Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity.

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

Community health status and outcomes after allogeneic hematopoietic cell transplantation in the United States.

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.

Comparison of High Doses of Total Body Irradiation in Myeloablative Conditioning before Hematopoietic Cell Transplantation.

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse but is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high-dose total body irradiation (TBI) divided into intermediate high dose (IH; 13-13.75 Gy) and high dose (HD; 14 Gy) with standard dose (SD; 12 Gy) with cyclophosphamide. A total of 2721 patients ages 18 to 60 years with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidences of nonrelapse mortality (NRM) at 5 years were 28% (95% confidence interval [CI], 25% to 30%), 32% (95% CI, 29% to 36%), and 34% (95% CI, 28% to 39%) for SD, IH, and HD, respectively (P = .02). Patients receiving IH-TBI had a 25% higher risk of NRM compared with those receiving SD-TBI (12 Gy) (P = .007). Corresponding cumulative incidences of relapse were 36% (95% CI, 34% to 38%), 32% (95% CI, 29% to 36%), and 26% (95% CI, 21% to 31%; P = .001). Hazard ratios for mortality compared with SD were 1.06 (95% CI, .94 to 1.19; P = .36) for IH and .89 (95% CI, .76 to 1.05; P = .17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with cyclophosphamide) leads to worse NRM and offers no survival benefit over SD, despite reducing disease relapse.

Community Risk Score for Evaluating Health Care Disparities in Hematopoietic Cell Transplantation.

There is a critical need for tools to comprehensively describe disparities in hematopoietic cell transplant (HCT) recipients. We conducted a retrospective cohort study to evaluate a Community Risk Score (CRS) tool for this purpose. CRS included 10 community health indicators based on county or state of residence obtained from several secondary data sources and a composite score was assigned to each county (range 0 to 40), that was further categorized into six tiers (I to VI) with higher tiers indicating poor community health. CRS was assessed for 509 allogeneic and 1033 autologous HCT recipients from 2003 to 2013. Our cohort represented allogeneic and autologous HCT recipients from 300 and 431 unique ZIP codes from 99 and 125 counties in 15 and 16 states, although 86% and 90% patients were from Ohio, respectively. A greater proportion of patients had adverse individual community risk indicators in higher-risk tiers (P < .001 for trend for all). In multivariable analysis, clear trends toward association of CRS with outcomes were not observed. For autologous HCTs, Tier III has higher risks of relapse mortality (hazard ratio [HR] 2.2, P = .02) and all-cause mortality (HR 1.8, P = 0.03). In conclusion, CRS was able to categorize patients into groups representing greater levels of health care disparities. We did not see a clear association between CRS and transplant outcomes, although our cohort was limited to a relatively small group of counties. Community-based risk score model may serve as a tool for evaluating disparities in HCT recipients, but its validation in a nationally representative cohort of patients is needed.

Association of Socioeconomic Status with Outcomes of Autologous Hematopoietic Cell Transplantation for Multiple Myeloma.

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for eligible patients with multiple myeloma. Health care disparities can influence transplantation outcomes. However, the association of socioeconomic status (SES), a major indicator of health care disparities, with outcomes in patients with myeloma after AHCT has not been previously described. We analyzed 346 consecutive AHCT recipients with myeloma who underwent transplantation between 2003 and 2013 in this retrospective cohort study. Zip code of residence at the time of AHCT was obtained to assess annual household income based on 2010 US census data (median, $49,054; range, $16,546 to $127,313). SES groups were divided into < $45,000 (low; n = 120), $45,000 to $60,000 (middle; n = 116), and > $60,000 (high; n = 110). The low-income cohort had smallest portion of Caucasians (69% versus 89% versus 91%); otherwise, patient, disease, and transplantation characteristics were comparable among cohorts or different without significant patterns found. Median follow-up was 49 months. There was no difference among SES groups in overall survival, progression-free survival, nonrelapse mortality, or relapse in univariate and multivariable analysis. Similarly, SES was not associated with survival in a subset analysis of 303 patients who had survived for 1 year after transplantation.

Impact of Race and Ethnicity on Outcomes After Umbilical Cord Blood Transplantation.

BACKGROUND: Umbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients. OBJECTIVE: To compare outcomes by social determinants of health. STUDY DESIGN: We designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS). RESULTS: For 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults. Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes. CONCLUSIONS: OS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children.

Trends in volumes and survival after hematopoietic cell transplantation in racial/ethnic minorities.

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 < .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.

A Pilot Trial of Patient-Reported Outcomes for Acute Graft-Versus-Host-Disease.

