Blood Or Marrow Transplantation Research Articles

Pre-frailty after blood or marrow transplantation and the risk of subsequent mortality.

We examined the prevalence, risk factors, and association between pre-frailty and subsequent mortality after blood or marrow transplantation (BMT). Study participants were drawn from the BMT Survivor Study (BMTSS) and included 3346 individuals who underwent BMT between 1974 and 2014 at one of three transplant centers and survived ≥2 years post-BMT. Participants completed the BMTSS survey at a median of 9 years from BMT and were followed for subsequent mortality for a median of 5 years after survey completion. Closest-age and same-sex biological siblings also completed the survey. Previously published self-reported indices (exhaustion, weakness, low energy expenditure, slowness, unintentional weight loss) classified participants as non-frail (0-1 indices) or pre-frail (2 indices). National Death Index was used to determine vital status and cause of death. Overall, 626 (18.7%) BMT survivors were pre-frail. BMT survivors had a 3.2-fold higher odds of being pre-frail (95% CI = 1.9-5.3) compared to siblings. Compared to non-frail survivors, pre-frail survivors had higher hazards of all-cause mortality (adjusted hazard ratio [aHR] = 1.6, 95% CI = 1.4-2.0). Female sex, pre-BMT radiation, smoking, lack of exercise, anxiety, and severe/life-threatening chronic health conditions were associated with pre-frailty. The novel association between pre-frailty and subsequent mortality provides evidence for interventions as pre-frail individuals may transition back to their robust state.

Late morbidity and mortality after autologous blood or marrow transplantation for lymphoma in children, adolescents and young adults—a BMTSS report

We determined the risk of late morbidity and mortality after autologous blood or marrow transplantation (BMT) for lymphoma performed before age 40. The cohort included autologous BMT recipients who had survived ≥2 years after transplantation (N = 583 [HL = 59.9%; NHL = 40.1%]) and a comparison cohort (N = 1070). Participants 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. Logistic regression estimated the odds of grade 3–4 conditions in survivors vs. comparison subjects. Proportional subdistribution hazards models identified predictors of grade 3–5 conditions among BMT recipients. Median age at BMT was 30.0 years (range: 2.0–40.0) and median follow-up was 9.8 years (2.0–32.1). Survivors were at a 3-fold higher adjusted odds for grade 3–4 conditions (95% CI = 2.3–4.1) vs. comparison subjects. Factors associated with grade 3–5 conditions among BMT recipients included age at BMT (>30 years: adjusted hazard ratio [aHR] = 2.31; 95% CI = 1.27–4.19; reference: ≤21 years), pre-BMT radiation (aHR = 1.52; 95% CI = 1.13–2.03; reference: non-irradiated), and year of BMT (≥2000: aHR = 0.54; 95% CI = 0.34–0.85; reference: <1990). The 25 years cumulative incidence of relapse-related and non-relapse-related mortality was 18.2% and 25.9%, respectively. The high risk for late morbidity and mortality after autologous BMT for lymphoma performed at age <40 calls for long-term anticipatory risk-based follow-up.

Symptom Cluster (sleep, fatigue, anxiety, and depression) and Cognitive Functioning in Hematologic Malignancy Patients Treated with Blood or Marrow Transplant (BMT)

Symptom Cluster (sleep, fatigue, anxiety, and depression) and Cognitive Functioning in Hematologic Malignancy Patients Treated with Blood or Marrow Transplant (BMT)

Health care utilization by long-term survivors of blood or marrow transplantation-A Bone Marrow Transplant Survivor Study report.

Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long-term BMT survivors were evaluated. Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT-related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care utilization (≥7 physician visits during the 2 years before the study). Clinical characteristics and therapeutic exposures were abstracted from medical records. In this cohort of 3342 BMT survivors (52% allogeneic), the prevalence of health care utilization declined over time since BMT for both allogeneic and autologous BMT survivors, such that among those who had survived ≥20 years, only 49%-53% had undergone routine checkups, 37%-38% reported BMT-related visits, and 28%-29% reported transplant/cancer center visits. The presence of severe/life-threatening conditions and chronic graft-vs-host disease increased the odds of health care utilization across all domains. Lower education, lack of insurance, and Hispanic ethnicity were associated with a lower prevalence of routine checkups and/or transplant/cancer center visits. Lower income increased the odds of ER visits but reduced the odds of hospitalizations or high health care utilization. This study identified vulnerable populations of long-term BMT survivors who would benefit from specialized risk-based anticipatory care to reduce high health care utilization, ER visits, and hospitalizations.

