Search

Background Late mortality was investigated in patients with chronic myelogenous leukemia (CML) who underwent blood or bone marrow transplant (BMT) with or without prior tyrosine kinase inhibitor (TKI) therapy. Methods By using data from the Blood or Marrow Transplant Survivor Study, the authors examined late mortality in 447 patients with CML who underwent BMT between 1974 and 2010, conditional on surviving ≥2 years post-BMT. For vital status information, the medical records, the National Death Index, and the Accurint database were used. Standardized mortality ratios (SMRs) were calculated using general population age-specific, sex-specific, and calendar-specific mortality rates. Kaplan-Meier techniques and Cox regression were used for all-cause mortality analyses. Cumulative incidence and proportional subdistribution hazards models for competing risks were used for cause-specific mortality analyses. Results The 10-year overall survival rate was 65.7% and 73% for those who underwent transplant with and without pre-BMT exposure to TKI therapy, respectively. Patients who underwent transplant with and without pre-BMT TKI experienced SMRs of 6.4 and 6.4, respectively (P = .8); and the SMRs were 11.6 and 8.1, respectively, for those with high-risk disease (P = .2). Independent predictors of non-CML-related mortality included chronic graft-versus-host disease (hazard ratio [HR], 2.8; 95% CI, 1.8-4.4) and busulfan/cyclophosphamide conditioning (HR, 0.5; 95% CI, 0.3-0.9; reference, total body irradiation/cyclophosphamide conditioning). The 20-year cumulative incidence of CML-related and non-CML-related mortality was 6% and 36%, respectively, for the entire cohort. Both CML-related mortality (HR, 1.0; 95% CI, 0.1-12.6) and non-CML-related mortality (HR, 1.3; 95% CI, 0.6-3.1) were comparable for those with and without pre-BMT TKI therapy. Conclusions The similar late mortality experienced by patients with CML who undergo transplantation with or without pre-BMT TKIs suggests that allogeneic BMT can be considered in the context of TKI intolerance or nonadherence. The prevention of post-BMT non-CML-related mortality could favorably affect long-term survival.

Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (n = 120) and SAA (n = 147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P

PURPOSE To examine the association between total body irradiation (TBI) and subsequent breast cancer in women treated with blood or marrow transplantation (BMT) for hematologic malignancies. PATIENTS AND METHODS Participants were drawn from the BMT Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived for ≥ 2 years after BMT. Patients with pre-BMT chest radiation or a history of breast cancer were excluded. Participants completed the BMTSS survey, which included details regarding breast cancer diagnosis. Subsequent breast cancer was confirmed by pathology report review or physician notes. Cox proportional hazards models assessed the association between TBI and subsequent breast cancer. Standardized incidence ratios were calculated to determine the excess risk of subsequent breast cancer compared with that in the general population. RESULTS A total of 1,464 female BMT survivors (allogeneic: n = 788; autologous: n = 676) participated, with a median follow-up of 9.3 years from BMT. TBI was used in 660 patients (46%). Thirty-seven women developed subsequent breast cancer (allogeneic: n = 19; autologous: n = 18). Multivariable analysis revealed that exposure to TBI was associated with an increased risk of subsequent breast cancer among allogeneic BMT survivors (hazard ratio [HR], 3.7 [95% CI, 1.2 to 11.8]; P = .03) and autologous BMT survivors (HR, 2.6 [95% CI, 1.0 to 6.8]; P = .048). Pre-BMT exposure to alkylating agents was associated with an increased risk of subsequent breast cancer among autologous BMT survivors (HR, 3.3 [95% CI, 1.0 to 9.0]; P = .05). Compared with that in the general population, exposure to TBI at age < 30 years was associated with a 4.4-fold higher risk of subsequent breast cancer in allogeneic BMT survivors and a 4.6-fold higher risk in autologous BMT survivors. CONCLUSION The association between TBI and subsequent breast cancer, especially among those exposed at a young age, as well as pre-BMT exposure to alkylating agents, should inform breast cancer screening for early detection.

