Impact of High Disease Burden on Survival in Pediatric Patients with B-ALL Treated with Tisagenlecleucel

Ravich, Jonas W.; Huang, Sujuan; Zhou, Yinmei; Brown, Patrick; Pui, Ching‐Hon; Inaba, Hiroto; Cheng, Cheng; Bonifant, Challice L.; Talleur, Aimee C

doi:10.1016/j.jtct.2021.11.019

Cited by 26 publications

(14 citation statements)

References 32 publications

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“…The impact of pre‐LD disease burden has been described in ALL previously, 18,22,23 and seems to hold regardless of the type of CAR‐T cells used. The disease burden was not assessed prior to LD in the ELIANA study, but real‐life data from tisagenlecleucel confirm this observation 24,25 . In our study patients with a high disease burden pre LD were those who failed bridging therapy or declined bridging therapy.…”

Section: Discussionsupporting

confidence: 50%

“…The disease burden was not assessed prior to LD in the ELIANA study, but real-life data from tisagenlecleucel confirm this observation. 24,25 In our study patients with a high disease burden pre LD were those who failed bridging therapy or declined bridging therapy. The response to bridging therapy was previously also associated with improved outcome following CD28-based CAR-T cells in adults.…”

Section: Discussionmentioning

confidence: 99%

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Parameters of long‐term response with CD28‐based CD19 chimaeric antigen receptor‐modified T cells in children and young adults with B‐acute lymphoblastic leukaemia

et al. 2022

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Summary CD28‐based CD19 chimaeric antigen receptor‐modified (CAR‐)Tcells were recently FDA‐approved for adult acute lymphoblastic leukaemia (ALL). We report long‐term outcome of 37 children and young adults treated with autologous CD19 CAR‐T cells. The complete remission rate was 86%, of which 71% were polymerase chain reaction (PCR) minimal residual disease (MRD)‐negative, 14% were MRD‐negative by flow cytometry, and 14% were PCR MRD‐positive. 26 patients proceeded to subsequent haematopoietic stem cell transplant (HSCT). 11 patients had a CD19‐postive relapse (eight post HSCT and three without) and one had a CD19‐negative relapse. All relapse events occurred within two years from cell therapy. With a median follow‐up of three years, the median event‐free survival (EFS) is 17 months and the median overall survival (OS) is not reached. The three‐year EFS is 41% and OS is 56%. Patients with >5% blasts in the bone marrow prior to lymphodepletion had an inferior EFS. All patients with a PCR MRD‐positive result at day 28 had relapsed after CAR‐T‐cell therapy. A prior HSCT did not significantly affect outcome, but a consolidative transplant after achieving remission improved long‐term results. Overall, prelymphodepletion disease burden and molecular MRD negativity following CAR‐T cells are predictors of long‐term outcome following CD19 CAR‐T‐cell therapy for ALL.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Parameters of long‐term response with CD28‐based CD19 chimaeric antigen receptor‐modified T cells in children and young adults with B‐acute lymphoblastic leukaemia

et al. 2022

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“…Additionally, a subset of patients (n=6) received repeat CD19-CAR T cell infusion(s) of the same product due to recurrent malignancy or early loss of BCA. The clinical outcomes with a focus on disease response to CAR T cell therapy ( 22 , 23 ), carHLH ( 18 ), and epigenetic reprograming of CAR T cells ( 24 ), have been reported elsewhere for a subset of these patients.…”

Section: Resultsmentioning

confidence: 99%

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

et al. 2022

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CD19-specific chimeric antigen receptor (CAR) T cell therapy has changed the treatment paradigm for pediatric, adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, data on the associated infectious disease challenges in this patient population are scarce. Knowledge of infections presenting during treatment, and associated risk factors, is critical for pediatric cellular therapy and infectious disease specialists as we seek to formulate effective anti-infective prophylaxis, infection monitoring schemas, and empiric therapy regimens. In this work we describe our institutional experience in a cohort of 38 pediatric and AYA patients with CD19-positive malignancy treated with lymphodepleting chemotherapy (fludarabine/cyclophosphamide) followed by a single infusion of CD19-CAR T cells (total infusions, n=39), including tisagenlecleucel (n=19; CD19/4-1BB) or on an institutional clinical trial (n=20; CD19/4-1BB; NCT03573700). We demonstrate that infections were common in the 90 days post CAR T cells, with 19 (50%) patients experiencing a total of 35 infections. Most of these (73.7%) occurred early post infusion (day 0 to 28; infection density of 2.36 per 100 patient days-at-risk) compared to late post infusion (day 29 to 90; infection density 0.98 per 100 patient days-at-risk), respectively. Bacterial infections were more frequent early after CAR T cell therapy, with a predominance of bacterial blood stream infections. Viral infections occurred throughout the post infusion period and included primarily systemic reactivations and gastrointestinal pathogens. Fungal infections were rare. Pre-infusion disease burden, intensity of bridging chemotherapy, lymphopenia post lymphodepleting chemotherapy/CAR T cell infusion and development of CAR-associated hemophagocytic lymphohistiocytosis (carHLH) were all significantly associated with either infection density or time to first infection post CAR T cell infusion. A subset of patients (n=6) had subsequent CAR T cell reinfusion and did not appear to have increased risk of infectious complications. Our experience highlights the risk of infections after CD19-CAR T cell therapy, and the need for continued investigation of infectious outcomes as we seek to improve surveillance, prophylaxis and treatment algorithms.

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“…3,8,14 We also found that a high disease burden correlated with a higher risk of early treatment failure. However, the definition of "high disease burden" is not consistent across studies, 6,8,10,[30][31][32] and thus needs to be interpreted in the context of each study.…”

Section: Discussionmentioning

confidence: 99%

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL

et al. 2022

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T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a Phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n=12). Treatment was well tolerated, with low incidence of both cytokine release syndrome (any grade, n=6) and neurotoxicity (any grade, n=3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow. High disease burden (≥40% morphologic blasts) prior to CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. Postinfusion, CD8+ CAR T cells had a proliferative advantage over CD4+ CAR T cells, and at peak expansion had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation had sustained, durable responses. In summary, initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy, while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03573700.

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Impact of High Disease Burden on Survival in Pediatric Patients with B-ALL Treated with Tisagenlecleucel

Cited by 26 publications

References 32 publications

Parameters of long‐term response with CD28‐based CD19 chimaeric antigen receptor‐modified T cells in children and young adults with B‐acute lymphoblastic leukaemia

Parameters of long‐term response with CD28‐based CD19 chimaeric antigen receptor‐modified T cells in children and young adults with B‐acute lymphoblastic leukaemia

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL

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