Burden of Long-Term Morbidity Borne By Survivors of Acute Myeloid Leukemia (AML) Treated with Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

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<0.0001). The odds of developing the following CHCs were significantly higher in BMT survivors when compared with siblings: subsequent malignant neoplasms (SMNs: odds ratio [OR]=10.0, 95% CI, 5.5-17.9, p<0.0001), diabetes (OR=5.3, 95% CI, 3.0-9.3, p<0.0001), venous thromboembolism (OR=3.8, 95%CI, 2.5-5.8 p<0.0001), cataracts (OR=3.7; 95%CI, 2.7-5.0, p<0.0001), and major joint replacement (OR=1.5, 95% CI, 1.1-2.1, p=0.02). Among BMT survivors: The 10- and 20y cumulative incidence of a grade 3-5 CHC was 52.0%±1.4% and 66.2%±1.6%, respectively (Figure 1). 75 survivors had developed SMNs: skin (melanoma/ squamous cell [56%]), breast (13%), colon (7%), prostate (7%), and other cancers (24%). The 10- and 20y-cumulative incidence of the most common CHCs were as follows (Figure 2): SMN (10y: 17.9%±1.7%, 20y: 32.1%±2.9%), cataract (10y: 21.5%±1.9%, 20y: 31.5%±3.0%), major joint replacement (10y: 12.5%±0.9%, 20y: 17.5%±3.4%), venous thromboembolism (10y: 8.6%±1.1%, 20y: 13.2%±2.1%), and diabetes (10y: 6.0%±1.9%, 20y: 8.0%±1.5%). 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.

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Burden of Morbidity Borne By Survivors of Multiple Myeloma (MM) Treated with Autologous Blood or Marrow Transplant (BMT) — Results of the BMT Survivor Study (BMTSS)

Blood ◽

10.1182/blood-2018-99-112702 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2127-2127

Author(s):

Mukta Arora ◽

Yanjun Chen ◽

Lindsey Hageman ◽

Jessica Wu ◽

Liton F. Francisco ◽

...

Keyword(s):

Cumulative Incidence ◽

Older Age ◽

Chronic Health Conditions ◽

Health Conditions ◽

Chronic Health ◽

Increased Risk ◽

Life Threatening ◽

Race Ethnicity ◽

Grade 3 ◽

Hispanic White

Abstract 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 <0.0001); TBI-based conditioning (RR=2.3; 95%CI, 1.1-4.8, p=0.02); and female sex (RR=1.6; 95%CI, 1.1-2.4, p=0.01) were associated with increased risk of cataracts. VTE: 10y cumulative incidence of thrombo-embolic events was 10.5% ± 1.6%. Older age at BMT (≥60y: RR=2.2; 95%CI, 1.2-3.9, p=0.007); non-Hispanic white race/ethnicity (RR=4.8; 95%CI, 2.0-11.2, p=0.0003); and pre-BMT exposure to doxorubicin (RR=2.1; 95%CI, 1.04-4.04, p=0.04) were associated with increased risk for VTE. SNs:10y cumulative incidence of SN was 14.0% ± 2.5%. Older age at BMT (≥60y: RR=2.2; 95%CI, 1.2-4.2, p=0.01), pre-BMT exposure to cyclophosphamide (RR=2.9, 95%CI,1.3-6.5, p=0.01) and IMiDs (thalidomide or lenalidomide: RR=3.8, 95%CI, 1.6-9.2, p=0.003); and non-Hispanic white race/ethnicity (RR=2.3; 95%CI, 1.1-4.8, p=0.03) were associated with increased risk for SNs. 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.

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Burden of Morbidity in 10+ Year Survivors of Hematopoietic Cell Transplantation (HCT): A Report From the Bone Marrow Transplant Survivor Study (BMTSS)

Blood ◽

10.1182/blood.v118.21.841.841 ◽

2011 ◽

Vol 118 (21) ◽

pp. 841-841

Author(s):

Can-Lan Sun ◽

John H. Kersey ◽

Liton Francisco ◽

K. Scott Baker ◽

Saro H. Armenian ◽

...

