Badawy, Sherif M

ABSTRACTBackgroundIn this study, we compared outcomes of intensified myeloablative conditioning regimens using large registry data from Japan (Japanese Society for Transplantation and Cellular Therapy) and the United States (Center for International Blood and Marrow Transplant Research).MethodsAdult patients who underwent their first myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia in remission between 2010 and 2018 using conditioning regimens of cyclophosphamide plus total‐body irradiation (CY/TBI), CY/TBI+cytarabine (AraC), or CY/TBI+etoposide (VP16) were included.ResultsThe acute myeloid leukemia (AML) cohort (N = 480, 38.8%) indicated that overall survival (OS) was poorer in CY/TBI+AraC (hazard ratio [HR] 1.46, p < 0.001) and CY/TBI+VP16 (HR 1.39, p = 0.059) compared to CY/TBI. Relapse was not suppressed, while treatment‐related mortality (TRM) was significantly higher (HR 1.78 and 1.74, p < 0.001 and 0.018, respectively). In the acute lymphoblastic leukemia (ALL) cohort (N = 3901, 61.2%), OS was comparable among these regimens. With intensified regimens, relapse was significantly suppressed in CY/TBI+VP16 (HR 0.74, p = 0.005), while TRM was higher (HR 1.21, p = 0.077). No interactions were observed regarding the country.ConclusionIn AML adding AraC and VP16 to CY/TBI had an adverse effect on OS. Conversely, in ALL, adding VP16 or AraC to CY/TBI did not affect survival, but the addition of VP16 reduced the risk of relapse.Clinical Trial RegistrationThe authors have confirmed clinical trial registration is not needed for this submission.

Abstract Although social determinants of health (SDoH) investigations have shown limited analyses of socioeconomic and race-ethnic status on certain hematologic malignancies, the impact of factors beyond those across a fuller scope of hematologic cancers remains unknown. The Social Vulnerability Index (SVI), a tool for assessing varied US census–derived sociodemographic factors, allows for the specific quantification of SDoH in dynamic, regional contexts for their associations with hematologic malignancy inequities. To assess the summative influence of varied SDoH factors on hematologic malignancy outcomes and discern which SDoH factors contributed the largest associations toward disparities, 796 005 adults with hematologic malignancies between 1975 to 2017 were identified for this retrospective cohort study. Vulnerability in 15 SDoH factors was measured using composite and subcategory SVI scores geographically matched to patients. Regressions between SVI factors and follow-up time after diagnosis and survival period were performed. Increasing overall SVI correlated with significantly decreased surveillance period in 11 of 14 hematologic malignancies, with decreases upward of 33.4% (39.0-26.0 months for acute lymphocytic leukemia). Increasing SVI significantly associated with decreased survival period across 11 of 14 hematologic malignancies, with decreases upward of 47.2% (89.5-47.3 months for Hodgkin lymphoma). Socioeconomic status and housing and transportation vulnerabilities showed the largest magnitude of contributions, followed by minority language and household composition. Significant decreases in hematologic malignancy prognosis associate with increasing overall SDoH vulnerability in varied sociodemographic contexts in the United States. Furthermore, there are quantifiable differences in which types of SDoH contribute more to trends per malignancy type. These findings demonstrate specific SDoH targets for further research and policy initiatives to combat hematologic malignancy disparity more effectively.

Abstract There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P &lt; .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

Abstract The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P &lt; .001 and HR 5.01, P &lt; .001, respectively) and OS (HR 3.85, P &lt; .001 and HR 8.13, P &lt; .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post–auto-HSCT.

Abstract Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.

AbstractWe studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008–2017 to develop a prognostic model to predict outcomes. High‐risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high‐risk cytogenetics [hazard ratio, (HR) 1·68 (1·3–2·17)] and pre‐AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33–2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07–1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three‐category system with low risk (0–3), intermediate risk (4–8) and high risk (9–10) showed 3‐year progression‐free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52–63) vs. 49% (95% CI: 43–56) vs. 31% (95% CI: 12–51), P < 0.001 respectively, and 3‐year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84–91) vs. 81% (95% CI: 76–86) vs. 64% (95% CI: 39–80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

BackgroundThe 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.MethodsThis 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.ResultsThe 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.ConclusionsPatients 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.

BackgroundUpfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults.MethodsThe authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression‐free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori.ResultsAn increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m2 overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m2. On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1‐1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9‐1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1‐1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1‐1.4 [P = .02]) compared with the reference group (those aged 60‐69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m2 was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m2, including day 100 NRM (1% [95% CI, 1%‐2%] vs 0% [95% CI, 0%‐1%]; P = .003]), 2‐year PFS (64% [95% CI, 60%‐67%] vs 69% [95% CI, 66%‐73%]; P = .003), and 2‐year OS (85% [95% CI, 82%‐87%] vs 89% [95% CI, 86%‐91%]; P = .01]), likely representing frailty.ConclusionsThe results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.

Abstract We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, &lt;1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was &lt;1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

Abstract There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P &lt; .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.