Background Blood or bone marrow transplantation (BMT) survivors with frailty are at a higher risk of subsequent mortality. Longitudinal trends in the frailty state are not known and could help identify vulnerable subpopulations at risk of subsequent adverse events. Methods This study included a cohort of 470 autologous and allogeneic BMT recipients who had survived ≥2 years after BMT and completed a baseline questionnaire (t1) at a median of 7.3 years after BMT and a follow-up questionnaire (t2) 13.2 years after t1. The main outcome was change in frailty state between t1 and t2. Frailty phenotype was defined as exhibiting ≥3 of the following characteristics: clinically underweight, exhaustion, low energy expenditure, slow walking speed, and muscle weakness. The following categories of change in frailty state were evaluated: worsened, improved, and stable. Results Of the 470 participants, 36.4% were aged ≥60 years at t1, and 50.6% were men. The prevalence of frailty increased from 4.8% at t1 to 9.6% at t2. Worsening was observed in 18.8% of patients, and improvement was reported in 9.7%. Pre-BMT exposure to vincristine (odds ratio [OR], 2.1; 95% CI, 1.3-3.39) was associated with worsening. Female sex (OR, 1.5; 95% CI, 0.93-2.4) was associated with a trend toward worsening. Pre-BMT exposure to vincristine (OR, 2.79; 95% CI, 1.44-5.43), a history of chronic graft-versus-host disease (OR, 2.58; 95% CI, 1.2-5.5), and grade 3 and 4 chronic health conditions at t1 (OR, 2.1; 95% CI, 1.08-4.33) were associated with frailty at t2. Conclusions In a cohort of BMT survivors who were followed longitudinally for a median of 20.6 years from BMT, the frailty status worsened for approximately20% over a 13-year timespan. BMT survivors who are at risk for worsening frailty could benefit from targeted interventions.

Background Autologous blood or bone marrow transplantation (aBMT) is considered the standard of care for patients with multiple myeloma (MM). Significantly improved survival necessitates an understanding of the morbidity burden borne by the growing survivor population. Methods The authors evaluated severe and/or life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs) in patients with MM who were treated with aBMT using the Bone Marrow Transplant Survivor Study. A total of 630 study participants had undergone aBMT for MM at 1 of 3 BMT centers, had survived ≥2 years after aBMT, and were aged ≥18 years at the time of survey completion. Survivors of aBMT identified 289 nearest-age siblings to constitute an unaffected comparison group. Scoring of CHCs was based on version 5 of the National Cancer Institute Common Terminology Criteria for Adverse Events to determine severity (with grade 3 indicating serious and grade 4 indicating life-threatening). Results The 10-year cumulative incidence of any grade 3 to 4 CHC among survivors of aBMT was 57.6 ± 3.2%. Survivors of MM were found to be at 40% higher odds of developing grade 3 to 4 CHCs when compared with siblings (95% confidence interval [95% CI], 1.0-1.9). Among SNs, 96% were solid tumors, yielding a 10-year cumulative incidence of 13.6% ± 2.5%. Pre-aBMT exposure to cyclophosphamide (hazard ratio [HR], 3.5; 95% CI, 1.5-8.1) and immunomodulatory drugs (HR, 3.9; 95% CI, 1.5-10.1) were associated with an increased risk of solid tumors. Melanoma (10-year cumulative incidence: 3.3% ± 1.2%) and squamous cell carcinoma (10-year cumulative incidence: 5.1% ± 1.8%), were the most common SNs. Pre-aBMT exposure to cyclophosphamide (HR, 6.02; 95% CI, 1.4-26.1) and immunomodulatory drugs (HR, 7.9; 95% CI, 0.9-68.5) was associated with an increased risk of melanoma. Conclusions The 10-year cumulative incidence of severe and/or life-threatening CHCs was found to approach 60% in long-term survivors of MM, with solid SNs constituting a large morbidity burden. The current study has provided evidence supporting the close monitoring of survivors to manage morbidity.

Background Blood or marrow transplantation (BMT) is increasingly offered to older adults with hematologic malignancies; however, their risk for severe pain is poorly understood. Using the Bone Marrow Transplant Survivor Study, the current study investigated the prevalence and predictors of pain after BMT (allogeneic or autologous) as well as its association with physical performance impairments and frailty. Methods The cohort included 736 patients with hematologic malignancies who underwent BMT at an age ≥ 60 years at 1 of 3 transplant centers between 1974 and 2014 and survived ≥2 years after BMT; 183 unaffected siblings also participated. Study participants reported on 4 pain domains (nonminor everyday pain, moderate to severe bodily pain, prolonged pain, and moderate to extreme pain interference), and the presence of 1 or more domains was indicative of a severe and/or life-interfering pain composite variable. Results Overall, 39.4% of the BMT survivors reported severe pain with 2.6-fold greater odds of reporting pain in comparison with sibling controls. Among BMT recipients, those with less education, lower incomes, and active chronic graft-versus-host disease had higher odds of reporting pain. In multivariable analyses, BMT survivors with pain were more likely to have impaired physical performance and were more likely to meet the frailty criteria. BMT survivors reported higher use of pain medications (17.8% vs 9.3%) and opioid pain medications (6.5% vs 2.2%) in comparison with sibling controls. Conclusions Nearly 40% of older BMT survivors who were followed for a median of 5 years after BMT reported pain, and BMT survivors had 2.6-fold higher odds of reporting severe, nonminor or life-interfering pain in comparison with siblings.