Keyword(s):

Cumulative Incidence ◽

Chronic Health Condition ◽

Health Condition ◽

Chronic Health Conditions ◽

Health Conditions ◽

Chronic Health ◽

Somatic Distress ◽

Healthcare Needs ◽

Life Threatening

Abstract Abstract 841FN2 Background: High-intensity therapeutic exposures and prolonged immunosuppression increase the risk of long-term complications after HCT, with an attendant increase in the healthcare needs of these long-term survivors. We have previously demonstrated that morbidity increases with increasing time after HCT (Sun CL, Blood, 2010;116:3129–39). However, the burden of morbidity in patients who survive extended lengths of time after HCT and the consequent healthcare needs of these survivors are unknown. Methods: Utilizing resources offered by the BMTSS, we evaluated the risk of chronic health conditions and psychological health of 366 10+ year HCT survivors and their siblings (n=309). A severity score (grade 1 [mild]; grade 2 [moderate], grade 3[severe], grade 4 [life-threatening], and grade 5 [death due to chronic health condition]) was assigned to each health condition using the CTCAE, v3.0. Cumulative incidence of chronic health conditions was evaluated, using competing risks method. Brief Symptom Inventory (BSI) was used to describe adverse psychological health. Multivariate regression analysis allowed identification of vulnerable subgroups. The current status of healthcare utilization by the HCT survivors was also evaluated. Results: The mean age at HCT was 22 years (range: 0.4–59.8) and at study participation was 37 years (range: 11–72); mean length of follow-up was 15 years (range: 10–28). Primary diagnoses included AML (28%), ALL (17%), CML (17%), NHL (11%), aplastic anemia (11%), HL (7%), and other diagnoses (9%). Stem cell graft was autologous (27%); allogeneic related (65%) and unrelated donor (8%); 72% of the patients received TBI-based conditioning. At least one chronic health condition was reported by 74% of the HCT survivors, compared with 29% of siblings (p<0.001); 25% of the survivors reported severe/life-threatening conditions compared to only 8% of the siblings (p<0.001). Commonly reported severe/life-threatening chronic health conditions included myocardial infarction, stroke, blindness, diabetes, musculoskeletal problems, and subsequent malignancies. As shown in Figure 1A, the 15-year cumulative incidence of any chronic health condition (grades 1–5) was 71% (95% CI, 67–75%), and of severe-life-threatening conditions or death was 40% (95% CI, 33–47%). HCT survivors were 5.6 times as likely to develop a severe/life-threatening condition (95% CI, 3.7–8.6), compared with age- and sex-matched siblings. The cumulative incidence of severe/life-threatening conditions did not differ by type of HCT (p=0.79, Figure 1B). Using BSI, we evaluated somatic distress, anxiety, and depression among HCT survivors and their siblings. While the prevalence of anxiety and depression were comparable between survivors and siblings, HCT survivors were 2.7 times more likely to report somatic distress (p<0.001). Among survivors, female gender (OR=3.6, 95% CI, 1.4–9.0), low household income (<$20,000 OR=4.4, 95% CI, 1.1–17.2), and poor self-rated health status (OR=10.6, 95% CI, 4.0–27.9) were associated with increased risk for somatic distress. Fortunately, 90% of HCT survivors carried health insurance coverage, because a high proportion needed ongoing specialized medical care; 69% of the HCT survivors reported cancer/HCT-related visits at an average of 15 years after HCT. Conclusions: The burden of long-term physical and emotional morbidity borne by 10+ year HCT survivors is substantial, resulting in a high utilization of specialized healthcare. Patients, families and healthcare providers need to be made aware of the high burden, such that they can plan for post-HCT care, even many years after HCT. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Morbidity and Mortality Experienced By Chronic Myeloid Leukemia (CML) Patients after Allogeneic Hematopoietic Cell Transplantation (HCT) - a Report from BMTSS-2

Blood ◽

10.1182/blood.v128.22.823.823 ◽

2016 ◽

Vol 128 (22) ◽

pp. 823-823

Author(s):

Jessica Wu ◽

Yanjun Chen ◽

Lindsey Hageman ◽

Can-Lan Sun ◽

Liton F. Francisco ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Chronic Health Conditions ◽

