Abstract
Background: The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes. Methods: This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied. Results: The median age was 55 years (range, 18-83 years). The median PCS was –0.21 (range, –1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was –0.13 (range, –1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P =.0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P =.0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P =.0004). CCS was not significantly associated with survival, relapse, or NRM. Conclusions: Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 609-618 |
| Number of pages | 10 |
| Journal | cancer |
| Volume | 127 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 15 2021 |
Funding
Siddhartha Ganguly reports personal fees from Seattle Genetics, Kite Pharma, and Kadmon outside the submitted work. Richard F. Olsson reports personal fees from AstraZeneca outside the submitted work. Jean A. Yared reports grants from Gilead and other from Jazz outside the submitted work. Sachiko Seo reports personal fees from Janssen Pharmaceutical KK outside the submitted work. Usama Gergis reports working on speakers' bureaus for Incyte, Merck, Kite, Astellas, and Jazz; consulting for Astellas; and working on ad boards for Mesoblast and Jazz. Akshay Sharma is the principal investigator of a clinical trial for gene therapy of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics, and the sponsor provides funding for the clinical trial, which includes salary support paid to Sharma's institution; this is not related in any way to the submitted work. In addition, Sharma reports research collaborations with Novartis, Magenta Therapeutics, and Bluebird Bio, for which he is not financially compensated in any way. Hélène Schoemans reports nonfinancial support from Celgene, AbbVie, and Incyte; personal fees from Jazz Pharmaceuticals, Novartis, Takeda, Incyte, and Janssen; and grants from Novartis outside the submitted work. Jan Cerny reports other from Jazz Pharmaceuticals, Incyte, and Daiichi‐Sankyo outside the submitted work. David Rizzieri reports personal fees from Amgen, Kite, AROG, Pharmacyclics, Seattle Genetics, Pfizer, Novartis, Sanofi‐Aventis, Incyte, Gilead, Jazz, and Celgene and other from AbbVie, Celltrion/Teva, Mustang, Bayer, and Stemline outside the submitted work. Bronwen E. Shaw reports personal fees from Orca Biosystems and Merck Sharp & Dohme outside the submitted work. William A. Wood reports grants from Pfizer and Genentech outside the submitted work. J. Douglas Rizzo reports other from the Health Resources and Services Administration and Optum Health during the conduct of the study. Navneet S. Majhail reports personal fees from Incyte, Anthem, and Mallinckrodt outside the submitted work. The other authors made no disclosures. Navneet S. Majhail is partially supported by a grant from the National Cancer Institute (R01‐CA215134). The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service grant/cooperative agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases; U24HL138660 from the National Heart, Lung, and Blood Institute and the National Cancer Institute; OT3HL147741, R21HL140314, and U01HL128568 from the National Heart, Lung, and Blood Institute; HHSH250201700006C, SC1MC31881‐01‐00, and HHSH250201700007C from the Health Resources and Services Administration; and N00014‐18‐1‐2850, N00014‐18‐1‐2888, and N00014‐20‐1‐2705 from the Office of Naval Research. Additional federal support is provided by P01CA111412, R01CA152108, R01CA215134, R01CA218285, R01CA231141, R01HL126589, R01AI128775, R01HL129472, R01HL130388, R01HL131731, U01AI069197, U01AI126612, and the Biomedical Advanced Research and Development Authority. Support is also provided by the Be the Match Foundation, Boston Children's Hospital, Dana‐Farber, the Japan Hematopoietic Cell Transplantation Data Center, St. Baldrick's Foundation, the National Marrow Donor Program, the Medical College of Wisconsin, and the following commercial entities: AbbVie; Actinium Pharmaceuticals, Inc; Adaptive Biotechnologies; Adienne SA; AlloVir, Inc; Amgen, Inc; Anthem, Inc; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc; Bluebird Bio, Inc; Bristol‐Myers Squibb Co; Celgene Corp; Chimerix, Inc; CSL Behring; CytoSen Therapeutics, Inc; Daiichi Sankyo Co, Ltd; Gamida‐Cell, Ltd; Genzyme; GlaxoSmithKline; HistoGenetics, Inc; Incyte Corporation; Janssen Biotech, Inc; Janssen Pharmaceuticals, Inc; Janssen/Johnson & Johnson; Jazz Pharmaceuticals, Inc; Kiadis Pharma; Kite Pharma; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Mallinckrodt LLC; Medac GmbH; Merck & Company, Inc; Merck Sharp & Dohme Corp; Mesoblast; Millennium (the Takeda Oncology Co); Miltenyi Biotec, Inc; Novartis Oncology; Novartis Pharmaceuticals Corporation; Omeros Corporation; OncoImmune, Inc; Orca Biosystems, Inc; Pfizer, Inc; Pharmacyclics, LLC; Regeneron Pharmaceuticals, Inc; REGiMMUNE Corp; Sanofi Genzyme; Seattle Genetics; Sobi, Inc; Takeda Oncology; Takeda Pharma; Terumo BCT; Viracor Eurofins; and Xenikos BV. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (grant P30 CA016672). The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, the Health Resources and Services Administration, or any other agency of the US government. Navneet S. Majhail is partially supported by a grant from the National Cancer Institute (R01-CA215134). The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service grant/cooperative agreement U24CA076518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases; U24HL138660 from the National Heart, Lung, and Blood Institute and the National Cancer Institute; OT3HL147741, R21HL140314, and U01HL128568 from the National Heart, Lung, and Blood Institute; HHSH250201700006C, SC1MC31881-01-00, and HHSH250201700007C from the Health Resources and Services Administration; and N00014-18-1-2850, N00014-18-1-2888, and N00014-20-1-2705 from the Office of Naval Research. Additional federal support is provided by P01CA111412, R01CA152108, R01CA215134, R01CA218285, R01CA231141, R01HL126589, R01AI128775, R01HL129472, R01HL130388, R01HL131731, U01AI069197, U01AI126612, and the Biomedical Advanced Research and Development Authority. Support is also provided by the Be the Match Foundation, Boston Children's Hospital, Dana-Farber, the Japan Hematopoietic Cell Transplantation Data Center, St. Baldrick's Foundation, the National Marrow Donor Program, the Medical College of Wisconsin, and the following commercial entities: AbbVie; Actinium Pharmaceuticals, Inc; Adaptive Biotechnologies; Adienne SA; AlloVir, Inc; Amgen, Inc; Anthem, Inc; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc; Bluebird Bio, Inc; Bristol-Myers Squibb Co; Celgene Corp; Chimerix, Inc; CSL Behring; CytoSen Therapeutics, Inc; Daiichi Sankyo Co, Ltd; Gamida-Cell, Ltd; Genzyme; GlaxoSmithKline; HistoGenetics, Inc; Incyte Corporation; Janssen Biotech, Inc; Janssen Pharmaceuticals, Inc; Janssen/Johnson & Johnson; Jazz Pharmaceuticals, Inc; Kiadis Pharma; Kite Pharma; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Mallinckrodt LLC; Medac GmbH; Merck & Company, Inc; Merck Sharp & Dohme Corp; Mesoblast; Millennium (the Takeda Oncology Co); Miltenyi Biotec, Inc; Novartis Oncology; Novartis Pharmaceuticals Corporation; Omeros Corporation; OncoImmune, Inc; Orca Biosystems, Inc; Pfizer, Inc; Pharmacyclics, LLC; Regeneron Pharmaceuticals, Inc; REGiMMUNE Corp; Sanofi Genzyme; Seattle Genetics; Sobi, Inc; Takeda Oncology; Takeda Pharma; Terumo BCT; Viracor Eurofins; and Xenikos BV. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (grant P30 CA016672). The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, the Health Resources and Services Administration, or any other agency of the US government. Siddhartha Ganguly reports personal fees from Seattle Genetics, Kite Pharma, and Kadmon outside the submitted work. Richard F. Olsson reports personal fees from AstraZeneca outside the submitted work. Jean A. Yared reports grants from Gilead and other from Jazz outside the submitted work. Sachiko Seo reports personal fees from Janssen Pharmaceutical KK outside the submitted work. Usama Gergis reports working on speakers' bureaus for Incyte, Merck, Kite, Astellas, and Jazz; consulting for Astellas; and working on ad boards for Mesoblast and Jazz. Akshay Sharma is the principal investigator of a clinical trial for gene therapy of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics, and the sponsor provides funding for the clinical trial, which includes salary support paid to Sharma's institution; this is not related in any way to the submitted work. In addition, Sharma reports research collaborations with Novartis, Magenta Therapeutics, and Bluebird Bio, for which he is not financially compensated in any way. H?l?ne Schoemans reports nonfinancial