Risky health behaviors and subsequent late mortality after blood or marrow transplantation: a BMTSS report

AbstractWe examined the association between risky health behaviors (smoking, heavy alcohol consumption, and lack of vigorous physical activity) and all-cause and cause-specific late mortality after blood or marrow transplantation (BMT) to understand the role played by potentially modifiable risk factors. Study participants were drawn from the BMT Survivor Study (BMTSS) and included patients who received transplantation between 1974 and 2014, had survived ≥2 years after BMT, and were aged ≥18 years at study entry. Survivors provided information on sociodemographic characteristics, chronic health conditions, and health behaviors. National Death Index was used to determine survival and cause of death. Multivariable regression analyses determined the association between risky health behaviors and all-cause mortality (Cox regression) and nonrecurrence-related mortality (NRM; subdistribution hazard regression), after adjusting for relevant sociodemographic, clinical variables and therapeutic exposures. Overall, 3866 participants completed the BMTSS survey and were followed for a median of 5 years to death or 31 December 2021; and 856 participants (22.1%) died after survey completion. Risky health behaviors were associated with increased hazard of all-cause mortality (adjusted hazard ratio [aHR] former smoker, 1.2; aHR current smoker, 1.7; reference, nonsmoker; aHR heavy drinker, 1.4; reference, nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity) and NRM (aHR former smoker, 1.3; aHR current smoker, 1.6; reference, nonsmoker; aHR heavy drinker, 1.4; reference: nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity). The association between potentially modifiable risky health behaviors and late mortality offers opportunities for development of interventions to improve both the quality and quantity of life after BMT.

Prediction of Coronary Heart Disease Events in Blood or Marrow Transplantation Recipients.

The long-term risk of coronary heart disease (CHD) and clinical models that predict this risk remain understudied in blood or marrow transplantation (BMT) recipients. This study sought to examine the risk of CHD after BMT and identify the associated risk factors. Participants included patients transplanted between 1974 and 2014 at City of Hope, University of Minnesota, or University of Alabama at Birmingham and those who survived≥2 years after BMT. Multivariable logistic regression models assessed CHD risk in BMT survivors compared with a sibling cohort. A self-reported questionnaire and medical records provided information regarding sociodemographics, comorbidities, and therapeutic exposures, which were used to develop a CHD risk prediction nomogram. Overall, 6,677 BMT recipients participated; the mean age at BMT was 43.9 ± 17.7 years, 58.3% were male, and 73.3% were non-Hispanic Whites. The median length of follow-up was 6.9 years (range: 2-46.2 years) from BMT. CHD was reported in 249 participants, with a 20-year cumulative incidence of 5.45% ± 0.39%. BMT survivors had a 1.6-fold greater odds of CHD compared with a sibling cohort (95% CI: 1.09-2.40). A nomogram was then developed to predict the risk of CHD at 10 and 20 years after BMT including age at BMT (HR: 1.06/y; 95% CI: 1.04-1.08), male sex (HR: 1.89; 95% CI: 1.15-3.11), a history of smoking (HR: 1.61; 95% CI: 1.01-2.58), diabetes (HR: 2.45; 95% CI: 1.23-4.89), hypertension (HR: 2.02; 95% CI: 1.15-3.54), arrhythmia (HR: 1.90; 95% CI: 0.89-4.06), and pre-BMT chest radiation (yes vs no: HR: 2.83; 95% CI: 1.20-6.67; unknown vs no: HR: 0.88; 95% CI: 0.34-2.28). The C-statistic was 0.77 in the test set (95% CI: 0.70-0.83). This study identified BMT recipients at high risk for CHD, informing targeted screening for early detection and aggressive control of risk factors.

Risk of COVID-19 infection in long-term survivors of blood or marrow transplantation: a BMTSS report.