Health Conditions ◽

Advisory Committees ◽

Chronic Health ◽

Life Threatening ◽

Related Mortality

Abstract 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 <45y at HCT; 68% received HCT in 1st chronic phase (CP); 63% received matched related [MRD], 34% matched unrelated donor (MUD) and 3% non-myeloablative HCTs; 79% received TBI; 65.8% developed chronic GvHD. Vital status information was collected as of May, 2016, using medical records, National Death Index and Lexis Nexis. US mortality rates were obtained from CDC's National Center for Health Statistics. Thirty percent (n=192) died after having survived at least 2 years after HCT; median time between HCT and death was 8.3y. Of the 445 patients alive at study, 288 (65%) completed the BMTSS health questionnaire used to examine the risk of CTCAE grade 3 (severe) or 4 (life-threatening) chronic health conditions. A sibling comparison group (n=404) also completed the BMTSS questionnaire. 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<0.0001) than age-, race-, and sex-adjusted normal populations. For patients transplanted in 1st CP and surviving 15y, mortality rates became comparable with the general population (SMR, 1.5, 95% CI, 0.9-2.3, p=0.1). Among CML patients receiving HCT at <45y with Bu/Cy (n=70), overall survival was 81.5% at 20y from HCT; the 20y cumulative incidence of relapse-related mortality was 2.9% and of non-relapse-related mortality was 14%. This cohort was at 3.3-fold higher risk of death when compared with the general population (95% CI=1.7-5.7, p<0.0001). Late Morbidity: The 20y cumulative incidence of a severe/life-threatening chronic health condition among HCT survivors was 47.2% (95% CI, 39.0-54.9%); the incidence was higher (p=0.0006) for MUD vs. MRD recipients (Figure 2). After adjusting for age, sex, race and SES, HCT survivors were at 2.7-fold higher risk for severe/life-threatening chronic health conditions as compared with siblings (95% CI, 1.8-3.9, p<0.0001). The 20y cumulative incidence of specific conditions experienced by survivors and siblings were: SMNs (10.1% vs. 1.7%, p<0.001); diabetes (11.1% vs. 1.5%, p<0.001) and coronary artery disease (6.9% vs. 3.2%, p<0.001). CML patients receiving MRD HCT at <45y with Bu/Cy were not at increased risk of severe/life-threatening chronic health conditions when compared with the sibling comparison group (HR=0.81, 95% CI, 0.26-2.54, p=0.7). 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 <45y with Bu/Cy conditioning enjoy survival rates exceeding 81% at 20y from HCT, and their burden of long-term morbidity is comparable to that experienced by siblings. These findings could help inform decisions regarding therapeutic options for management of CML. 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.

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Severe/Life-Threatening/Fatal Chronic Health Conditions (CHCs) after Allogeneic Blood or Marrow Transplantation (BMT) in Childhood - a Report from the BMT Survivor Study (BMTSS)

Blood ◽

10.1182/blood-2020-133895 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-13

Author(s):

Anna Sallfors Holmqvist ◽

Yanjun Chen ◽

Jessica Wu ◽

Lindsey Hageman ◽

Kevin D. Battles ◽

...

Keyword(s):