support from Celgene, AbbVie, and Incyte; personal fees from Jazz Pharmaceuticals, Novartis, Takeda, Incyte, and Janssen; and grants from Novartis outside the submitted work. Jan Cerny reports other from Jazz Pharmaceuticals, Incyte, and Daiichi-Sankyo outside the submitted work. David Rizzieri reports personal fees from Amgen, Kite, AROG, Pharmacyclics, Seattle Genetics, Pfizer, Novartis, Sanofi-Aventis, Incyte, Gilead, Jazz, and Celgene and other from AbbVie, Celltrion/Teva, Mustang, Bayer, and Stemline outside the submitted work. Bronwen E. Shaw reports personal fees from Orca Biosystems and Merck Sharp & Dohme outside the submitted work. William A. Wood reports grants from Pfizer and Genentech outside the submitted work. J. Douglas Rizzo reports other from the Health Resources and Services Administration and Optum Health during the conduct of the study. Navneet S. Majhail reports personal fees from Incyte, Anthem, and Mallinckrodt outside the submitted work. The other authors made no disclosures. Access to allogeneic hematopoietic cell transplantation (HCT) and its outcomes can be influenced by several factors contributing to health care disparity.1-6 Health care disparity is a complex construct; multilevel patient, provider, institutional, community, and societal factors are important in the context of allogeneic HCT.2,3 These factors may influence patients' choices and behaviors as well as transplant center practices. The role of patient-level factors is easier to understand and evaluate; age, sex, race/ethnicity, and socioeconomic status have been frequently studied as social determinants of HCT access and recipient outcomes.1-4 The impact of health disparities as determined by community factors on allogeneic HCT outcomes is less clear and has been only partially described with sociodemographic factors such as race, ethnicity, and income. Community factors may be associated with allogeneic HCT outcomes because transplant centers and providers cannot always identify, address, or mitigate patient-specific community and social issues that may directly or indirectly influence recipient outcomes. In addition, the health status of the community where a center is located may affect its practices, referral patterns, and care delivery system, which may ultimately be reflected in individual patient outcomes and the aggregate outcomes of all patients undergoing transplantation at that center. As noted previously, the HCT literature has mostly focused on sex, race/ethnicity, and socioeconomic status.7,8 A significant challenge in comprehensively describing the myriad health care disparity factors in allogeneic HCT is the lack of a tool that can objectively evaluate community and social determinants of health among transplant recipients. The County Health Rankings and Roadmaps (CHRR) project uses information on sociodemographic, environmental, and community health status from several national data resources and summarizes them into a composite measure of the health status for all counties in the United States.9 The county health status based on this resource has been associated with access to and outcomes of complex surgical procedures and has been investigated in solid organ transplantation.10-12 We used data on community health disparity factors from the CHRR and data on patient characteristics and transplant outcomes from the Center for International Blood and Marrow Transplant Research (CIBMTR) to test our hypothesis that the community health status of the patient and the center is associated with patient outcomes after allogeneic HCT. The primary objective of our study was to evaluate associations of the community health status of patient residence and the community health status of transplant center location with patient survival, relapse, and nonrelapse mortality (NRM). The CIBMTR administers the Stem Cell Therapeutic Outcomes Database, a component of the C.W. Bill Young Transplantation Program, through a contract with the Health Resources and Services Administration. Under the purview of this law, transplant centers in the United States are required to report data for all allogeneic HCT recipients to the CIBMTR. As part of this contract, the CIBMTR performs an annual center-specific outcomes analysis (CSA) and reports risk-adjusted 1-year survival for first allogeneic HCT within a rolling 3-year window for each center in the United States.13-15 The CSA method