There is limited information regarding COVID-19 in long-term blood or marrow transplant (BMT) survivors. We leveraged the BMT Survivor Study (BMTSS) to address this gap. BMTSS included patients who underwent BMT at 1 of 3 sites in the United States between 1974 and 2014 and survived ≥2 years after BMT. A sibling cohort serves as a non-BMT comparison group. Participants (2430 BMT survivors; 780 non-BMT participants) completed the BMTSS survey between October 2020 and November 2021 about COVID-19 testing, risk mitigation behaviors, morbidity, and health care use. Median age at BMT was 46 years (range, 0-78 years) and median follow-up since BMT was 14 years (6-46 years); 76% were non-Hispanic White, 54% had received allogeneic BMT. The risk of COVID-19 infection was comparable for BMT survivors vs non-BMT participants (15-month cumulative incidence, 6.5% vs 8.1%; adjusted odd ratio [aOR]= 0.93; 95% confidence interval [CI], 0.65-1.33; P= .68). Among survivors, being unemployed (aOR 1.90; 95%CI, 1.12-3.23; P= .02; reference: retired) increased the odds of infection; always wearing a mask in public was protective (aOR= 0.49; 95%CI, 0.31-0.77; P= .002; reference: not always masking). When compared with COVID-positive non-BMT participants, COVID-positive BMT survivors had higher odds of hospitalization (aOR= 2.23; 95%CI, 0.99-5.05; P= .05); however, the odds of emergency department visits were comparable (aOR= 1.60; 95%CI= 0.71-3.58; P= .25). COVID-19 infection status did not increase the odds of hospitalization among BMT survivors (aOR=1.32; 95%CI= 0.89-1.95; P= .17) but did increase the odds of emergency department visits (aOR= 2.63; 95%CI, 1.74-3.98; P <.0001). These findings inform health care providers about the management of care for long-term BMT survivors during the ongoing pandemic.

Adherence and satisfaction with remote cognitive training in blood or marrow transplant (BMT) survivors: The cognitive training and attitudes towards genetics (cTAG) study.

7009 Background: Cognitive impairment is prevalent in hematologic cancer survivors treated with BMT. There is a need for remote, accessible, and engaging interventions in order to mitigate adverse cognitive outcomes following treatment. We report on feasibility, satisfaction and preliminary efficacy of a remote cognitive training intervention in BMT survivors. Methods: Participants enrolled in the cTAG study were randomized to either using the online brain games Lumosity program daily for 12 weeks, or the waitlist arm. Cognitive function was assessed using a comprehensive battery covering executive function, processing speed, attention, memory and learning domains, and PROMIS Short Form4a for cognitive complaints. Participants’ satisfaction was measured using an exit survey. Standardized T-scores (mean: 50; standard deviation: 10), were used for domain-specific outcomes. An intention-to-treat analysis was used to model the change in cognition at 12 weeks compared to baseline, between study arms, controlling for baseline cognitive reserve, age, sex and race/ethnicity to enhance estimate precision. Results: Feasibility: 150 eligible patients were approached, 88 (58.7%) consented and 71 (80.7%) were randomized. Fifty-five patients completed the study (28 on active and 27 on waitlist arm). Post-randomization attrition rate was 19.7%. Median age at time of test was 58y (range: 27-74); 60% males, 83.6% Non-Hispanic White and 16.4% non-Hispanic Black, and 49% with low cognitive reserve. There were no significant differences between study arms. Adherence on active arm: Median of 87.5% for 4.9 days/week and 10/12 weeks. Preliminary Efficacy: Compared to the waitlist arm, scores improved for the active arm in attention (2.14 points, SE=1.01, p-value=0.039) and memory domains (5.63, SE=2.40, p-value=0.02). There was no significant change on cognitive complaints between the two arms. Satisfaction: Overall 78.2% of patients had no prior experience with cognitive training, 58.7% felt it helped their recovery, 82.6% found time commitment reasonable, 87% found it easy to follow, fun, engaging and appropriately challenging. The intervention had a 91.3% satisfaction rate; 73.9% indicating they would continue training and 87% would recommend it to others. Participants’ perceived benefit from training was highest for attention (89.1%), memory (73.9%), and visual tasks (69.6%). Only 11% of participants perceived benefits for real word tasks. Conclusions: The intervention was feasible, favorably rated, and associated with both perceived and objective improvements in attention and memory domains. Remote cognitive training carries several advantages for BMT patients including early and convenient at home administration supporting its clinical utility and potential long-term adoption following treatment. Clinical trial information: NCT03094026 .