Joint Replacement ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Gvhd ◽

Health Conditions ◽

Limited Information ◽

Allogeneic Bmt ◽

Life Threatening ◽

Grade 3

Background: Allogeneic BMT 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 thereby the risk of developing CHCs. Yet, there is limited information regarding CHC risk after allogeneic BMT performed in childhood. We address this gap in patients undergoing allogeneic BMT between 1974 and 2014 at 3 participating transplant centers. Methods: BMT recipients and a sibling comparison group (or the parents of participants <18y) completed a 255-item questionnaire that included sociodemographics and health conditions. A severity score (grades 3 [severe] or 4 [life-threatening]) was assigned to CHCs using CTCAE, v. 5.0. Deceased BMT recipients received a CHC-specific grade 5. Risk of severe/life-threatening CHC in BMT survivors vs. siblings: We calculated the cumulative incidence of CHCs for survivors and siblings as a function of attained age. We used logistic regression for estimating the risk of grade 3-4 conditions in survivors compared to siblings, adjusting for sex, age at study, race/ethnicity, education, household income, and health insurance. Risk of severe/life-threatening/fatal CHC in BMT recipients: We used proportional subdistribution hazards model (Fine-Gray) for competing risks to identify predictors of grade 3-5 CHCs, adjusting for demographics, primary disease, conditioning agents, disease status at BMT and chronic GvHD status. Results: 848 patients had received allogeneic BMT at age ≤22 and survived ≥2y after BMT (563 alive at study; 285 deceased after surviving ≥2y). Primary diagnoses included ALL (29%), AML/MDS (28%), SAA (13%), other (30%); median age at BMT: 11.5y (range: 0.4-22.0); median length of follow-up 10.7y (2.0-41.4). Risk of severe/life-threatening CHC in 563 BMT survivors vs. 515 siblings: Cumulative incidence of grade 3-4 condition by age 30y among BMT recipients was significantly higher than that among siblings (38.5±2.7% vs. 5.4±1.0%, p<0.0001), Figure 1. The adjusted odds of developing grade 3-4 CHCs were 8.9-fold higher in BMT survivors (95%CI 6.4-12.5). Higher odds were observed for developing cataracts (OR=48.2; 95%CI 17.9-129.5), heart disease (OR=11.4, 95%CI, 3.9-33.3), diabetes (OR=11.1; 95%CI 3.5-34.8), thyroid nodules (OR=6.6, 95%CI, 2.6-17.0), joint replacement (OR=4.4, 85%CI, 1.7-10.9), and sensorineural disorders (hearing loss/balance disorder/legally blind); OR=3.2, 95%CI, 1.5-6.8). Risk of severe/life-threatening/fatal CHCs in 848 BMT recipients: cumulative incidence of grades 3-5 CHCs was 60.5±3.0% at 40y (Figure 2). The most prevalent grade 3-5 CHCs were second malignancy (11.8%), cataract (5.9%), cardiovascular disease (5.8%), sensorineural disorder (4.4%), diabetes (3.4%), and joint replacement (2.9%). The risk of grades 3-5 CHCs was higher among females (HR=1.3, 95%CI 1.0-1.6), age >12y at BMT (HR=1.4, 95%CI 1.1-1.8) and among those exposed to TBI (HR=1.7, 95%CI 1.2-2.3). Conclusions: Two-year survivors of allogeneic BMT performed in childhood had an almost 10-fold higher risk of severe/life-threatening CHCs compared to siblings. By age of 30, 39% of the survivors had developed a severe or life-threatening CHC. The results of the present study call for close follow-up, from the time of transplantation continuing throughout life. Disclosures Weisdorf: Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Fate Therapeutics: Consultancy; Syndax: Research Funding; Kadmon: Research Funding; Pharmacyclics: Research Funding.

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Burdern of Long-Term Morbidity after Hematopoietic Cell Transplantation: A Report from the Bone Marrow Transplant Survivor Study (BMTSS).

Blood ◽

10.1182/blood.v110.11.832.832 ◽

2007 ◽

Vol 110 (11) ◽

pp. 832-832 ◽

Cited By ~ 2

Author(s):

Can-Lan Sun ◽

Liton Francisco ◽

Toana Kawashima ◽

Leslie L. Robison ◽

K.S. Baker ◽

...

Keyword(s):

Health Condition ◽

Chronic Health Conditions ◽

Health Conditions ◽

Unrelated Donor ◽

Chronic Health ◽

Threatening Condition ◽

Life Threatening ◽

Grade 3

Abstract Long-term survival is an expected outcome after HCT. However, no study has assessed the burden of long-term morbidity in these survivors, or attempted to identify subpopulations at highest risk for severe, debilitating conditions. In this study, we determined the prevalence and severity of chronic health conditions in a large population of long-term HCT survivors and compared these outcomes with their siblings. BMTSS, a collaborative effort between City of Hope National Medical Center and University of Minnesota, examined self-reported chronic health conditions in individuals who underwent HCT between 1976 and 1998, and survived two or more years. A severity score (grade 1 through 4, ranging from mild to life-threatening or disabling) was assigned to each health condition according to the Common Terminology Criteria for Adverse Events (version 3). A partial list of conditions graded as severe or life-threatening (grade 3 or 4) included congestive heart failure, second malignant neoplasms, coronary artery disease, cerebrovascular accident, renal failure/dialysis/renal transplant, and active chronic graft vs. host disease. Adverse psychosocial outcomes were not included. Cox proportional-hazard models were used to estimate hazard ratios and their 95% confidence intervals. We compared the prevalence and severity of chronic conditions in 1013 HCT survivors (455 autologous, 460 related donor, and 98 unrelated donor HCT survivors) with 309 siblings. The median age at study participation was 44 (range 18–73) and 45 years (range 17–79) for survivors and siblings, and the median follow-up for the survivors was 7.3 years (range 2–28) from HCT. Among the 1013 survivors, 69% had at least one chronic condition, and 29% had a severe or life-threatening condition (grade 3 or 4). The comparable figures in siblings were 39% and 7%, respectively (p<0.001 compared to survivors). After adjustment for age at HCT, sex and race/ethnicity, survivors were 2.4 times as likely as their siblings to develop any chronic health conditions (95%CI, 2.0–2.9), and 4.5 times more likely to develop severe/life threatening conditions (95%CI, 3.0–6.7). Groups at highest risk for a severe or life-threatening condition are summarized in the Table. Among survivors, the cumulative incidence of a chronic health condition reached 84% at 20 years post HCT, with a cumulative incidence of 55% for severe/life threatening conditions at 15 years after HCT. The chronic health burden of this population is significant, and life-long follow-up of patients who receive transplantation is recommended. Table: Groups at highest risk for severe or life-threatening condition Risk Factors Relative Risk 95% CI Siblings 1.0 __ CML 5.8 3.8–8.9 AML 4.9 3.2–7.5 ALL 5.2 3.3–8.3 Allogeneic sibling donor 5.9 3.9–8.7 Unrelated donor 7.4 4.9–11.1 TBI 5.0 3.4–7.5