Hemostatic complications are commonly encountered in blood or marrow transplantation (BMT) recipients, increasing their morbidity and mortality and are well described in the immediate post-transplantation period. The risk of venous thromboembolism (VTE) in long-term survivors of autologous BMT has not been studied previously. Patients who underwent autologous BMT between January 1, 1974, and December 31, 2010 for a hematologic malignancy, lived 2 years or more after transplantation, and were age ≥18 years were surveyed for long-term outcomes. The median duration of follow-up was 9.8 years (interquartile range, 6.4 to 14.3 years). We analyzed the risk of VTE in 820 autologous BMT recipients who survived for ≥2 years, compared with 644 siblings. BMT survivors were at a 2.6-fold higher risk of VTE compared with siblings (95% confidence interval [CI], 1.6 to 4.4; P =.0004), after adjusting for sociodemographic characteristics. Conditional on surviving for ≥2 years after BMT, the mean cumulative incidence of VTE was 3.9 ± .8% at 5 years and 6.1 ± 1.1% at 10 years. A diagnosis of plasma cell disorder (hazard ratio [HR], 2.37; 95% CI, 1.3 to 4.2; P = .004) and annual household income ≤$50,000 (HR, 2.02; 95% CI, 1.2 to 3.6; P = .015) were associated with increased VTE risk. Our data indicate that autologous BMT survivors are at elevated risk for developing late-occurring VTE. The development of risk prediction models to identify autologous BMT survivors at greatest risk for VTE and thromboprophylaxis may help decrease the morbidity and mortality associated with VTE.

BACKGROUND: Patients with non-Hodgkin lymphoma (NHL) have increased risk of venous thromboembolism (VTE), particularly when receiving treatment. Blood or marrow transplantation (BMT) is recommended for relapsed/refractory NHL, and the risk of VTE after they undergo BMT is uncertain. METHODS: We surveyed NHL patients who survived 2 years or more after BMT, for long-term health outcomes including VTE. Median follow up was 8.1 years (IQR: 5.6 – 12.9 years). We analyzed the risk of VTE in 734 NHL patients as compared to 897 siblings without a history of cancer and the risk factors associated with VTE. RESULTS: BMT survivors of NHL were at increased risk of VTE as compared to siblings (OR=4.61, p30), and a history of chronic graft vs host disease (HR=3.33, 95%CI: 1.59–6.97, p=0.001) were associated with an increased risk of VTE. Among autologous BMT recipients, diagnosis of coronary artery disease (HR=5.94, 95%CI: 1.7–20.71, p=0.005) and prior treatment with carmustine (HR=4.91, 95%CI: 1.66–14.51, p=0.004) were associated with increased VTE risk. CONCLUSION: NHL patients who survive BMT are at risk for developing late-occurring VTE and ongoing vigilance for this complication is required. Future studies assessing the role of thromboprophylaxis in high risk NHL patients are needed.

Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM performed between 1974 and 2014. The most prevalent IEM in our cohort were X-linked adrenoleukodystrophy (ALD; 37.3%), Hurler syndrome (35.1%), and metachromatic leukodystrophy (MLD; 10.2%). Conditional on surviving ≥2 years after BMT, the overall survival for the entire cohort was 85.5 ± 2.4% at 10 years and 73.5 ± 3.7% at 20 years. The cohort had a 29-fold increased risk of late death compared with an age- and sex-matched cohort from the general US population (95% CI, 22- to 38-fold). The increased relative mortality was highest in the 2- to 5-year period after BMT (standardized mortality ratio [SMR], 207; 95% confidence interval [CI], 130 to 308) and declined with increasing time from BMT, but remained elevated for ≥21 years after BMT (SMR, 9; 95% CI, 4 to 18). Sequelae from the progression of primary disease were the most common causes of late mortality in this cohort (76%). The use of T cell-depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our findings demonstrate relatively favorable overall survival in ≥2-year survivors of allogeneic BMT for IEM, although primary disease progression continues to be responsible for the majority of late deaths.

Importance: Allogeneic blood or marrow transplantation (BMT) is a curative option for malignant and nonmalignant diseases of childhood. However, little is known about trends in cause-specific late mortality in this population during the past 3 decades. Objectives: To examine cause-specific late mortality among individuals who have lived 2 years or more after allogeneic BMT performed in childhood and whether rates of late mortality have changed over time. Design, Setting, and Participants: A retrospective cohort study was conducted of individuals who lived 2 years or more after undergoing allogeneic BMT performed in childhood between January 1, 1974, and December 31, 2010. The end of follow-up was December 31, 2016. Exposure: Allogeneic BMT performed in childhood. Main Outcomes and Measures: All-cause mortality, relapse-related mortality, and non-relapse-related mortality. Data on vital status and causes of death were collected using medical records, the National Death Index Plus Program, and Accurint databases. Results: Among 1388 individuals (559 females and 829 males) who lived 2 years or more after allogeneic BMT performed in childhood, the median age at transplantation was 14.6 years (range, 0-21 years). In this cohort, there was a total of 295 deaths, yielding an overall survival rate of 79.3% at 20 years after BMT. The leading causes of death were infection and/or chronic graft-vs-host disease (121 of 244 [49.6%]), primary disease (60 of 244 [24.6%]), and subsequent malignant neoplasms (45 of 244 [18.4%]). Overall, the cohort had a 14.4-fold increased risk for death (95% CI, 12.8-16.1) compared with the general population (292 deaths observed; 20.3 deaths expected). Relative mortality remained elevated at 25 years or more after BMT (standardized mortality ratio, 2.9; 95% CI, 2.0-4.1). The absolute excess risk for death from any cause was 12.0 per 1000 person-years (95% CI, 10.5-13.5). The cumulative incidence of non-relapse-related mortality exceeded that of relapse-related mortality throughout follow-up. The 10-year cumulative incidence of late mortality decreased over time (before 1990, 18.9%; 1990-1999, 12.8%; 2000-2010, 10.9%; P =.002); this decrease remained statistically significant after adjusting for demographic and clinical factors (referent group