Malignant Neoplasms of the Gastrointestinal Tract After Blood or Marrow Transplant

Survivors of blood or marrow transplant (BMT) are at increased risk of subsequent malignant neoplasms (SMNs). Cancers of the gastrointestinal (GI) system are of special interest because their clinical behavior is often aggressive, necessitating early detection by increasing awareness of high-risk populations. To describe the risk of SMNs in the GI tract after BMT. A cohort study of 6710 individuals who lived at least 2 years after BMT performed between January 1, 1974, and December 31, 2014, at City of Hope, University of Minnesota, or University of Alabama at Birmingham. End of follow-up was March 23, 2020. Data analysis was performed between September 1, 2022, and September 30, 2022. Demographic and clinical factors; therapeutic exposures before or as part of BMT. Development of SMNs in the GI tract after BMT. Participants self-reported SMNs in the GI tract; these were confirmed with pathology reports, medical records, or both. For deceased patients, death records were used. Standardized incidence ratios determined excess risk of SMNs in the GI tract compared with that of the general population. Fine-Gray proportional subdistribution hazard models assessed the association between risk factors and SMNs in the GI tract. The cohort of 6710 individuals included 3444 (51.3%) autologous and 3266 (48.7%) allogeneic BMT recipients. A total of 3917 individuals (58.4%) were male, and the median age at BMT was 46 years (range, 0-78 years). After 62 479 person-years of follow-up, 148 patients developed SMNs in the GI tract. The standardized incidence ratios for developing specific SMNs ranged from 2.1 for colorectal cancer (95% CI, 1.6-2.8; P < .001) to 7.8 for esophageal cancer (95% CI, 5.0-11.6; P < .001). Exposure to cytarabine for conditioning (subdistribution hazard ratio [SHR], 3.1; 95% CI, 1.5-6.6) was associated with subsequent colorectal cancer. Compared with autologous BMT recipients, allogeneic BMT recipients with chronic graft-vs-host disease were at increased risk for esophageal cancer (SHR, 9.9; 95% CI, 3.2-30.5). Conditioning with etoposide (SHR, 2.0; 95% CI, 1.1-3.5) and pre-BMT anthracycline exposure (SHR, 5.4; 95% CI, 1.3-23.4) were associated with an increased risk of liver cancer compared with no exposure to the respective agents. The findings of this cohort study are relevant for oncologists and nononcologists who care for the growing number of survivors of transplant. Awareness of subgroups of survivors of BMT at high risk for specific types of SMNs in the GI tract may influence recommendations regarding modifiable risk factors, as well as individualized screening.

Financial Burden in Blood or Marrow Transplantation Survivors During the COVID-19 Pandemic: A BMTSS Report.

The financial burden experienced by blood or marrow transplant (BMT) survivors during the COVID-19 pandemic remains unstudied. We evaluated the risk for high out-of-pocket medical costs and associated financial burden experienced by BMT survivors and a sibling comparison group during the COVID-19 pandemic. This study included 2,370 BMT survivors and 750 siblings who completed the BMT Survivor Study survey during the pandemic. Participants reported employment status, out-of-pocket medical costs, and financial burden. Medical expenses ≥ 10% of the annual household income constituted high out-of-pocket medical costs. Logistic regression identified factors associated with high out-of-pocket medical costs and financial burden. BMT survivors were more likely to incur high out-of-pocket medical costs (11.3% v 3.1%; adjusted odds ratio [aOR], 2.88; 95% CI, 1.84 to 4.50) than the siblings. Survivor characteristics associated with high out-of-pocket medical costs included younger age at study (aORper_year_younger_age, 1.02; 95% CI, 1.00 to 1.03), lower prepandemic annual household income and/or education (< $50,000 US dollars and/or < college graduate: aOR, 1.96; 95% CI, 1.42 to 2.69; reference: ≥ $50,000 in US dollars and ≥ college graduate), > 1 chronic health condition (aOR, 2.82; 95% CI, 2.00 to 3.98), ≥ 1 hospitalization during the pandemic (aOR, 2.11; 95% CI, 1.53 to 2.89), and being unemployed during the pandemic (aOR, 1.52; 95% CI, 1.06 to 2.17). Among BMT survivors, high out-of-pocket medical costs were significantly associated with problems in paying medical bills (aOR, 10.57; 95% CI, 7.39 to 15.11), deferring medical care (aOR, 4.93; 95% CI, 3.71 to 6.55), taking a smaller dose of medication than prescribed (aOR, 4.99; 95% CI, 3.23 to 7.70), and considering filing for bankruptcy (aOR, 3.80; 95% CI, 2.14 to 6.73). BMT survivors report high out-of-pocket medical costs, which jeopardizes their health care and may affect health outcomes. Policies aimed at reducing financial burden in BMT survivors, such as expanding access to patient assistance programs, may mitigate the negative health consequences.