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Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study

Blood ◽

10.1182/blood-2009-06-229369 ◽

2010 ◽

Vol 116 (17) ◽

pp. 3129-3139 ◽

Cited By ~ 141

Author(s):

Can-Lan Sun ◽

Liton Francisco ◽

Toana Kawashima ◽

Wendy Leisenring ◽

Leslie L. Robison ◽

...

Keyword(s):

Cell Transplantation ◽

Cumulative Incidence ◽

Chronic Condition ◽

Hematopoietic Cell Transplantation ◽

Health Condition ◽

Chronic Health Conditions ◽

Health Conditions ◽

Chronic Health ◽

Life Threatening

Abstract Long-term survival is now an expected outcome after hematopoietic cell transplantation (HCT). However, the burden of morbidity long-term after HCT remains unknown. We examined the magnitude of risk of chronic health conditions reported by 1022 HCT survivors and their siblings (n = 309). A severity score (grades 1 [mild] through 4 [life-threatening]) was assigned to each health condition using the Common Terminology Criteria for Adverse Events, Version 3. Sixty-six percent of the HCT survivors reported at least one chronic condition; 18% reported severe/life-threatening conditions; comparable values in siblings were 39% and 8%, respectively (P < .001). The cumulative incidence of a chronic health condition among HCT survivors was 59% (95% confidence interval [CI], 56%-62%) at 10 years after HCT; for severe/life-threatening conditions or death from chronic health conditions, the 10-year cumulative incidence approached 35% (95% CI, 32%-39%). HCT survivors were twice as likely as siblings to develop a chronic condition (95% CI, 1.6-2.1), and 3.5 times to develop severe/life-threatening conditions (95% CI, 2.3-5.4). HCT survivors with chronic graft-versus-host disease were 4.7 times as likely to develop severe/life-threatening conditions (95% CI, 3.0-7.2). The burden of long-term morbidity borne by HCT survivors is substantial, and long-term follow-up of patients who received transplantation is recommended.

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Long-Term Health-Related Outcomes In Survivors Of Childhood Hematopoietic Cell Transplantation (HCT): A Report From The Bone Marrow Transplant Survivor Study (BMTSS)

Blood ◽

10.1182/blood.v122.21.553.553 ◽

2013 ◽

Vol 122 (21) ◽

pp. 553-553

Author(s):

Saro Armenian ◽

Can-Lan Sun ◽

Mukta Arora ◽

K. Scott Baker ◽

Liton Francisco ◽

...

Keyword(s):