Introduction: Frailty is a state of increased vulnerability resulting in a decline in reserve and function across multiple physiologic systems such that the ability to cope with every day or acute stressors is compromised. We previously reported that BMT recipients with frailty were at a 2.8-fold higher risk of subsequent mortality (JAMA Oncol. 2016;2:1277-86) when compared with non-frail survivors. However, longitudinal trends in frailty several years after BMT are not known, and could possibly help in identifying the vulnerable sub-populations at highest risk of subsequent adverse events. We used BMTSS to report transitions in the frailty state over time. Methods: We included 484 patients who were i) transplanted for a hematologic malignancy between 1974 and 1998 at 2 sites and had survived ≥2y post-BMT; ii) were ≥18y of age at study participation; and iii) were alive both at completion of the baseline survey (t1: median of 7.3 y after BMT) and at follow-up survey (t2: median of 20.6y after BMT); median interval between t1 and t2 was 13.2y. Frailty phenotype used the previous definition (JAMA Oncol. 2016;2:1277-86), and included the presence of ≥3 of the following indices: 1) clinically underweight (body mass index [BMI] Results: Median age (range) at t1 was 42.9y (18.5-67.4) and at t2 was 56.5y (31.0-80.0); 49.4% were females; 85.4% non-Hispanic whites; 15% had Conclusions: In a cohort of patients followed longitudinally for a median of 20.6y from BMT, with measurement of frailty status 13.2y apart, we observed that the frailty status worsened for ~20% of the patients. Pre-transplant exposure to vincristine was associated with worsening of frailty status. Patients with cGvHD or morbidity at t1, as well as pre-BMT vincristine exposure placed BMT survivors at high risk for subsequent frailty, identifying sub-populations that could benefit from targeted interventions. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

Background: BMT is now an integral part of consolidation and/or salvage for patients with AML. With the growing population survivors, there is a need to understand the quality of survival. This would allow for appropriate resource allocation and implementation of risk-based screening for early detection of chronic health conditions over time. Yet, a comprehensive evaluation of the long-term burden of morbidity borne by AML patients treated with BMT remains unknown. We addressed this gap by evaluating long-term severe/life-threatening/fatal chronic health conditions (CHCs) in AML patients treated with BMT using the BMTSS. Methods: Patients were eligible if they had undergone an allogeneic or autologous BMT for AML between 1974 and 2014 at one of 3 BMT centers in the US, had survived for ≥2y after BMT, and were ≥21y of age at BMT. Of the 1,113 eligible subjects, 711 (64%) participated. BMT survivors identified a nearest-age sibling to constitute an unaffected comparison group (N=1,136). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHC diagnosis by their healthcare provider, including age at onset of CHC. Scoring was based on Common Terminology Criteria for Adverse Events ([CTCAE] v 5.0) to determine the severity of CHCs. Using multivariable logistic regression, we determined the risk of any severe (CTCAE grade 3) or life-threatening (CTCAE grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information regarding therapeutic exposures (pre-BMT and transplant-related) was abstracted from medical records. Cumulative incidence of CHCs (including fatal [CTCAE grade 5] CHCs) were calculated for BMT survivors, treating relapse-related death as a competing risk. Results: Mean age at BMT was 48.6±13.8y and at survey was 58.2±11.5y. Mean interval between BMT and study participation was 9.7±6.8y; 53% were females, and 78% were non-Hispanic white; 86% received allogeneic BMT (48% from an unrelated donor). Conditioning was Fludarabine/Melphalan-based in 53% and TBI-based in 35%; stem cell source was peripheral blood (70.3%), bone marrow (19.3%), and cord (10.4%). For the siblings, the mean age at survey was 56.9+13.4y; 61% were females, and 88% were non-Hispanic white. BMT survivors vs. sibs: 53.3% of the BMT survivors and 30.4% of the sibs reported grades 3-4 CHCs, placing the survivors at a 3.0-fold higher odds of grades 3-4 CHC (95%CI, 2.4-3.7, p Conclusion: The burden of severe/life-threatening CHCs is substantially higher in BMT survivors when compared with an unaffected comparison group. The incidence of severe/ life-threatening/ fatal chronic health condition following BMT for AML exceeds 50% at 10y, and continues to increase with time, approaching 70% at 20y post-BMT. Subsequent malignant neoplasms, diabetes, thrombo-embolic events, cataracts, and major joint replacement constitute the largest burden of morbidity. These findings suggest the need for increased awareness of the long-term burden of morbidity, to ensure close monitoring of these survivors to anticipate and manage morbidity. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