Potentially inappropriate medications in geriatric blood or marrow transplantation (BMT) survivors: A BMT Survivor Study report.

Blood or marrow transplantation (BMT) is increasingly offered to older individuals with hematologic malignancies. The high prevalence of chronic health conditions in such individuals necessitates use of multiple medications. Beers Criteria represent a list of potentially inappropriate medications (PIMs) shown to increase the risk of health problems in the elderly. We sought to determine the prevalence and predictors of PIM use in older BMT survivors and identify associations with health problems. Study participants were drawn from the BMT Survivor Study, a cohort study of patients transplanted at three US transplant centers between 1974 and 2014 and surviving ≥2years. For this report, the survivors were aged ≥65 years. Siblings served as a comparison group. Participants self-reported sociodemographics, chronic health conditions, and medication use. Logistic regression analyses identified predictors of PIM use and associations with health problems. Overall, PIM use was comparable between BMT survivors (49.4%) and siblings (49.3%) (odds ratio [OR]=0.9; 95% CI,0.7-1.2); however, BMT survivors were more likely to use >1 PIM (17.4% vs. 12.4%; OR=1.5; 95% CI,1.01-2.4) and central nervous system-related PIMs (8.3% vs. 4.3%; OR=2.18; 95% CI,1.17-4.09). Predictors of PIM use included presence of severe/life-threatening chronic health conditions (OR=1.5; 95% CI,1.1-2.0), and chronic graft versus host disease (OR=1.7; 95% CI,1.1-2.7). Survivors taking >1 PIM reported more issues with vertigo (OR=2.3; 95% CI,1.1-4.7), balance (OR=2.6; 95% CI,1.7-4.1), faintness/dizziness (OR=2.8; 95% CI,1.8-4.6), and personal care (OR=4.5; 95% CI,1.4-14.8). This study shows the health problems associated with PIM use and identifies vulnerable populations at higher risk for PIM use, providing evidence for caution in using PIMs in high-risk populations.

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

Processing Speed Improvement in Hematologic Cancer Survivors Treated with Allogeneic Blood or Marrow Transplantation- a Randomized Online Cognitive Training Intervention

Introduction: Patients with hematologic malignancies are at increased risk of cognitive impairment following allogeneic blood or marrow transplantation (BMT) when compared with healthy controls. Cognitive deficits persist for at least 3-5 years in 40% of BMT survivors (Sharafeldin et al., J Clin Oncol, 2018); which negatively impacts self-management, relationships, quality of life, societal reintegration and overall survival. There is, thus, an unmet need to test interventions to improve cognitive function in BMT survivors. Here we report on the preliminary efficacy of a randomized wait-listed controlled trial at a single center, using home-based computerized cognitive training, in patients with hematologic malignancy treated with allogeneic BMT. We hypothesized that computerized cognitive training will result in significantly higher cognitive function scores in BMT recipients on the active intervention arm when compared with the waitlist arm. Methods: We prospectively enrolled a cohort of 53 adult (≥21y) allogeneic BMT recipients. Eligible patients were at least 3 months post-BMT at time of enrollment. The intervention used the Lumosity online cognitive training program for 12 weeks. The waitlist arm was offered the training program post-intervention. Cognitive function was measured at baseline and 12 weeks using standardized neuropsychological tests assessing executive function, attention, processing speed and memory cognitive domains. Study personnel were blinded to randomization assignment at time of baseline cognitive assessment. Participants' usage of the program was monitored to measure adherence to the intervention. Feasibility parameters included participation, completion, and attrition rates. We modeled the change in score between baseline and post-intervention by randomization group (active vs waitlist) as the main independent factor adjusted for baseline intervention test score as primary covariate. Models were further adjusted for cognitive reserve, age, sex, race, fatigue, sleep, depression, anxiety, and receipt of radiation. Results: The intervention had a 59% consent rate and a 79% randomization rate, 27 patients were randomized to active arm and 26 to waitlist arm. Mean age was 55y (SD=12.2y), 57.7% males, 84.6% non-Hispanic white; 57.7% with acute leukemia and 23% with myelodysplastic syndrome. Post-randomization attrition rate was 19.7% (17.6% on active arm; 20.5% on waitlist arm). Median adherence on the active arm for patients who completed 12 weeks of training was 87.5%; patients used the program for a median of 4.9 days/week and a median of 10/12 weeks. Compared to waitlist arm, we found improved scores for the active arm in global impairment deficit scores (0.08, SE=0.038, p-value=0.03) and in processing speed T-scores (3.43, SE=1.42, p-value=0.02). Conclusion: Our pilot study provides evidence for the feasibility and high adherence to a home-based cognitive training intervention in BMT survivors. Cognitive training as a compensatory intervention may be most efficacious in improving processing speed, however, additional interventions may be needed to further target other cognitive domains, e.g., executive function, attention, or memory domains.