reflects recommendations of the 2010 Center-Specific Outcomes Analysis Forum.16,17 The CSA model is a complex statistical model and currently considers more than 30 variables. Variables for which adjustments are to be made are determined through model selection procedures. As a secondary objective, we explored whether the patient community risk score (PCS) and the center community risk score (CCS) would be independent predictors of 1-year survival; we used the same exact model (a pseudo-value logistic regression model) and parameters that are currently analyzed in the CSA model. The CIBMTR is a voluntary and international working group of transplantation centers that contribute data on HCT to statistical centers located at the Medical College of Wisconsin (Milwaukee, Wisconsin) and the National Marrow Donor Program (Minneapolis, Minnesota). Participating centers are required to report all transplantations consecutively; patients are followed longitudinally. Computerized checks for discrepancies, physician reviews of submitted data, and onsite audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with the privacy rule (Health Insurance Portability and Accountability Act) as a public health authority and with all applicable federal regulations, as determined by continuous review of the institutional review board of the National Marrow Donor Program. The CIBMTR is a voluntary and international working group of transplantation centers that contribute data on HCT to statistical centers located at the Medical College of Wisconsin (Milwaukee, Wisconsin) and the National Marrow Donor Program (Minneapolis, Minnesota). Participating centers are required to report all transplantations consecutively; patients are followed longitudinally. Computerized checks for discrepancies, physician reviews of submitted data, and onsite audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with the privacy rule (Health Insurance Portability and Accountability Act) as a public health authority and with all applicable federal regulations, as determined by continuous review of the institutional review board of the National Marrow Donor Program. The CHRR project is a collaboration between the University of Wisconsin Population Health Institute and the Robert Wood Johnson Foundation. The CHRR provides annually updated information on county-level health factors and outcomes that can serve as surrogate measures of disparities among communities.9,18 Data on these measures are obtained from a variety of public data sources.18 The measures are standardized among all counties across the United States, are combined with scientifically informed weights, and are publicly available at https://www.countyhealthrankings.org/. Details of the ranking methodology and measures are available through the CHRR website. Briefly, counties in each of the 50 US states are ranked according to summaries of a variety of health measures. The overall Health Factors summary score is a weighted composite of 4 components: health behaviors, clinical care, social and economic environment, and physical environment. For example, the measures included within the health behaviors domain are rates of adult smoking, adult obesity, physical inactivity, excessive drinking, alcohol-impaired driving deaths, sexually transmitted diseases, and teen birth as well as the food environment index and access to exercise opportunities. The clinical care domain consists of rates of uninsurance, preventable hospital stays, diabetes monitoring, and mammography screening and the availability of primary care physicians, dentists, and mental health providers. Using the 2018 CHRR data, we created patient- and center-specific composite scores based on health factors assigned to the zip code of the patient residence and center location; this allowed the calculation of a nationally standardized score for each patient and center, respectively. We normalized the Z scores of 30 variables constituting health factors from the CHRR to bring all measures into the same scale by subtracting the national average of that measure and dividing by the national standard deviation (SD). For most measures, a higher score indicated worse health factors. For the few measures for which this was reversed (ie, diabetes monitoring and mammography screening), the Z scores were multiplied by ?1 to maintain directional consistency. We computed the final PCS by multiplying