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Acute GVHD is associated with severe physical and psychosocial symptoms. We sought to evaluate the feasibility of capturing patient-reported outcome (PRO) measures in acute GVHD to better measure symptom burden and quality of life (QOL). We conducted a pilot study of adult patients undergoing first allogeneic HCT. Questions from Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT), Patient-Reported Outcomes Measurement Information System (PROMIS-10), and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) were selected, and the survey was administered electronically before HCT, at days 14, 50, and 100 after HCT. In addition, patients who developed grade 2-4 acute GVHD received it weekly for 4 weeks and then monthly up to 3 months. From 2018 to 2020, 73 patients were consented, of which 66 went on to undergo HCT and were included in the analysis. Median age at transplantation was 63 years, and 92% were Caucasian. Only 47% of expected surveys were completed (range 0%-67% for each time point). Descriptive exploratory analysis demonstrate an expected trajectory of QOL using the FACT-BMT and PROMIS-10 scores throughout transplantation. Patients who developed acute GVHD (N = 15) generally had lower QOL scores compared to those with no or mild GVHD post-HCT. The PRO-CTCAE captured several physical and mental/emotional symptoms in all patients and those with GVHD. Fatigue (100%), decreased appetite (92%), problem tasting (85%), loose stools (77%), pain (77%), skin itching (77%), and depression (feeling sad) (69%) were the most prevalent symptoms among patients with grade 2-4 acute GVHD. Patients with acute GVHD generally reported worse symptoms than those with no/mild GVHD in frequency, severity, and interference in normal activities. Several challenges were identified including poor access/literacy of electronic surveys, acute illness, and need for extensive research/resource support. We demonstrate the challenges yet potential of using PRO measures in acute GVHD. We demonstrate that the PROMIS-10 and PRO-CTCAE measures are able to capture several symptoms and QOL domains of acute GVHD. Further investigation into making PROs feasible in acute GVHD are needed.

Health-Related Quality of Life in Double Umbilical Cord Blood versus Haploidentical Marrow Transplantation: A Quality of Life Analysis Report of BMT CTN 1101.

The Blood and Marrow Transplant Clinical Trials Network study 1101 (BMT CTN 1101; ClinicaTrials.gov identifier NCT01597778) was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QoL) of patients with hematologic malignancies undergoing double umbilical cord blood transplantation (dUCBT) or HLA-haploidentical bone marrow transplantation (haplo-BMT) after reduced-intensity conditioning. At a 5-year follow-up, there were no significant differences in progression- free survival (PFS) or overall survival (OS) between the 2 cohorts. The impact of alternative donor source on QoL is unknown, however. English- and Spanish-speaking patients completed the Functional Assessment of Cancer Therapy-General (FACT-G), Short Form 36 (SF-36), EuroQoL-5 Dimensions EQ-5D, and Global QoL patient-reported outcome (PRO) assessments pretransplantation and at 12 and 24 months post-transplantation. We compared longitudinal QoL measures between the dUCBT and haplo-BMT cohorts and investigated the association of QoL and clinical outcomes using an inverse probability weighted-independent estimating equations method, accounting for missingness and baseline variables. We found no significant differences between the 2 cohorts in any of the QoL scores pretransplantation and at 12 and 24 months post-transplantation. Pretransplantation scores were the only significant predictors of post-transplantation QoL scores. Relapse and grade III-IV acute graft-versus-host disease (GVHD) were associated with significant declines in mean FACT-BMT and SF-36 Physical Component scores, and chronic GVHD was associated with a decline in mean EQ-5D utility scores. There were no significant associations between pretransplantation QoL scores and OS or PFS. Donor type did not impact post-transplantation QoL. Pretransplantation QoL scores and clinical events of GVHD and relapse were the only predictors of post-transplantation QoL. QoL was not associated with survival in either treatment arm. PROs may be valuable tools in pretransplantation risk assessment strategies to improve QoL outcomes.

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation.

Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune reactions and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation.

Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

Health-Related Quality of Life Outcomes in Older Hematopoietic Cell Transplantation Survivors.

The use of hematopoietic cell transplantation (HCT) has been increasing in older patients. However, the levels if distress, psychosocial functioning, and health-related quality of life (HRQOL) among older HCT survivors remains largely unknown. In this secondary analysis using data from 2 randomized controlled trials, we analyzed baseline Cancer and Treatment Distress (CTXD) and Confidence In Survivorship Information (CSI) surveys of HCT survivors who were age ≥60 years at the time of transplantation and alive and disease-free ≥1 year post-autologous or -allogeneic HCT. We analyzed associations of these parameters with the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the 12-Item Short Form Survey (SF-12) and a healthcare adherence (HCA) scale, after adjusting for transplantation and patient demographic factors. A total of 567 patients were included. The median patient age at HCT was 65 years, and 68% of the patients underwent autologous HCT. The median CTXD score was .7 (mild), and the greatest distress was reported in the "health burden" subscale. The median CSI score was 1.4 (moderate-high), with the lowest confidence reported in the "late effects" subscale. We found negative Spearman correlations between CTXD score and SF-12 PCS (P = -.59) and MCS (P = -.54) and positive Spearman correlations between CSI score and SF-12 PCS (P = .23) and MCS (P = .30). The median HCA scale score was high at .8. Male sex, autologous HCT, increased distress level, and worse CSI score were associated with lower use of preventive care. Older survivors experienced a low level of distress and moderate-high level of CSI at ≥1 year post-HCT. As lower distress and higher CSI were associated with improved HRQOL and optimized preventive HCA, CTXD/CSI measures can be used to individualize the care of older adult HCT survivors.