BACKGROUND: BMT recipients are vulnerable to accelerated atherosclerosis due to prior exposure to radiation with or without chemotherapy, and consequent long-term cardiovascular morbidity, such as stroke. A comprehensive evaluation of the risk of late-occurring stroke in adult BMT survivors and the associated risk factors has not been performed. We addressed this gap using the resources offered by the BMTSS. METHODS: BMTSS includes patients transplanted between 1974 and 2014 at 3 US sites who survived ≥2y after BMT, were alive and ≥18y at BMTSS survey completion. The survey asked participants to report if a healthcare provider had diagnosed specific chronic health conditions (including stroke), or relapse of primary cancer or development of new cancer, along with age at diagnosis. The participants provided information on sociodemographics, health behaviors and medication use. Medical record abstraction was used for information regarding primary cancer diagnosis, therapeutic exposures (pre-BMT chemotherapy/radiation, transplant preparative regimens), stem cell source (autologous, allogeneic), graft type (bone marrow, cord blood or peripheral blood stem cells), and history of chronic graft vs. host disease (GvHD). A cohort of 908 siblings also completed the BMTSS survey and served as a comparison group. Informed consent was obtained from all participants. RESULTS: The study included 3,479 BMT survivors; 50.3% had received an allogeneic BMT, 54.8% were males; 71.4% were non-Hispanic whites. Median age at study participation was 59y (range: 18-89y) for BMT survivors and 57y (range: 18-90y) for siblings. Patient characteristics are shown in Table 1. BMT survivors were followed for a median of 9y (range: 2-41 y) from BMT. Stroke was reported by 136 BMT survivors (67 allogeneic, 69 autologous); of these, 75 (55%) patients developed stroke ≥2y after BMT. Conditional on surviving ≥2y after BMT, the 10y cumulative incidence of stroke was 3.8% (Fig 1), and was comparable for allogeneic (3.4±0.5%) and autologous (4.2±0.6%) BMT recipients, p=0.3. Stroke in BMT recipients compared with siblings: Using logistic regression, and after adjusting for sociodemographics, physical activity and relevant comorbidities, we found that allogeneic BMT survivors were at a 2.1-fold higher odds of reporting stroke as compared to siblings (95%CI: 1.2-3.7, p=0.01), and autologous BMT recipients were at a 1.7-fold higher odds of reporting stroke compared to siblings (95%CI: 0.9-3.0, p=0.09). Stroke after Allogeneic BMT: History of hypertension (HR=2.2, 95%CI: 1.2-3.9, p=0.007), venous thromboembolism (HR=3.4, 95%CI: 1.6-7.1, p=0.002), diagnosis of acute lymphoblastic leukemia (HR=4.9, 95%CI: 1.6-15.0, p=0.006), acute myeloid leukemia/ myelodysplastic syndrome (HR=5.2, 95%CI: 1.4-19.0, p=0.013) (ref: non Hodgkin lymphoma), pre-BMT exposure to alkylating agents (HR=3.3, 95%CI: 1.3-8.5, p=0.01) and pre-BMT neck radiation (HR=5.4, 95%CI: 1.2-23.8, p=0.03) were associated with increased stroke risk. Exercise was associated with lower stroke risk (HR: 0.5, 95%CI: 0.3-0.9, p=0.01). Stroke after Autologous BMT: The risk factors for stroke in autologous BMT survivors included: increasing age at BMT (HR=1.02/y, 95%CI: 1.0-1.1, p=0.05), history of hypertension (HR=1.8, 95%CI: 1.1-3.2, p=0.03), coronary heart disease (HR=2.8, 95%CI: 1.3-6.4, p=0.01) and venous thromboembolism (HR=2.3, 95%CI: 1.1-4.7, p=0.02). Relapse of primary disease or development of new cancer were not associated with increased stroke risk in either autologous or allogeneic BMT recipients. CONCLUSION: In this large study, we found that the incidence of stroke was 4% among BMT survivors, and that they are at an increased risk of developing stroke when compared to an unaffected comparison group. The study also identified subgroups among BMT survivors at increased risk of stroke such as those who received neck radiation and those with cardiovascular comorbidity. These findings suggest a need for increased awareness of stroke as a late complication of BMT, such that aggressive management of cardiovascular risk factors can be instituted among those at highest risk. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

