and 473 allogeneic HCT). No CAR-T cell and gene therapy patient developed IFD; while 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. Further analysis was performed only in allogeneic HCT recipients. Possible IFD was documented in 31/473 at a median of 112 (range 7-1353) post-transplant day, probable in 11/473 (5: positive galactomannan, 6: positive cultures) at 154 (12-469), proven in 10/473 (3: positive galactomannan, 7: positive cultures) at 226 (25-1146) day. Concurrence of bacterial or viral infection was documented in 20/52 and 17/52 patients respectively. Second IFD episode occurred in 3 patients (1: probable, 2: proven IFD), that succumbed to TRM (1) and relapse (2). Candida species were isolated in 9 patients, Fusarium in 2 and Aspergillus in 2. Mucormycosis was diagnosed in 2 patients, while the remaining IFD were attributed to aspergillosis. During the aplastic period, caspofungin had been administered as primary prophylaxis (41/52) and amphotericin as secondary prophylaxis (11/52), which were then changed to posaconazole and isavuconazole respectively for the immunosuppression period. Independent risk factors for IFD were type of donor (20% in alternative, 12% in unrelated, and 5% in sibling donors, p=0.006) and moderate/severe chronic GVHD (15% versus 8%, p=0.029). Five-year OS was significantly lower in patients with IFD, especially those with proven IFD (p=0.041). IFD remained a predictor of OS (p=0.044) independently of donor type and chronic GVHD. Conclusions: Our large real-world cohort indicates the relatively low prevalence of proven IFD in the era of novel antifungal prophylaxis, which is however associated with poor outcomes in allogeneic HCT recipients. Possible IFD, assessed by host and clinical factors including updated documentation of imaging, has shown similar outcomes to probable IFD. Therefore, wider application of sensitive mycological testing is needed for high-risk populations, such as alternative alloHCT recipients or chronic GVHD patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

DNA Methylation Changes in Autologous Hematopoietic Stem Cell Transplant Patients.

Blood cancers may be potentially cured with hematopoietic stem cell transplantation (HCT); however, standard pre-assessments for transplant eligibility do not capture all contributing factors for transplant outcomes. Epigenetic biomarkers predict outcomes in various diseases. This pilot study aims to explore epigenetic changes (epigenetic age and differentially methylated genes) in patients before and after autologous HCT, that can serve as potential biomarkers to better predict HCT outcomes. This study used a prospective longitudinal study design to compare genome wide DNA methylation changes in 36 autologous HCT eligible patients recruited from the Cellular Immunotherapies and Transplant clinic at a designated National Cancer Center. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 850K BeadChip, showed a significant difference in DNA methylation patterns post-HCT compared to pre-HCT. Compared to baseline levels of DNA methylation pre-HCT, 3358 CpG sites were hypo-methylated and 3687 were hyper-methylated. Identified differentially methylated positions overlapped with genes involved in hematopoiesis, blood cancers, inflammation and immune responses. Enrichment analyses showed significant alterations in biological processes such as immune response and cell structure organization, however no significant pathways were noted. Though participants had an advanced epigenetic age compared to chronologic age before and after HCT, both epigenetic age and accelerated age decreased post-HCT. Epigenetic changes, both in epigenetic age and differentially methylated genes were observed in autologous HCT recipients, and should be explored as biomarkers to predict transplant outcomes after autologous HCT in larger, longitudinal studies.

Characteristics and outcomes of autologous hematopoietic stem cell transplant recipients admitted to intensive care units: A multicenter study.

Studies of critically ill hematopoietic stem cell transplantation (HSCT) recipients have mainly been single-center and focused on allogenic HSCT recipients. We aimed to describe a cohort of autologous HSCT with an unplanned intensive care unit (ICU) admission. This study is a retrospective cohort study of autologous HSCT performed as a treatment for a hematological malignancy, during their first unplanned ICU admission in 50 hospitals in Brazil. We assessed the hospital mortality and the association between mechanical ventilation, vasopressors, and renal replacement therapy and hospital mortality in autologous HSCT recipients, adjusted for potential confounders. We included 301 patients. Multiple myeloma was the most common malignancy driving to HSCT. ICU and hospital mortality were 22.9% and 37.5%, respectively. After adjustment for potential confounders, mechanical ventilation (OR = 9.10; CI 95%, 4.82-17.15) was associated with hospital mortality, but vasopressors (OR = 1.43; CI 95%, 0.77-2.64) and renal replacement therapy (OR = 1.30; CI 95%, 0.63-2.66) were not. In this large cohort of critically ill autologous HSCT recipients, mechanical ventilation was the only organ support-therapy associated with increased mortality in autologous HSCT recipients.