Comparison of Quality of Life and Outcomes between Haploidentical and Matched Related/Unrelated Donor Allogeneic Hematopoietic Cell Transplantation.

Haploidentical (haplo) donor grafts are a well-established alternative donor source for allogeneic hematopoietic cell transplantation (HCT); however, data comparing health-realted quality of life (HRQOL) measures between haplo-HCT and HCT using other donor sources are lacking. We hypothesized that post-transplantation HRQOL might not differ between haplo-HCT and HCT with other graft sources. We conducted a single-institution retrospective analysis comparing HRQOL of haplo-HCT with matched-related donor (MRD) HCT and matched unrelated donor (MUD) HCT for hematologic diseases. We included 90 haplo, 102 MRD, and 229 MUD adult first allogeneic HCTs performed between May 2014 and December 2019. HRQOL for haplo-HCT, MRD-HCT, and MUD-HCT were compared separately for myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC). HRQOL was assessed using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale pretransplantation and at days +100 and +180 post-transplantation. MAC haplo-HCT showed no difference in all domains of HRQOL and other transplantation outcomes, including overall survival, compared with MAC MRD/MUD-HCT, except for a higher incidence of non-cytomegalovirus infections (P = .003). RIC haplo-HCT was associated with significantly better emotional well-being (P = .008) and functional well-being (P = .011) compared with MUD-HCT. RIC haplo-HCT was associated with higher rates of non-cytomegalovirus infections (P < .001) and relapse mortality (P = .044) but a lower rate of nonrelapse mortality (P = .008) compared with RIC MUD-HCT. Haplo-HCT had comparable total HRQOL scores and overall survival to MRD/MUD-HCT in both the MAC and RIC cohorts. Interrogation of HRQOL among disease-specific groups may further elucidate the existence of any additional benefits with these different transplantation modalities.

Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy.

Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI, .73 to 2.31; P = .38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

Increasing access to allotransplants in the United States: the impact of race, geography, and socioeconomics.

Allogeneic hematopoietic cell transplantation (HCT) is particularly susceptible to racial, socioeconomic, and geographic disparities in access and outcomes given its specialized nature and its availability in select centers in the United States. Nearly all patients who need HCT have a potential donor in the current era, but racial minority populations are less likely to have an optimal donor and often rely on alternative donor sources. Furthermore, prevalent health care disparity factors are further accentuated and can be barriers to access and referral to a transplant center. Research has primarily focused on defining and quantifying a variety of social determinants of health and their association with access to allogeneic HCT, with a focus on race/ethnicity and socioeconomic status. However, research on interventions is lacking and is an urgent unmet need. We discuss the role of racial, socioeconomic, and geographic disparities in access to allogeneic HCT, along with policy changes to address and mitigate them and opportunities for future research.

Survival following relapse after allogeneic hematopoietic cell transplantation for acute leukemia and myelodysplastic syndromes in the contemporary era.

OBJECTIVE/BACKGROUND: Relapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). No standard of care exists, and a wide range of treatments are used for post-alloHCT relapse. In the recent era, several novel therapies including targeted agents are available for acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). METHODS: We reviewed outcomes after alloHCT relapse, with or without use of these newer agents for ALL, AML, and MDS. In total, 115 adults with relapsed or refractory ALL (n = 17), AML (n = 67), and MDS (n = 31) at median 5 (range, 1-64) months after their first alloHCT in 2010-2018 were included. RESULTS: Median follow-up was 19 (range, 6-80) months after relapse from alloHCT. Targeted agents were given to 29 (25%) patients. In multivariable analysis, use of targeted agent at any time point after relapse was not associated with survival. Matched unrelated (vs. matched sibling; hazard ratio [HR] 1.70; p = .027) or haploidentical donor grafts (vs. matched sibling; HR 2.69; p = .003), presence of grade II-IV acute graft-versus-host disease before relapse (HR 2.46; p < .001), and less than 12 months from HCT to relapse (<6 vs. > 12 months; HR 6.34; p < .001; 6-12 vs. > 12 months; HR 3.16; p = .005) were adverse prognostic factors for post-relapse survival. CONCLUSION: Outcomes after alloHCT relapse remain poor regardless of the novel agent use. Innovative treatment strategies are needed to improve outcomes after relapse post-alloHCT.

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation.

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vß sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.

Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia.

Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.

Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant.

IMPORTANCE: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. OBJECTIVE: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTS: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. CONCLUSIONS AND RELEVANCE: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.