Neighborhood disadvantage, health status, and health care utilization after blood or marrow transplant: BMTSS report

AbstractLiving in a disadvantaged neighborhood is associated with poor health outcomes. Blood or Marrow Transplant (BMT) survivors remain at risk of chronic health conditions requiring anticipatory management. We hypothesized that among BMT survivors, neighborhood disadvantage was associated with poor self-reported routine health care utilization and health. We leveraged data from BMTSS – a retrospective cohort study examining long-term outcomes among individuals surviving ≥2 y following BMT at three institutions between 1974 and 2014. Participants in this analysis completed the BMTSS survey (sociodemographics; chronic health conditions; time since routine check-up; self-reported health). The Area Deprivation Index (ADI) represented neighborhood disadvantage; this composite indicator of 17 census measures is a percentile rank (0 = least deprived to 100 = most deprived). Multivariable ordered logit regression adjusted for clinical factors and individual-level sociodemographics, modeling associations between ADI, time since routine check-up, and self-reported health. Among 2,857 survivors, median ADI was 24 (interquartile range: 10-46). Adjusting for self-reported individual-level socioeconomic indicators and chronic health conditions, patients in more disadvantaged neighborhoods had higher odds of reporting longer intervals since routine check-up (ORADI_continuous = 1.007, P < .001) and poorer health status (controlling for time since check-up; ORADI_continuous = 1.005, P = .003). Compared with patients living in the least disadvantaged neighborhood (ADI = 1), patients in the most disadvantaged neighborhood (ADI = 100), had twice the odds (ORADI = 1.007^99 = 2.06) of reporting no routine visits and 1.65-times the odds of reporting poor health (ORADI = 1.005^99 = 1.65). In BMT survivors, access to health care and health status are associated with area disadvantage. These findings may inform strategies to address long-term care coordination and retention for vulnerable survivors.

Burden of Long-Term Morbidity Borne by Survivors of Acute Myeloid Leukemia Treated With Blood or Marrow Transplantation: The Results of the BMT Survivor Study.

PURPOSEBlood or marrow transplantation (BMT) is an integral part of consolidation and/or salvage therapy for patients with acute myeloid leukemia (AML). With the growing population of AML survivors, there is a need to understand the quality of their survival.MATERIALS AND METHODSThis multisite study included 1,369 2-year survivors who underwent BMT for AML between 1974 and 2014 at age ≥ 21 years and 1,310 siblings. Using Common Terminology Criteria for Adverse Events, severe/life-threatening and fatal chronic health conditions were identified. Multivariable regression analysis was used to compare the risk of severe/life-threatening conditions and health status between survivors and siblings, and to identify risk factors for health conditions among BMT survivors.RESULTSThe prevalence of severe/life-threatening conditions was 54.9% in BMT survivors compared with 28.5% in siblings (P < .001), yielding 3.8-fold higher odds of severe/life-threatening conditions (95% CI, 3.1 to 4.7) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (odds ratio [OR], 3.8; 95% CI, 2.8 to 5.1), activity limitation (OR, 3.7; 95% CI, 3.0 to 4.5), and functional impairment (OR, 2.9; 95% CI, 2.3 to 3.6). Among BMT recipients, the 20-year cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft-versus-host disease was associated with a higher risk of pulmonary disease (hazard ratio [HR], 3.1; 95% CI, 1.0 to 9.3), cataract (HR, 2.6; 95% CI, 1.4 to 3.8), and venous thromboembolism (HR, 2.3; 95% CI, 1.3 to 4.7). Relapse-related mortality (RRM) plateaued at 30%, whereas non-RRM increased to 50% at 30 years.CONCLUSIONThe burden of severe/life-threatening conditions is substantially higher in BMT recipients when compared with an unaffected comparison group, contributing to an increasing incidence of non-RRM over time. Chronic graft-versus-host disease was an important risk factor for severe/life-threatening/fatal conditions among BMT recipients, informing the need for close monitoring to anticipate and manage morbidity.