Pilot Trial of Homebound Hematopoietic Cell Transplantation

For eligible patients with multiple myeloma (MM) and amyloid light chain (AL) amyloidosis, high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) is a standard and widely used consolidation therapy. Autologous HCT requires specialized care at a transplantation center and investment from patients and caregivers. We studied the safety and feasibility of delivering transplantation care in a homebound setting to decrease the burden of therapy and increase access to autologous HCT. Patients with MM and AL amyloidosis undergoing autologous HCT were eligible if they resided in designated ZIP codes and had a full-time caregiver, Wi-Fi connection, HCT Comorbidity Index ≤3, and Karnofsky Performance Status score ≥80. High-dose melphalan (on day -2) and hematopoietic cell reinfusion (day 0) were administered in the outpatient clinic. Protocol-specific home care was provided from day +1 through engraftment. Patients were assessed and blood was drawn daily by advanced practice providers. Interventions were delivered by registered nurses. Attending physicians communicated daily through telemedicine. Quality of life, patient and caregiver satisfaction, and fecal microbiota profiling data were collected. Fifteen patients were enrolled and received transplantation care at home starting on day +1 following hematopoietic cell infusion. Patients remained in the program for an average of 12 days and required an average of 2 outpatient visits while receiving home care. Seven of 15 patients were admitted for a median of 4 days (range, 3 to 10 days); admission occurred on day +7 in 5 patients, on day +8 in 1 patient, and on day +12 in 1 patient for neutropenic fever in 2 patients, fever attributed to engraftment syndrome in 2 patients, diarrhea in 2 patients, and dehydration in 1 patient. Only 1 patient had a documented infection (Clostridioides difficile). One patient admitted with neutropenic fever required intensive care unit admission for a gastrointestinal bleed. Forty-seven percent of the patients experienced a grade ≥3 nonhematologic toxicity. There were no deaths on the study. Patients and caregivers reported high satisfaction with care. Microbiota diversity patterns were similar to those of autologous HCT recipients who did not receive post-HCT care at home, although a subset of the cohort maintained microbiota diversity throughout. Homebound HCT in an urban setting is safe and feasible, with less than one-half of patients requiring inpatient admission. Despite increased patient and caregiver responsibility in the homebound setting compared with an inpatient setting, patient and caregiver satisfaction was high. These results support expansion of homebound transplantation care programs.

424.1: Epidemiology of Cytomegalovirus Infection and Disease in Hematopoietic Stem Cell Transplant Recipients in Selected Countries Outside of North America and Europe: A Systematic Review