Premature Death ◽

Chronic Health Condition ◽

Health Condition ◽

Chronic Health Conditions ◽

Health Conditions ◽

Chronic Health ◽

Allogeneic Hct ◽

Increased Risk ◽

Life Threatening ◽

Grade 3

Abstract Introduction HCT is frequently offered as a curative option for children with benign and malignant conditions. Improvement in HCT strategies have increased survival by approximately 10% per decade. Adult HCT survivors are at increased risk for chronic health conditions (Sun, Blood 2010), and premature death (Bhatia, Blood 2007; 2005). The magnitude of risk of these chronic health conditions and of premature death in childhood HCT survivors is not known. Methods Participants were drawn from the BMTSS, and included patients undergoing HCT between 1976 and 1998 at City of Hope or University of Minnesota. Participants were ≤21 years of age at HCT and were ≥2 yrs from myeloablative HCT. Participants completed a questionnaire addressing the diagnosis of physical health conditions (endocrinopathies, central nervous system compromise, cardiopulmonary dysfunction, gastrointestinal sequelae, musculoskeletal abnormalities, and subsequent malignancies), chronic GvHD (cGVHD), and sociodemographics. Chronic physical health conditions were graded using CTCAE v 3.0 (grade 1-5, ranging from mild to death due to chronic health condition). Relative risk (RR) regression was used to identify risk of health conditions and 95% confidence interval (CI). Information on vital status and cause of death was obtained from medical records, National Death Index, and Social Security Death Index, and compared with age-, sex-and calendar-specific mortality of the US general population (standardized mortality ratio [SMR]). Results The current study included 317 BMTSS participants. Median age at HCT was 7.9 yrs, and at study participation was 19.9 yrs; time from HCT was 10.3 yrs; 42% were female, 86.7% were non-Hispanic white, and 79% underwent allogeneic HCT. The most frequent indications for HCT included AML (27%), ALL (21%), SAA (13%), lymphoma (6%), and CML (5%). Total body irradiation (TBI) was used in 61% of 2 year survivors, and cGvHD was reported in 26%. Health Conditions: The cumulative incidence of a chronic health condition (grade 1-5) was 56% (95% CI: 51%-60%) at 15 years after HCT, with a cumulative incidence of 25% (95% CI: 20%-30%) for severe/life-threatening or fatal condition (grade 3-5, Figure). The highest incidence of grade 3-5 conditions was in allogeneic HCT recipients with cGvHD (32% at 15 years, 95% CI: 20%-44%; Figure). Risk Factors: After adjustment for age at HCT, follow-up, ethnicity/race, diagnosis, relapse risk at HCT, and treatment era, female participants were 1.2 (1.0-1.4, p=0.02) times more likely to report a chronic health condition, and 1.6 (1.1-2.4, p=0.01) times more likely to report a severe/life-threatening/fatal condition. Exposure to TBI was associated with a 1.3-fold (1.0-1.5, p=0.02) risk of a chronic health condition, and a 2.6-fold (1.4-4.91, p=0.003) risk of a severe/life-threatening/fatal condition compared to chemotherapy-only conditioning. Among allogeneic HCT recipients, cGvHD was associated with a 2.0-fold (1.2-3.2, p<0.01) risk of severe/life-threatening/fatal conditions when compared to survivors without cGvHD. Healthcare utilization: 92% of the survivors carried health insurance and 68% had been seen at their transplant center within the past 2 yrs. Late mortality: Overall survival in 2 year survivors was 80% at 10 years (68% autologous, 83% allogeneic, p<0.01). The primary cause of death included primary disease (61%), secondary cancer (8%), cGvHD (6%), cardiopulmonary compromise (5%), and other causes (21%). The cohort was at a 22-fold (SMR 22.0, 18.9-25.5, p<0.01) increased risk of premature death compared to age-and sex-matched general population. Female participants, those treated with TBI, and autologous HCT survivors had the highest risk of premature death (Table). Conclusions Childhood HCT survivors carry a substantial burden of morbidity, years following completion of therapy, providing clear evidence for their close monitoring in a specialized setting targeting these high risk complications. Disclosures: No relevant conflicts of interest to declare.

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Increasing risk of chronic health conditions in aging survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.9514 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 9514-9514

Author(s):

Gregory T. Armstrong ◽

Toana Kawashima ◽

Wendy M. Leisenring ◽

Marilyn Stovall ◽

Charles A Sklar ◽

...

Keyword(s):