Mismatched donor transplantation with post-transplantation cyclophosphamide for advanced cutaneous T-cell lymphoma: A single-center experience.

e19045 Background: Mismatched blood or marrow transplantation (BMT) using post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis has not been well-studied in CTCL. Methods: We analyzed all patients above 18 years old with relapsed/refractory CTCL undergoing mismatched alloBMT. Primary endpoints included disease-free survival (DFS) and overall survival (OS). Secondary endpoints included time to neutrophil and platelet recovery, GvHD outcomes, and day +30 and day +60 donor chimerism. Results: From 2003-2020, 8 patients with relapsed CTCL underwent mismatched related (n=7) or mismatched unrelated (n=1) BMT. Mean age was 50 years (range 30-62); median time from diagnosis was 2 years (range 1.3-11.4). All had received prior treatment for their disease; two (25%) had received immune checkpoint inhibitors. Four (50%) were in partial response and 4 (50%) were in complete remission prior to BMT. Six received bone marrow grafts. Two received mobilized peripheral blood. Five (62.5%) achieved full donor chimerism by day 30 after BMT; 6 (75%) had achieved full donor chimerism by day 60 after BMT. One patient failed to engraft. Mean time to neutrophil recovery was 17.3 days (range 17-45); mean time to platelet recovery was 28.4 days (range 11-69). Median DFS was 11.3 months (95% confidence interval 2.6 months-not reached). Median OS was not reached. One patient developed grade 1 acute GvHD, and 2 patients developed mild chronic GvHD. There were no instances of transplantation-related mortality (TRM). At 1 year post-BMT, 4 patients had relapsed (50%), and no patients had died. At 3 years post-BMT, 7 patients had relapsed (87.5%), and 1 patient had died (12.5%). Conclusions: In our preliminary retrospective study, partially mismatched BMT with PTCy-based GVHD prophylaxis for advanced-stage CTCL was associated with minimal GvHD, no TRM, and good long-term survival. Investigation into relapse reduction is warranted.[Table: see text]

Major risk factors associated with severe COVID-19 outcomes in patients with multiple myeloma: Report from the National COVID-19 Cohort Collaborative (N3C).

8008 Background: Patients with multiple myeloma (MM), an age-dependent neoplasm of antibody-producing plasma cells, have compromised immune systems due to multiple factors that may increase the risk of severe COVID-19. The NCATS’ National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multi-center cohort of ̃12M COVID-19 cases and controls nationwide. In this study, we aim to analyze risk factors associated with COVID-19 severity and death in MM patients using the N3C database. Methods: Our cohort included MM patients within the N3C registry diagnosed with COVID-19 based on positive PCR or antigen tests or ICD-10–CM. The outcomes of interest include all-cause mortality (including discharge to hospice) during the index encounter, and clinical indicators of severity (hospitalization/ED visit, use of mechanical ventilation, or extracorporeal membrane oxygenation/ECMO). Results: As of 09/10/2021, the N3C registry included 690371 cancer patients, out of which 17791 were MM patients (4707 were COVID-19+). The mean age at diagnosis was 65.9yrs, 57.6% were &gt;65yo, 46.4% were females, and 21.8% were Blacks. 25.6% had a Charlson Comorbidity Index (CCI) score of ≥2. 55.6% required an inpatient or ED visit, and 3.65% required invasive ventilation. 11.4% developed acute kidney injury during hospitalization. Multivariate logistic regression analysis showed histories of pulmonary disease (OR 2.2; 95%CI: 1.7-2.8), renal disease (OR 1.8; 95%CI: 1.4-2.4), and black race (p&lt;0.001) were associated with higher risk of severity. Interestingly, smoking status was significantly associated with a lower risk of severity (OR 0.7; 95%CI: 0.5-0.9). Further, protective association was also observed between COVID-19 severity and blood or marrow transplant (BMT) (OR 0.52; 95%CI: 0.4-0.7), daratumumab therapy (OR 0.64; 95%CI: 0.42-0.99) and COVID-19 vaccination (OR 0.28; 95%CI: 0.18-0.44). IMiDs were associated increase in the risk of COVID-19 severity (OR 2.1; 95%CI: 1.6-2.7). 2.3% of N3C-myeloma COVID-19+ patients died within the first 10 days, while 4.95% died within 30 days of COVID-19 hospitalization. Overall, the survival probability was 90.5% across the course of the study. Multivariate cox proportional hazard model showed that CCI score ≥2 (HR 4.4; 95%CI: 2.2-8.8), hypertension (HR 1.6; 95%CI: 1.02-2.4), IMiD (HR 2.6; 95%CI: 1.8-3.8) and proteasome inhibitor (HR 1.6; 95%CI: 1.1-2.5) therapy were associated with worse survival. COVID-19 vaccination (HR 0.195; 95%CI: 0.09-0.45) and BMT (HR 0.65; 95%CI: 0.4-0.995) were associated with lower risk of death. Conclusions: We have identified previously unpublished potential risk factors for COVID-19 severity and death in MM as well as validated some published ones. To the best of our knowledge, this is the largest nationwide study on multiple myeloma patients with COVID-19.

Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation.

Cognitive impairment is prevalent in blood or marrow transplantation (BMT) recipients, albeit with inter-individual variability. We conducted a genome-wide association study of objective cognitive function assessed longitudinally in 239 adult BMT recipients for discovery and replicated in an independent cohort of 540 BMT survivors. Weighted genome-wide polygenic risk scores (PRS) were constructed using linkage disequilibrium pruned significant SNPs. Forty-four genome-wide significant SNPs were identified using additive (n = 3); codominant (n = 20) and genotype models (n = 21). Each additional copy of a risk allele was associated with a 0.28-point (p = 1.07 × 10-8) to a 1.82-point (p = 6.7 × 10-12) increase in a global deficit score. We replicated two SNPs (rs11634183 and rs12486041) with links to neural integrity. Patients in the top PRS quintile were at increased risk of cognitive impairment in discovery (RR = 1.95, 95%CI: 1.28-2.96, p = 0.002) and replication cohorts (OR = 1.84, 95%CI, 1.02-3.32, p = 0.043). Associations were stronger among individuals with lowest clinical risk for cognitive impairment. These findings support potential utility of PRS-based risk classification in the development of targeted interventionsaimed at improving cognitive outcomes in BMT survivors.

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.

Outcome of donor-derived TAA-T cell therapy in patients with high-risk or relapsed acute leukemia post allogeneic BMT

AbstractPatients with hematologic malignancies relapsing after allogeneic blood or marrow transplantation (BMT) have limited response to conventional salvage therapies, with an expected 1-year overall survival (OS) of <20%. We evaluated the safety and clinical outcomes following administration of a novel T-cell therapeutic targeting 3 tumor-associated antigens (TAA-T) in patients with acute leukemia who relapsed or were at high risk of relapse after allogeneic BMT. Lymphocytes obtained from the BMT donor were manufactured to target TAAs WT1, PRAME, and survivin, which are over-expressed and immunogenic in most hematologic malignancies. Patients received TAA-T infusions at doses of 0.5 to 4 × 107/m2. Twenty-three BMT recipients with relapsed/refractory (n = 11) and/or high-risk (n = 12) acute myeloid leukemia (n = 20) and acute lymphoblastic leukemia (n = 3) were infused posttransplant. No patient developed cytokine-release syndrome or neurotoxicity, and only 1 patient developed grade 3 graft-versus-host disease. Of the patients who relapsed post-BMT and received bridging therapy, the majority (n = 9/11) achieved complete hematologic remission before receiving TAA-T. Relapsed patients exhibited a 1-year OS of 36% and 1-year leukemia-free survival of 27.3% post–TAA-T. The poorest prognosis patients (relapsed <6 months after transplant) exhibited a 1-year OS of 42.8% postrelapse (n = 7). Median survival was not reached for high-risk patients who received preemptive TAA-T posttransplant (n = 12). Although as a phase 1 study, concomitant antileukemic therapy was allowed, TAA-T were safe and well tolerated, and sustained remissions in high-risk and relapsed patients were observed. Moreover, adoptively transferred TAA-T detected by T-cell receptor V-β sequencing persisted up to at least 1 year postinfusion. This trial was registered at clinicaltrials.gov as #NCT02203903.