Background: Cytomegalovirus (CMV) is a highly prevalent herpes virus with a seroprevalence higher in South America, Africa, and Asia than in Europe and North America. In hematopoietic stem cell transplant recipients (HSCT), CMV infection is a common opportunistic infection and a major cause of morbidity and mortality. To better understand the epidemiology of CMV infection and disease post-HSCT in selected countries outside of Europe and North America, a systematic review was conducted. Methods: Observational studies that included HSCT recipients (any age) from 15 selected countries in Asia-Pacific, Latin America, Russia and the Middle East were considered (search period: 01 Jan. 2011 – 21 Jul. 2021). Outcomes of interest were incidence, recurrence rates and risk factors of CMV infection and CMV disease, and CMV-related mortality at any time point. Indexed publications (Ovid® MEDLINE and Embase, Cochrane Database of Systematic Reviews and World Health Organization database Global Index Medicus) were searched, supplemented by pragmatic searches of the grey literature and snowballing of references lists. The protocol was registered in PROSPERO (CRD42020205559). Results: A total of 63 studies (range: 33 to 10,206 patients), most conducted in adults (≥ 18 years; n=49 studies, 77.8%) and allogeneic HSCT recipients (n=53, 84.1%), were included in the review. In 43 of 54 studies reporting on incidence of CMV infection, within 1 year post-HSCT, estimates were uniformly distributed between 24.8% and 61.2% (Figure 1). Lower estimates were reported in autologous HSCT recipients (5.3%), and younger patients at the time of transplantation (9.3% in adults with a median age of 25 years and 18.6% in patients aged ≤20 years). Higher estimates (range: 69.4% to 88.2%) were found in 8 studies from China and South Korea, most with a follow-up period > 1 year (median: 27 to 54 months in 5 studies) (Figure 2). Incidence of CMV disease following HSCT was below 20%, with estimates uniformly distributed between 0% and 15.7% in allogeneic HSCT. According to 11 studies, reported rates of CMV recurrence ranged between 19.8% and 37.9%. Commonly reported risk factors for CMV infection or disease in HSCT recipients were high-risk CMV serostatus (R+) (hazard ratio [HR]: 2.6 and 3.7, odds ratio [OR]: 2.2 and 5.4), older age of recipients (HR for each additional year: 1.03-1.04), presence of acute or chronic graft versus host disease (HR: 1.1-2.5), haploidentical HSCT (HR: 2.7-6.4), and use of immunosuppressive agents (OR: 5.0-9.3). CMV-related mortality was reported in up to 10% of patients following HSCT (n=30 studies; period of assessment not reported). Conclusion: Relatively high rates of CMV infection, CMV disease and CMV recurrence were reported post-HSCT, with CMV-related mortality observed in up to 1 in every 10 patients. High rates of CMV infection and disease post-HSCT may impact graft outcomes and increase disease burden in patients post-transplantation.This review was funded by Takeda International AG – Singapore Branch. CMM has received honoraria from Takeda and MSD (advisory board, speaker, educational events, meeting). S-YC has served as a consultant for Takeda Pharmaceutical, and has received research support and payment for lectures from Merck Sharp & Dohme, Pfizer and Gilead. MS has received grants from F2G, Gilead, Merck and personal fees from Gilead, Pfizer, Takeda and Roche for work outside of this research; IS is an employee of Takeda Pharmaceuticals India Pvt Ltd. AS and DD are employees of Takeda International AG – Singapore Branch and hold stock options. WD has no conflicts of interest to disclose. Literature retrieval, analysis and medical writing support were provided by Aurore Bergamasco, Camille Goyer, and Yola Moride of YolaRX Consultants and funded by Takeda International AG – Singapore Branch.

Scheduled removal of central venous catheters (CVC) to prevent CVC-related bloodstream infections in patients with hematological disease or autologous stem cell transplantation: a registry-based randomized simulation-study

Although not generally recommended, scheduled central venous catheter (CVC) removal is sometimes carried out in order to reduce the CVC-related bloodstream infection (CRBSI) incidence. We conducted a simulation for scheduled CVC removal within the multicenter CRBSI registry (SECRECY). Non-tunneled jugular and subclavian CVC in patients with hematological disease or with germ cell tumors (including patients receiving autologous stem cell transplantation [SCT]) were included. Cases were randomized in a 1:1:1:1 ratio to either a simulated, scheduled CVC removal after 7, 14, and 21 days, or to non-simulated, unscheduled CVC removal (control group). The primary endpoint was definitive CRBSI incidence for a scheduled CVC removal after 14 days (dCRBSI-D14rmv). Among other, secondary endpoints were definite CRBSI incidence for a scheduled removal after 7 days (dCRBSI-D7rmv) and 21 days (dCRBSI-D21rmv). Data on 2984 CVC were included. Patients’ median age was 59 (range 16–95) years, 58.8% being male. The vast majority (98.4%) were patients with hematological malignancies. Jugular veins were the main insertion site (93.2%). dCRBSI-D14rmv was 3.10/1000 CVC days as compared to 4.15/1000 CVC days in the control group (p = 0.23). There was a significant difference between dCRBSI-D7rmv (0.86/1000 CVC days) and controls (p < 0.001), but not between dCRBSI-D21rmv (4.10/1000 CVC days) and controls (p = 0.96). Our data suggest that in patients with hematological diseases or autologous SCT recipients scheduled CVC removal after 14 days does not result in a lower CRBSI incidence compared to unscheduled removal.Trial registration: DRKS00006551, 2014/09/29, retrospectively registered.