Background: BMT is increasingly offered to older patients with HM. The high burden of comorbidity in older BMT survivors places them at a higher risk for chronic severe pain - an issue that has not been comprehensively evaluated. We used BMTSS to investigate the prevalence and predictors of chronic severe pain several years after BMT. We examined the impact of pain on physical performance and frailty and also examined the relation between chronic severe pain and use of prescription pain medications and opioids in this population. Methods: The cohort included 601 HM patients who had received a BMT at age ≥60y at one of 3 transplant centers between 1974 and 2014 and had survived ≥2y after BMT; 183 unaffected siblings also participated. Self-reported domains included sociodemographics, chronic GvHD, physical performance, frailty, and medication use. Clinical information obtained from institutional databases included primary HM diagnosis, donor source, and conditioning regimen. Study participants completed a detailed questionnaire that examined pain in the following 3 domains: moderate-to-severe bodily pain, prolonged pain, and moderate-to-extreme pain interference; these 3 domains were used to create a composite variable, wherein presence of ≥1 domain was indicative of "chronic severe pain". An adjusted multivariable logistic regression model for chronic severe pain was used to compare BMT survivors to siblings. Analyses restricted to BMT survivors were stratified by donor type. Results: Survey participation rates were 62.7% and 60%, for the BMT survivors and siblings, respectively. Median age at study participation was 69.8y (61-89) for BMT survivors and 68.9y (65-80) for siblings. Median time from BMT was 5.0y (2-17) for BMT survivors. Chronic severe pain: Overall, 39.4% of the BMT survivors reported chronic severe pain; multivariable analysis revealed a 2.5-fold greater odds of BMT survivors reporting chronic severe pain (95%CI, 1.7-3.8, p college) and lower income ( Conclusions: Nearly 40% of older BMT survivors followed for a median of 5y after BMT, report chronic severe pain. BMT survivors are at a 2.5-fold higher odds of reporting chronic severe, life-interfering pain as compared with siblings. Chronic severe pain is associated with impaired physical performance and frailty. Finally, nearly 18% of long-term BMT survivors report use of prescription medications and 6.5% are using opioids. This study draws attention to the vulnerability of older BMT survivors and provides evidence for the need to develop effective strategies to address the underlying causes of pain. Disclosures No relevant conflicts of interest to declare.

Background: Autologous BMT (either as a planned procedure after completion of initial treatment or as salvage therapy for relapse) is considered standard of care for patients with MM. Therapeutic advances have resulted in significant improvement in survival, necessitating an understanding of the burden of morbidity borne by MM survivors - an understudied topic. We addressed this gap by conducting a comprehensive evaluation of chronic health conditions (CHCs) in MM patients treated with autologous BMT using BMTSS. Methods: Patients were eligible if they had undergone autologous BMT for MM between 1974 and 2014 at one of 3 BMT centers, had survived for ≥2y after BMT, and were ≥18y of age at participation. Of the 1,116 subjects approached, 630 (56.5%) participated. A nearest-age sibling was invited to participate in the study, and served as an unaffected comparison group (n=289). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHCs, including age at onset of each CHC. Each CHC was scored (CTCAE v 4.03) to determine severity. Using multivariable logistic regression, we determined the risk of any severe (grade 3) or life-threatening (grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information on initial pre-BMT treatment exposures, conditioning regimens and post-BMT maintenance treatment was abstracted from medical records. Cumulative incidence of CHCs overall, and by specific types were calculated for BMT survivors, treating death as a competing risk. Cox regression was used to determine clinical, demographic and therapeutic predictors of CHCs in BMT survivors. Results: Mean age at BMT was 57.6±8.5y and at survey was 64.2±7.9y. Mean interval between BMT and study participation was 6.6±3.7y; 58% were males, and 62% were non-Hispanic white. Conditioning was melphalan based in 98%, TBI was used in only 5.5%. Mean age at survey for the siblings was 64±8.08y; 58% were male and 84% were non-Hispanic whites. BMT survivors vs. siblings: Overall, 43.3% of the survivors reported a grade 3-4 CHC, placing them at a 1.4-fold higher odds when compared with siblings (95%CI, 1.0-1.9, p=0.03). The odds of developing the following CHCs were significantly higher in BMT survivors when compared with siblings (Fig 1): cataracts (odds ratio [OR]=2.3; 95%CI, 1.4-3.7, p=0.0006), venous thrombo-embolism (VTE: OR=2.4, 95%CI, 1.2-4.6 p=0.01), and subsequent neoplasms (SNs: OR=4.4, 95% CI, 1.8-10.6, p=0.0009). BMT survivors only: 10y cumulative incidence of any grade 3-4 CHC in BMT survivors was 57.6% ± 3.2% (Fig 2). Cataracts: 10y cumulative incidence of cataracts was 24.8% ± 2.7%. Older age at BMT (≥60y: relative risk [RR]=3.3; 95%CI, 2.2-5.1, p Conclusion: The 10y cumulative incidence of a severe/life-threatening chronic health condition approaches 60% in multiple myeloma patients treated with autologous BMT. Cataracts, thrombo-embolic events and subsequent neoplasms constitute the largest burden of morbidity. This study identifies demographic factors and treatment exposures associated with increased risk of chronic health conditions, and provides evidence for close monitoring of these survivors to anticipate and manage morbidity. Disclosures Weisdorf: Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Equillium: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

