Abstract
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell ...therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.
We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell ...therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.
The safety and efficacy of CAR T‐cell therapy are unknown in pediatric and adolescent patients with relapsed or refractory primary mediastinal large B‐cell lymphoma (R/R PMBCL) which is associated ...with dismal prognosis. Here, we present a case report of a 16‐year‐old patient with R/R PMBCL treated with lisocabtagene maraleucel including correlative studies. Patient achieved complete response at 6 months without cytokine release syndrome and immune effector cell‐associated neurotoxicity syndrome. She only experienced mild cytopenias, requiring filgrastim once. This report highlights the safety and efficacy of lisocabtagene maraleucel in this population, warranting prospective studies to improve clinical outcomes.
BackgroundFludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the ...exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy.Methods84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC.ResultsBest complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts.ConclusionsBendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.
Immune checkpoint inhibitors against Programmed Cell Death Protein 1/Programmed Cell (PD-1/PD-L1) and CTLA-4/B7 axes have had limited success in hematologic malignancies, requiring the need to ...explore alternative targets such as T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 to improve durable clinical responses. We undertook this study to investigate the expression profile of TIGIT such that the potential efficacy of TIGIT blockade could be mapped among lymphoma subtypes. We validated an immunohistochemical assay for TIGIT and evaluated its expression in lymphoma and tumor microenvironment (TME) cells in 661 lymphoma/leukemia biopsies. Multiplex immunofluorescence was used for correlation with normal TME cell subsets. Tumor or TME TIGIT-positivity was defined as moderate to strong membrane staining in at least 10% of tumor or TME cells, respectively. TME TIGIT expression was correlated with overall survival and progression-free survival and comparison with PD-L1 expression. In most cases, lymphoma cells were TIGIT-negative except for angioimmunoblastic and peripheral T-cell lymphomas, which showed 91% and 47% positivity, respectively. A high proportion of small B-cell lymphoma and anaplastic large cell lymphoma cases had TIGIT-positive TME cells. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients with TIGIT-negative TME cells showed significantly shorter overall survival ( P =0.04). No other statistically significant differences were found. When TIGIT was expressed in TME cells, there were a comparable number of TIGIT-positive only and dual TIGIT/PD-L1 positive cases except for more TIGIT-positive only cases in CLL/SLL. TIGIT expression shows distinctive profiles among lymphoma subtypes. Chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD-L1, with a high proportion of dual TIGIT and PD-L1-positivity. Our results are likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1.
Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic White (NHW) patients despite more favorable genetics and younger age. A ...discrete survival analysis was performed on 822 adult patients with AML from 6 urban cancer centers and revealed inferior survival among NHB (hazard ratio HR = 1.59; 95% confidence interval CI: 1.15, 2.22) and Hispanic (HR = 1.25; 95% CI: 0.88, 1.79) patients compared with NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across 6 composite variables: structural racism (census tract disadvantage, affluence, and segregation), tumor biology (European Leukemia Network risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization), and intensive care unit (ICU) admission during induction chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, and treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.
•Structural racism assessed by census tract variables accounts for nearly all Black-White and Hispanic-White disparity in AML survival.•Structural racism is a stronger mediator of survival disparities than molecular features, comorbidities, health care access, and treatment.
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