Serologic response and safety of COVID-19 vaccination in HSCT or CAR T-cell recipients: a systematic review and meta-analysis

BackgroundPatients receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cell (CAR T-cell) therapy are immunocompromised and at high risk of viral infection, including SAR2-CoV-2 infection. However, the effectiveness and safety of COVID-19 vaccines in these recipients is not well characterized. The present meta-analysis evaluated the serologic response and safety of COVID-19 vaccines in these population.MethodsLiterature databases (MEDLINE, EMBASE, Web of Science, MedRvix and BioRvix) were searched for original studies with serologic response post COVID-19 vaccination in HSCT or CAR T-cell recipients published until July 14, 2022. The analysis included 27 observational studies with a total of 2899 patients receiving allogeneic HSCT (2506), autologous HSCT (286) or CAR T-cell therapy (107), and 683 healthy participants with serologic response data. Random effects models were used to pool the rate of serologic response to COVID-19 vaccination in HSCT or CAR T-cell recipients and odds ratio comparing with healthy controls.ResultsThe pooled seropositivity rates in HSCT and CAR T-cell recipients were 0.624 [0.506–0.729] for one dose, 0.745 [0.712–0.776] for two doses. The rates were significantly lower than those in healthy controls (nearly 100%). In subgroup analysis, CAR T-cell recipients exhibited an even lower seroconversion rate (one dose: 0.204 [0.094–0.386]; two doses: 0.277 [0.190–0.386]) than HSCT counterparts (one dose: 0.779 [0.666–0.862]; two doses: 0.793 [0.762–0.821]). The rates were comparable between autologous and allogeneic HSCT recipients. Other possible impact factors related to seropositivity were time interval between therapy and vaccination, use of immunosuppressive drugs and immune cell counts. Most vaccine-related adverse effects were mild and resolvable, comparable to general population.ConclusionsThis analysis revealed a diminished response to COVID-19 vaccines in HSCT or CAR T-cell recipients. Our findings may inform regular COVID-19 vaccination at appropriate intervals after HSCT or CAR T-cell therapy.

Practical Applications of Prolonged Private Equity Holding Periods: Six Years is the New Normal

AIM--To determine whether there are characteristic immunohistological changes in the colonic mucosa in acute graft versus host disease (GvHD). METHODS--Consecutive allogeneic (n = 11) and autologous (n = 11) bone marrow transplant recipients underwent endoscopic biopsy of sigmoid mucosa before transplant and on day 30 post-transplant. Immunohistochemical staining and quantitation of intraepithelial and lamina propria mononuclear cells were undertaken using a panel of monoclonal antibodies and a Streptavidin-biotin alkaline phosphatase staining technique. RESULTS--In the allogeneic group (nine of whom had clinical acute GvHD) there was a fivefold increase in lamina propria CD16+ mononuclear cells (3.1 +/- 4.3 to 17.0 +/- 12.2 per 100 lamina propria nucleated cells), compared with autologous transplant recipients in whom this rise was twofold (5.5 +/- 4.6 to 10.6 +/- 7.1 per 100 lamina propria nucleated cells). The CD16+ mononuclear cells had morphological appearances of tissue macrophages, but in neither the allogeneic nor autologous groups was there an increase in total macrophage numbers (CD14+). In patients with acute GvHD the lamina propria CD4+:CD8+ lymphocyte ratio fell (1.97 +/- 1.12 to 1.07 +/- 1.01), primarily because of a fall in the number of lamina propria CD4+ lymphocytes. In both allogeneic and autologous groups there was a fall in intraepithelial lymphocyte numbers, but there was no change in CD19+ (B cell), CD25+ (interleukin-2 receptor positive) or CD56+ (natural killer) cell numbers. CONCLUSION--Following bone marrow transplantation, there appears to be upregulation of lamina propria tissue macrophage CD16 (an Fc receptor for IgG), a change which is more noticeable after allogeneic transplantation and which may be related to the development of acute GvHD. In patients with acute GvHD there was a fall in the lamina propria CD4+:CD8+ lymphocyte ratio. If these changes are functionally important, they may have significant implications for understanding the pathogenesis of GvHD.