Childhood Cancer ◽

Cumulative Incidence ◽

Premature Aging ◽

Chronic Health Conditions ◽

Health Conditions ◽

High Risk Population ◽

Chronic Health ◽

Increased Risk ◽

Grade 3 ◽

Survivors Of Childhood Cancer

9514 Background: Survivors of childhood cancer are at an increased risk for treatment-related chronic health conditions during early adulthood. However, the incidence, severity, and spectrum of chronic health conditions in the fourth and fifth decades of life have not been well studied. Methods: Analyses included 14,358 > 5 yr survivors of childhood cancer (median age at last follow-up 32.3 yrs, range 8.0-58.0; 21.4% > 40 years) and a sibling comparison group (n = 4,031). Self-reported health conditions were classified using NCI CTCAE 4.0 grading system. Analyses focused on two primary outcomes: severe/life-threatening/fatal conditions (grades 3-5), and multiple (≥ 2) conditions. Cumulative incidence of a new chronic health condition was calculated from age 26 yrs. Cox proportional hazards models adjusted for gender and race, were evaluated using age as the time scale. Results: Among survivors with no previous health conditions through age 25, the cumulative incidence for a new grade 3-5 condition by age 50 compared to siblings was 45.9% (95% CI 45.9-45.9) vs. 13.9%, (95% CI 13.9-14.0) and for new onset of ≥ 2 conditions 33.0% (95% CI 33.0-33.1) vs. 24.9% (95% CI 24.8-24.9) . Survivors ≥ 40 yrs of age had a 5.8-fold (95% CI 5.3 – 6.5) increased risk of a grade 3-5 condition compared to same age siblings, in contrast to those < 40 years of age (HR 2.7, 95% CI 2.5-3.0). A similar magnitude of difference was present for risk of >2 conditions (HR 2.7 vs. 1.2). In comparison to siblings, survivors > 40 years of age had a significantly increased risk for: congestive heart failure (HR 15.7, 95% CI 9.2-26.7), myocardial infarction (HR 8.8, 95% CI 6.0-12.9), stroke (HR 8.6, 95% CI 5.6-13.2),joint replacement (HR 6.8, 95% CI 4.1-11.4), renal failure (HR 5.1, 95% CI 2.2-11.9) among other serious conditions. Conclusions: As they age, adult survivors of childhood cancer continue to develop new and serious health conditions at substantially higher rates than siblings. These data emphasize the importance of placing a greater focus on investigations of premature aging and organ senescence in this high risk population.

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Temporal trends in chronic disease among survivors of childhood cancer diagnosed across three decades: A report from the Childhood Cancer Survivor Study (CCSS).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.18_suppl.lba10500 ◽

2017 ◽

Vol 35 (18_suppl) ◽

pp. LBA10500-LBA10500 ◽

Cited By ~ 1

Author(s):

Todd M. Gibson ◽

Sogol Mostoufi-Moab ◽

Kayla Stratton ◽

Dana Barnea ◽

Eric Jessen Chow ◽

...

Keyword(s):

Chronic Disease ◽

Childhood Cancer ◽

Hodgkin Lymphoma ◽

Cumulative Incidence ◽

Wilms Tumor ◽

Lymphoblastic Leukemia ◽

Chronic Health Conditions ◽

Health Conditions ◽

Malignant Neoplasms ◽

Chronic Health

LBA10500 Background: Modifications in childhood cancer treatments in recent decades have contributed to reductions in late mortality among 5-year survivors. We used the recently expanded CCSS cohort to investigate whether these changes have also reduced the incidence of chronic disease. Methods: We evaluated the incidence of severe, disabling/life-threatening, or fatal chronic health conditions (Common Terminology Criteria for Adverse Events, CTCAE grades 3-5) among 5-year survivors diagnosed prior to age 21 years from 1970 through 1999. We calculated the 15-year cumulative incidence of chronic health conditions by decade of cancer diagnosis and compared risk across decades using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 23,601 survivors, median age 28 years (range 5-63), 21 years from diagnosis (5-43), the 15-year cumulative incidence of grade 3-5 conditions decreased from 12.7% in survivors diagnosed in the 1970s to 10.1% and 8.8% in those diagnosed in the 1980s and 1990s (per 10 years, HR 0.84 [95% CI = 0.80-0.89]). The association with diagnosis decade was attenuated (HR 0.92 [0.85-1.00]) when detailed treatment data were included in the model, indicating that treatment reductions mediated risk. Adjusted for sex and attained age, significant reduction in risk over time was found among survivors of Wilms tumor (HR 0.57 [0.46-0.70]), Hodgkin lymphoma (HR 0.75 [0.65-0.85]), astrocytoma (HR 0.77 [0.64-0.92]), non-Hodgkin lymphoma (HR 0.79 [0.63-0.99]), and acute lymphoblastic leukemia (HR 0.86 [0.76-0.98]). Decreases were largely driven by a reduced incidence of endocrine conditions (1970s: 4.0% v. 1990s:1.6%; HR 0.66 [0.59-0.73]) and subsequent malignant neoplasms (1970s: 2.4% v. 1990s: 1.6%; HR 0.85 [0.76-0.96]). Significant reductions were also found for gastrointestinal (HR 0.80 [0.66-0.97]) and neurological conditions (HR 0.77 [0.65-0.91]), but not cardiac or pulmonary conditions. Conclusions: Changes in childhood cancer treatment protocols have not only extended lifespan for many survivors, but have also reduced the incidence of serious chronic morbidity in this population.

