Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been ...established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.
Summary
Primary central nervous system lymphoma (PCNSL) risk is highly increased in immunosuppressed individuals, such as those with human immunodeficiency virus infection and solid organ transplant ...recipients, but rates are increasing among immunocompetent older adults (age ≥65 years). We utilized data from a large, nationally‐representative cohort of older adults in the United States and found that PCNSL is significantly associated with systemic lupus erythematosus, polyarteritis nodusa, autoimmune hepatitis, myasthenia gravis and uveitis. Immunosuppressive drugs given to treat these conditions may increase PCNSL risk, but these associations cannot explain the observed temporal increase in PCNSL rates, given the low prevalence of these conditions.
Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite ...subtotal infiltration remain unknown. We report on a single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyze 148,630 PC from 24 different locations in 10 patients and observe vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we find an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL are characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1, HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS, DUSP1 and HBB. Assessment of PC from longitudinally collected samples reveals transcriptional changes after induction therapy. Our study contributes to the understanding of destructive myeloma bone disease.
Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since ...2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000-2005, 2006-2010 and 2011-2016. The risk of tMDS increased significantly after NSCLC across all time periods (P
= 0.002) while tAML risk decreased from 2006-2010 to 2011-2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (P
= 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.
•Patients who were ineligible for the ZUMA-1 trial still had a durable response with axi-cel.•Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS.•Patient selection ...for axi-cel should consider comorbidities and risk-to-benefit ratio.
Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval CI, 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year 95% CI, 57% to 66% versus 67% 95% CI, 62% to 72%). Patients age ≥65 years had favorable ORR (odds ratio OR, 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio HR for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.
To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome.
Retrospective ...cohort study.
Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative.
Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019.
Demographics, toxicities, specific interventions, and outcomes were collected.
One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3-4 toxicities (66.7%); 15.2% had grade 3-4 cytokine release syndrome and 64% grade 3-4 immune effector cell-associated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64-not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progression-free survival.
This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.
•Overall survival and most safety outcomes with axi-cel were consistent across race/ethnicity in relapsed/refractory large B-cell lymphoma.•Real-world outcomes with CAR T-cell therapy are different ...in non-Hispanic Black patients, possibly related to barriers to access.
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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.
Locke and colleagues describe the safety and efficacy outcomes of axicabtagene ciloleucel for large B-cell lymphoma across racial and ethnic groups for 1290 standard-of-care patients in the Center for International Blood and Marrow Transplant Research registry and 275 patients treated in clinical trials. While consistency in survival and most safety outcomes were evident across groups, non-Hispanic Black patients had significantly lower response rates and progression-free survival in routine practice, potentially reflecting barriers to access.
Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown.
Investigate risk factors for melanoma after allogeneic hematopoietic cell ...transplantation.
We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research.
Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio OR = 1.77; 95% confidence interval CI = 1.00-3.15) or reduced-intensity conditioning containing melphalan (OR = 2.60; 95% CI = 1.13-6.02) or fludarabine (OR = 2.72; 95% CI = 1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR = 1.92; 95% CI = 1.19-3.10), chronic GvHD without skin involvement (OR = 1.91; 95% CI = 1.03-3.57), or keratinocytic carcinoma (OR = 2.37; 95% CI = 1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3 = 1.64; 95% CI = 1.01-2.67).
Data on individual-level ultraviolet radiation exposure and clinical data on melanoma characteristics were lacking. Additionally, misclassification of melanoma is possible as not all pathology reports were available for review.
These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk.
It is unclear whether the established association between cutaneous melanoma (CM) and lymphoid neoplasms (LNs) differs across LN subtypes. This study quantifies risk for developing CM after specific ...LNs and, conversely, for developing specific LNs after CM, as well as assessing clinical impact.
We identified a cohort of Caucasian adults (age 20-83 years) initially diagnosed with CM or LN, as reported to 17 US population-based cancer registries, 2000-2014. Standardized incidence ratios (SIRs) quantified second cancer risk. We assessed impact of second cancer development on risk of all-cause mortality using Cox regression.
Among 151 949 one-or-more-year survivors of first primary LN, second primary CM risk was statistically significantly elevated after chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR = 1.96, 95% confidence interval CI = 1.74 to 2.21), follicular lymphoma (SIR = 1.32, 95% CI = 1.09 to 1.58), and plasma cell neoplasms (SIR = 1.33, 95% CI = 1.07 to 1.63). Risks for these same subtypes were statistically significantly elevated among 148 336 survivors of first primary CM (SIR = 1.44, 95% CI = 1.25 to 1.66; SIR = 1.47, 95% CI = 1.21 to 1.77; SIR = 1.25, 95% CI = 1.06 to 1.47; respectively). Risk for CM was statistically significantly elevated after diffuse large B-cell lymphoma (SIR = 1.22, 95% CI = 1.02 to 1.45) and Hodgkin lymphoma (SIR = 1.75, 95% CI = 1.33 to 2.26), but the reciprocal relationship was not observed. There were no statistically significant associations between marginal zone lymphoma and CM. Among survivors of most LN subtypes, CM statistically significantly increased risk of death (hazard ratio HR range = 1.52, 95% CI = 1.25 to 1.85, to 2.46, 95% CI = 1.45 to 4.16). Among survivors of CM, LN statistically significantly increased risk of death (HR range = 1.75, 95% CI = 1.15 to 2.65, to 6.28, 95% CI = 5.00 to 7.88), with the highest risks observed for the most aggressive LN subtypes.
Heterogeneous associations between CM and specific LN subtypes provide novel insights into the etiology of these malignancies, with the mutual association between CM and certain LN suggesting shared etiology. Development of second primary CM or LN substantially reduces overall survival.
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