BACKGROUND: Patients undergoing BMT are uniquely vulnerable to venous thromboembolism (VTE) due to high-intensity therapeutic exposures, prolonged hospitalizations (and attendant immobility), a high burden of comorbidities, and the pro-inflammatory state induced by graft-versus-host disease (GvHD) in allogeneic BMT recipients. An assessment of the long-term risk of VTE in BMT survivors and subsequent cause-specific late mortality remains unstudied. We used the BMTSS to address this gap. METHODS: In patients with hematologic malignancy treated with BMT at 3 sites in US, had survived ≥2y after BMT, were alive and ≥18yo at BMTSS survey completion, we examined: i) incidence/risk factors for VTE; ii) subsequent mortality by VTE status. The survey covered sociodemographics, tobacco use, diagnosis by a healthcare provider of specific chronic health conditions, including VTE, relapse, or development of new cancer and medication use. The outcome of interest (VTE) was defined as self-report of VTE diagnosed by a health care provider, supplemented by history of anticoagulant use. BMTSS survey was administered over two time periods: i) Survey completed between 2000 and 2004: 1,022 patients transplanted between 1974 and 1998 and survived ≥2y (original BMTSS cohort; participation rate: 63%). This cohort was followed for a median of 15.1y (range: 0.04-17.9) after survey completion, to determine the association between VTE and subsequent mortality using National Death Index; ii) Survey completed between 2014 and 2017: 1,711 patients transplanted between 1974 and 2010 and survived ≥2y (expanded BMTSS cohort; participation rate: 68%) - this cohort was used to determine demographic/clinical variables associated with VTE risk. A cohort of 644 siblings also completed the survey and served as a comparison group. Human Subjects Committee at participating sites approved the protocol. RESULTS: Risk of VTE: Of the 1,711 participants, 891 (52.1%) had received an allogeneic BMT; 53.5% were males and 78.8% were non-Hispanic whites; median age at BMT was 48y. The cohort was followed for a median of 10.9y (3.8-40.6). BMT survivors were at a 2.8-fold higher risk of VTE as compared to siblings (95%CI:1.7-4.5, p Risk of VTE in allogeneic BMT recipients: History of chronic GvHD (HR=3.6, 95%CI:2.2-6.0, p Risk of VTE in autologous BMT recipients: Diagnosis of a plasma cell disorder (HR=2.4, 95%CI: 1.3-4.2, p=0.004) (ref: NHL) and annual house hold income $50,000) were associated with increased VTE risk. Of note, relapse of primary disease or development of new cancer were not associated with increased VTE risk in either autologous or allogeneic BMT patients. Subsequent mortality: In this cohort of 1,022 BMT survivors, median age at BMT was 34.9y; 55% had received allogeneic BMT. The overall survival among patients with and without VTE was 50.4% vs. 72.3%, respectively at 15y from survey completion, p CONCLUSION: BMT survivors are at a 2.8-fold increased risk of developing VTE when compared with a non-BMT sibling comparison group. Those with VTE are at an increased risk of subsequent NRM. Development of risk prediction models to identify BMT survivors at highest risk would facilitate targeted thromboprophylaxis. Disclosures Weisdorf: Equillium: Consultancy; SL Behring: Consultancy; Seattle Genetics: Consultancy; FATE: Consultancy; Pharmacyclics: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Background: AlloBMT is a curative option for children with malignant and non-malignant diseases. Nonetheless, the high intensity of therapeutic exposures at a young age increases the risk of organ compromise and may lead to premature death. However, there remains a gap in knowledge regarding cause-specific late mortality experienced by children undergoing alloBMT. Furthermore, it is not clear whether mortality rates have changed over the past 4 decades. We address these gaps by examining premature death (all-cause, relapse-related mortality [RRM] and non-relapse-related mortality [NRM]) in patients undergoing alloBMT between 1974 and 2010 at City of Hope, University of Minnesota or University of Alabama at Birmingham. Methods: To be included in this analysis, the patients had to have received alloBMT before age 22, and survived for ≥2y after transplantation. Vital status information was ascertained as of Dec 31, 2016, using medical records, the National Death Index (NDI), and Accurint databases. Information on cause of death was obtained from the NDI Plus program and medical records. Using Kaplan-Meier techniques, we describe overall survival conditional on surviving 2+ and 20+y from alloBMT. We describe cumulative incidence of RRM and NRM using competing risk methods. We also describe all-cause late mortality for patients transplanted over 3 time periods: 2000: 10.7%, p=0.001) (Fig 2). Adjusting for demographic and clinical variables, as well as conditioning, the hazard ratio (HR) of all-cause death decreased with more recent treatment eras ( Disclosures Arora: Takeda Oncology: Consultancy.