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Differential Morbidity by Ethnicity in Long-Term Survivors of Hematopoietic Cell Transplantation (HCT): A Report from the Bone Marrow Transplant Survivor Study (BMTSS)

Blood ◽

10.1182/blood.v112.11.454.454 ◽

2008 ◽

Vol 112 (11) ◽

pp. 454-454

Author(s):

Saro Armenian ◽

Can-Lan Sun ◽

Liton Francisco ◽

K. Scott Baker ◽

Stephen J. Forman ◽

...

Keyword(s):

Chronic Health Condition ◽

Health Condition ◽

Chronic Health Conditions ◽

Health Conditions ◽

Malignant Neoplasms ◽

Chronic Health ◽

Allogeneic Hct ◽

Healthcare Needs ◽

Life Threatening

Abstract Improvement in transplantation strategies have contributed to incremental change in post-HCT survival rates of 10% per decade; but this improvement is not enjoyed equally by all. Data from the CIBMTR (J Clin Oncol2005;23:7032–42) found Hispanics to be at a higher risk of treatment failure (relapse or death: hazard ratio [HR]=1.3, 95% confidence interval [CI], 1.1–1.5), when compared to non-Hispanic whites. According to the 2005 census, Hispanics form the largest ethnic minority group in the U.S., constituting 14.4% of the entire population. Compared to non-Hispanic whites, Hispanics are considered to be a vulnerable population for adverse health outcomes, due to reasons that include socioeconomic, cultural, and language barriers as well as barriers within the healthcare system. The purpose of this study was to determine the prevalence of and risk factors for chronic health conditions in a large population of Hispanic and non-Hispanic white HCT survivors. The BMTSS (a collaborative effort between City of Hope National Medical Center and University of Minnesota) examined self-reported chronic health conditions in individuals who underwent HCT between 1976 and 1998, and survived two or more years. A severity score (grade 1 through 4, ranging from mild to life-threatening or disabling) was assigned to each health condition according to the Common Terminology Criteria for Adverse Events (version 3). Some of the conditions graded as severe (grade 3) or life-threatening (grade 4) in this study included congestive heart failure, second malignant neoplasms, cerebrovascular accident, renal failure, and active chronic graft vs. host disease (GvHD). Adverse psychosocial outcomes were not included. Cox proportional-hazard models were used to estimate HR and 95% CI. The current study included 984 HCT survivors (443 [45.0%] allogeneic HCT and 541 [55.0%] autologous HCT recipients; 825 [83.8%] non-Hispanic whites and 159 [16.2%] Hispanics). Median age at study participation was 44.5 years (range, 18.2–73.0) for whites and 41.5 years (range 20.0–67.4) for Hispanics, and median follow-up was 7.3 years (range 2.0–27.8) and 8.0 years (range 2.5–25.2), respectively. There were no differences with respect to gender, BMI, presence of active chronic GvHD, relapse risk, and cancer surveillance practices, between the two ethnic groups. Hispanics were significantly less likely to have completed high school (55.1% vs. 96.6%, p<0.001) and to be currently insured (75.9% vs. 93.7%, p<0.001). Hispanics were significantly more likely to have undergone allogeneic HCT (67.9% vs. 52.5%; P<0.01), and received the majority of their continued medical care at a cancer center (90.1% vs. 77.8%; p<0.01). Hispanics were significantly less likely to report a chronic health condition of any severity (60.4% vs. 72.0%; p<0.01). In fact, the cumulative incidence of a self-reported severe/life threatening chronic health condition was significantly higher for whites, when compared with Hispanics (54% vs. 41% at 10 years after HCT, p=0.02). After adjustment for age at HCT, gender, health insurance, primary diagnosis, type of HCT, exposure to TBI, length of follow-up after HCT, exposure to alcohol and tobacco, non-Hispanic whites were 1.34 (95% CI, 1.1–1.6) times as likely as Hispanics to report a chronic health condition; 1.38 (1.0–1.8) times as likely to report a mild/moderate condition; and 1.39 (1.1–1.8) times more likely to report a severe/life threatening condition. However, adjustment for education resulted in a mitigation of the ethnic differences, and the residual differences in chronic health conditions between whites and Hispanics were statistically non-significant (HR=1.18 [0.95–1.5, p=0.1], 1.13 [0.9–1.5, p=0.40, and 1.16 [0.9–1.5], respectively). This study demonstrates that the ability to self-report the presence of chronic health conditions may be a function of the educational status, and underscores the critical need for culturally adapted awareness of healthcare needs and issues among the educationally disadvantaged survivors, in order to improve their ability to seek and obtain adequate healthcare and reduce the associated morbidity and mortality.

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