Clinical Characteristics and Outcomes of COVID-19 in Pediatric and Early Adolescent and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Cohort Study

Adult hematopoietic stem cell transplantation (HSCT) recipients are at a high risk of adverse outcomes after COVID-19. Although children have had better outcomes after COVID-19 compared to adults, data on risk factors and outcomes of COVID-19 among pediatric HSCT recipients are lacking. We describe outcomes of HSCT recipients who were ≤21 years of age at COVID-19 diagnosis and were reported to the Center for International Blood and Marrow Transplant Research between March 27, 2020, and May 7, 2021. The primary outcome was overall survival after COVID-19 diagnosis. We determined risk factors of COVID-19 as a secondary outcome in a subset of allogeneic HSCT recipients. A total of 167 pediatric HSCT recipients (135 allogeneic; 32 autologous HSCT recipients) were included. Median time from HSCT to COVID-19 was 15 months (interquartile range [IQR] 7-45) for allogeneic HSCT recipients and 16 months (IQR 6-59) for autologous HSCT recipients. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (1-179) for allogeneic and autologous HSCT recipients, respectively. Although COVID-19 was mild in 87% (n = 146/167), 10% (n = 16/167) of patients required supplemental oxygen or mechanical ventilation. The 45-day overall survival was 95% (95% confidence interval [CI], 90-99) and 90% (74-99) for allogeneic and autologous HSCT recipients, respectively. Cox regression analysis showed that patients with a hematopoietic cell transplant comorbidity index (HCT-CI) score of 1-2 were more likely to be diagnosed with COVID-19 (hazard ratio 1.95; 95% CI, 1.03-3.69, P = .042) compared to those with an HCT-CI of 0. Pediatric and early adolescent and young adult HSCT recipients with pre-HSCT comorbidities were more likely to be diagnosed with COVID-19. Overall mortality, albeit higher than the reported general population estimates, was lower when compared with previously published data focusing on adult HSCT recipients.

Neuropathy and Muscle Cramps in Autologous and Allogeneic Hematopoietic Cell Transplantation Survivors

Although autologous and allogeneic hematopoietic cell transplantation are used to treat hematologic diseases, they are associated with high morbidity and mortality. The goal of this cross-sectional study was to describe the incidence, characteristics, severity and clinical correlates of neuropathy and muscle cramps, as self-reported by hematopoietic cell transplantation survivors. We included all respondents to a survey conducted July 1, 2020, to June 30, 2021. Surveys were completed online or on-paper according to participants’ preferences; they received one reminder if no survey was received 1 month after distribution. Statistics are primarily descriptive comparing subgroups of patients. Of 4641 potentially eligible patients, 1745 responded and are included in the analysis. Participants (615 [35%] autologous, 1130 [65%] allogeneic) were a median age of 64.1 years (interquartile range [IQR] 55.2-70.8) and surveyed at a median of 11 years (IQR 4-21) after their most recent transplantation. Neuropathy symptoms were reported by 65% of autologous recipients, 66% of allogeneic transplant recipients with current chronic graft versus host disease (GVHD), and 45% of allogeneic recipients who never developed chronic GVHD. Muscle cramps were reported by 56% of autologous recipients, and 52% of allogeneic recipients and were rated as “very painful” by nearly half of patients who experienced them. These results suggest that neuropathy symptoms and muscle cramps are much more prevalent among survivors after hematopoietic cell transplantation than previously recognized. Better approaches for prevention and treatment of these bothersome complications are needed.

Energy Sources for Exosome Communication in a Cancer Microenvironment.