Increased activity of lung epithelial sodium channels (ENaCs) contributes to the pathophysiology of cystic fibrosis (CF) by increasing the rate of epithelial lining fluid reabsorption. Inter-α-inhibitor (IαI), a serum protease inhibitor, may decrease ENaC activity by preventing its cleavage by serine proteases. High concentrations of IαI were detected in the bronchoalveolar lavage fluid (BALF) of children with CF and lower airway diseases. IαI decreased amiloride-sensitive (IENaC) but not cAMP-activated Cl(-) currents across confluent monolayers of rat ATII, and mouse nasal epithelial cells grew in primary culture by 45 and 25%, respectively. Changes in IENaC by IαI in ATII cells were accompanied by increased levels of uncleaved (immature) surface α-ENaC. IαI increased airway surface liquid depth overlying murine nasal epithelial cells to the same extent as amiloride, consistent with ENaC inhibition. Incubation of lung slices from C57BL/6, those lacking phenylalanine at position 508 (∆F508), or CF transmembrane conductance regulator knockout mice with IαI for 3 hours decreased the open probability of their ENaC channels by 50%. ∆F508 mice had considerably higher levels the amiloride-sensitive fractions of ENaC nasal potential difference (ENaC-NPD) than wild-type littermates and only background levels of IαI in their BALF. A single intranasal instillation of IαI decreased their ENaC-NPD 24 hours later by 25%. In conclusion, we show that IαI is present in the BALF of children with CF, is an effective inhibitor of ENaC proteolysis, and decreases ENaC activity in lung epithelial cells of ∆F508 mice.

Background: Tyrosine kinase inhibitors have become the treatment of choice for CML. However, the high cost and need for life-long treatment contribute to non-adherence and represent a major challenge in their use. Allogeneic HCT is potentially curative, but the very long-term health of the survivors is not known. It is also not clear whether a subgroup of CML patients carries a relatively low risk of long-term morbidity. Methods: We addressed these gaps by studying long-term outcomes in 637 CML patients treated with allogeneic HCT between 1981 and 2010 at City of Hope or Univ MN, and surviving for at least 2y after HCT (median follow-up: 16.7y from HCT); 80% of the cohort was Results: Late Mortality: Overall survival was 72.1% at 20y and 69.9% at 30y from HCT. The 20y cumulative incidence of relapse-related mortality was 3.9% (95% CI, 2.6-5.8%) and of non-relapse-related mortality was 18.2% (95% CI, 19.8-28.1%) (Figure 1). 20y cumulative incidence of mortality by cause of death was as follows: infection (7%), chronic GvHD (6%), subsequent malignant neoplasms (SMNs: 3%). HCT recipients were at 4.4-fold increased risk of death (95% CI, 3.8-5.1, p Conclusions: Conditional on surviving the first 2y after HCT, the overall survival exceeds 70% at 20y and remains stable at 70% at 30y after HCT. Non-relapse related mortality (infections, chronic GvHD, SMNs) is by far the major contributor to the late mortality. Conditional on surviving the first 15y, mortality rates are similar to those observed in the general population. HCT survivors are at a 2.7-fold higher risk of severe/life-threatening morbidity when compared with siblings. The more common morbidities include SMNs, diabetes and coronary artery disease. However, CML patients receiving HCT at Disclosures Snyder: BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.

Background: The high intensity of therapeutic exposures (for autologous and allogeneic HCT) and chronic GvHD and its management (in allogeneic HCT) increase the risk for late mortality. Significant changes in transplantation strategies have been instituted over the past 4 decades, with the overarching goal of improving outcomes. The impact of these changes on late mortality remains unknown. Methods: We evaluated late mortality in 5,566 patients who had survived at least 2y after HCT performed between 1974 and 2010. Vital status information was ascertained as of May 2016, using medical records, National Death Index and Accurint databases. Separate analyses were conducted for allogeneic and autologous HCT. For all-cause mortality, relapse-related (RRM) and non-relapse-related (NRM) mortality, we examined trends over 4 time periods: Results: Allogeneic HCT:The cohort included 2,999 2y survivors followed for a median of 12.4y (range, 2.0-40.7) from HCT. Significant differences in HCT strategies (p Conclusions: Changes in transplantation strategies have contributed to a progressive decline in late mortality for both allogeneic and autologous HCT. The all-cause mortality has declined 44% for allogeneic HCT recipients and 75% for autologous HCT recipients over the 4 decades examined in this study. The decline in risk, while evident for relapse-related mortality, is more prominent for non-relapse mortality. Disclosures Forman: Mustang Therpapeutics: Other: Construct licensed by City of Hope.