Z scores for all measures by their weights and then adding all weighted measures. For PCS, we linked the zip codes of patient residences at the time of HCT to county information by using the Federal Information Processing Standards (FIPS) from the Centers for Disease Control and Prevention.19 Similarly, we assigned CCS by deriving a composite score from the zip code and FIPS of each transplant center location. For our study, we used data on patients included in the CIBMTR's 2018 CSA data set. The data set included 24,141 adult recipients who underwent their first allogeneic HCT at US centers from 2014 to 2016. We excluded recipients who were younger than 18 years at the time of HCT because of the concern that different factors influenced their outcomes in comparison with adults (n = 3784). We excluded patients who had missing zip code or FIPS information (n = 506) or had not consented to research (n = 1166). We also excluded 138 patients residing in counties for whom no data were available in the CHRR. Categories with a very small number of recipients were also excluded (2 recipients with inherited erythrocyte abnormalities and 1 related cord blood transplant recipient). Hence, our final study cohort consisted of 18,544 patients (Table 1). The main objective of our study was to evaluate the association of PCS and CCS with patient survival after allogeneic HCT. Because we were also interested in assessing the association of PCS and CCS with relapse and NRM, we conducted a subgroup analysis in patients with hematologic malignancies (n = 17,793) after excluding 735 patients with nonmalignant diseases and 19 with solid tumors (Table 1). For our secondary objective, we explored whether patient- and center-level health disparity factors would make a significant contribution to the center-specific analysis focused on 1-year survival. We included our study cohort of 18,544 patients to test whether the addition of PCS or CCS provided any additional information on center-specific survival, which was estimated by a validated methodology. For this analysis, we used the exact same model, parameters, and outcome currently used in the CSA model. For the primary objective, we used a Cox proportional hazards model to test the association of PCS and CCS with overall survival (OS), relapse, and NRM. For relapse and NRM analysis, the cohort was further restricted to those with hematologic malignancies (n = 17,793). Variables included for the analyses were as follows: recipient age/sex, recipient race/ethnicity, donor age/sex, donor race/ethnicity, performance score at HCT, disease indication, HCT comorbidity index,20 transplant year, recipient and donor cytomegalovirus status, graft sources, donor types, human leukocyte antigen match status, donor parity, history of mechanical ventilation, history of invasive fungal infection, socioeconomic status, and disease-specific variables (eg, time from diagnosis to transplant for acute myeloid leukemia [AML] and acute lymphoblastic leukemia [ALL], therapy-related AML or myelodysplastic syndrome, AML European LeukemiaNet risk group,21 ALL cytogenetic risk group,22 cell lineage for ALL, myelodysplastic syndrome risk score,23 chemotherapy sensitivity for lymphomas, subtype of non-Hodgkin lymphoma, cytogenetic risk group,24 and International Staging System score for myeloma). Conditioning intensity was additionally considered as a covariate.25 Given the very large sample size, we used the ? level of.01 as a significance level for this analysis. For our secondary exploratory analysis, we evaluated whether PCS and CCS provided any additional information on the endpoint used in the annual center-specific analysis of 1-year survival. We examined whether the addition of PCS and CCS to regression models was significantly associated with the adjusted odds of 1-year survival; the center-specific analysis uses a pseudo-value logistic regression model that allows censoring to be accommodated. CSA uses an ? level of.05 to declare significance; thus, the same threshold was used for this analysis.13 As noted previously, we included all adult recipients with all disease indications in this analysis (n = 18,544). All analyses were performed with SAS 9.4 (SAS, Cary, North Carolina). All tests were 2-sided.
Keywords
- allogeneic transplant
- community health
- hematopoietic cell transplantation
- survival
ASJC Scopus subject areas
- Oncology
- Cancer Research