Simple SummaryExosomal communication in the tumor microenvironment plays a crucial role in cancer development, progression, and metastasis, and is achieved by either short-distance communication with neighboring cells or long-distance communication with distant organs. Nevertheless, how exosomes gain energy to establish such communication and the different sources of energy are unclear. Recently, a handful of studies have demonstrated the presence of mitochondria, adenosine triphosphate, and glycolytic enzymes, which may serve as potential energy sources for exosomes. This review clarifies how exosomes maintain their structural integrity and stability during their intracellular communication, and reviews evidence of their energy source. Exosomes are crucial extracellular vesicles (EVs) with a diameter of approximately 30–200 nm. They are released by most cell types in their extracellular milieu and carry various biomolecules, including proteins and nucleic acids. Exosomes are increasingly studied in various diseases, including cancer, due to their role in local and distant cell–cell communication in which they can promote tumor growth, cancer progression, and metastasis. Interestingly, a tremendous number of exosomes is released by malignant cancer cells, and these are then taken up by autologous and heterologous recipient stromal cells such as immune cells, cancer stem cells, and endothelial cells. All these events demand an enormous amount of energy and require that exosomes remain stable while having the capacity to reach distant sites and cross physical barriers. Nevertheless, there is a dearth of research pertaining to the energy sources of exosomes, and questions remain about how they maintain their motility in the tumor microenvironment (TME) and beyond. Moreover, exosomes can produce adenosine triphosphate (ATP), an important energy molecule required by all cells, and mitochondria have been identified as one of the exosomal cargoes. These findings strengthen the prospect of exosomal communication via transfer of mitochondria and the bioenergetics of target recipient cells. In the TME, the accumulation of ATP and lactate may facilitate the entry of exosomes into cancer cells to promote metastasis, as well as help to target cancer cells at the tumor site. This review highlights how exosomes obtain sufficient energy to thrive in the TME and communicate with distant physiological destinations.

Trends in Late Mortality and Life Expectancy After Autologous Blood or Marrow Transplantation Over Three Decades: A BMTSS Report.

We determined trends in life expectancy and cause-specific late mortality after autologous blood or marrow transplantation (BMT) performed over a 30-year period, using the BMT Survivor Study. We constructed a cohort of 4,702 individuals with hematologic neoplasms who lived ≥ 2 years after autologous BMT performed between 1981 and 2014 at three transplant centers. The end of follow-up was April 19, 2021. The primary exposure variable was autologous BMT performed in four eras: 1981-1999; 2000-2005; 2006-2010; and 2011-2014. Vital status and cause of death were obtained from National Death Index Plus program and Accurinct databases. The median age at BMT was 53 years (range, 0-78 years), 58.7% were male, 67.8% were non-Hispanic White, and 28.3% had undergone transplantation between 2011 and 2014. Autologous BMT recipients experienced a 7-year reduction in life expectancy. The adjusted hazard of 5-year all-cause mortality declined over the four eras (reference: 1981-1999; hazard ratio [HR]2000-2005 = 0.77; 95% CI, 0.62 to 0.94; HR2006-2010 = 0.64; 95% CI, 0.51 to 0.79; HR2011-2014 = 0.56; 95% CI, 0.45 to 0.71; Ptrend < .001), as did years of life lost (5.0 years to 1.6 years). The reduction in all-cause mortality was most pronounced among those transplanted for Hodgkin lymphoma or plasma cell dyscrasias, but was not observed among those transplanted for non-Hodgkin lymphoma or those conditioned with total-body irradiation. We also observed a decline in late deaths because of infection (Ptrend < .0001; primarily for BMTs before 2006) and subsequent neoplasms (Ptrend = .03; confined to decline in therapy-related myeloid neoplasm-related mortality) but not because of cardiovascular or renal disease. Late mortality among autologous BMT recipients has declined over a 30-year period. However, ongoing efforts are needed to mitigate development of infections, subsequent neoplasms, and cardiovascular and renal disease to further reduce late mortality.

184 - Prevalence and Predictors of Pre-HCT Frailty in Autologous and Allogeneic Hematopoietic Cell Transplant Recipients

184 - Prevalence and Predictors of Pre-HCT Frailty in Autologous and Allogeneic Hematopoietic Cell Transplant Recipients