CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials

Leahy, Allison Barz; Newman, Haley; Li, Yimei; Liu, Hongyan; Myers, Regina M.; DiNofia, Amanda M.; Dolan, Joseph G.; Callahan, Colleen; Baniewicz, Diane; Devine, Kaitlin; Wray, Lisa; Aplenc, Richard; June, Carl H.; Grupp, Stephan A.; Rheingold, Susan R.; Maude, Shannon L.

doi:10.1016/s2352-3026(21)00238-6

Cited by 67 publications

(79 citation statements)

References 27 publications

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“…32 Smaller institutional studies have shown efficacy and tolerability for patients with CNS disease, and commercial use of tisagenlecleucel for these patients continues to expand. 24,26 The data presented here further supports feasibility of treating patients with CNS leukemia with tisagenlecleucel without excess CRS or neurotoxicity. These results are consistent with another report of adult patients with CNS lymphoma who received tisagenlecleucel without evidence of greater than grade 1 neurotoxicity.…”

Section: Discussionsupporting

confidence: 70%

“…[8][9][10]13 No differences in RFS rates between patients with CNS disease and those without have been reported in patients who received CTL019. 26 Similarly, we demonstrate that patients with EM disease, both CNS (relapse rate 38%) and non-CNS EM (relapse rate 40%) disease, have similar rates of relapse after tisagenlecleucel to patients with BM only disease. CD19 negative relapse occurred more often in the bone marrow only group compared to the R/R EM group.…”

Section: Discussionsupporting

confidence: 64%

“…This finding is consistent with the recent report of improved OS in patients with isolated CNS disease compared with those with BM disease using tisagenlecleucel or humanized CD19 CAR T-cell therapy on clinical trials. 26 This cohort of 23 patients included both patients with on-treatment/early relapses (n = 12) and late relapses (n = 11). These patients also did not receive more cranial or craniospinal radiation than those with combined BM disease.…”

Section: Discussionmentioning

confidence: 99%

“… 25 Patients receiving either CTL019 and CTL119 for relapsed CNS disease similarly show clearance of CNS disease without increased risk of neurotoxicity and similar survival rates compared with patients without CNS disease at infusion. 26 Herein, we report the results of patients who received tisagenlecleucel for R/R EM B-ALL disease as part of the multi-institutional Pediatric Real World CAR Consortium (PRWCC) and describe how patients with R/R EM disease have similar rates of toxicity and survival compared with patients with BM-only disease.…”

Section: Introductionmentioning

confidence: 99%

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Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

et al. 2022

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Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell ALL. Data for CAR therapy in extramedullary (EM) involvement is limited. Retrospective data was abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (CR) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both CNS3 and non-CNS EM) were compared to bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease prior to CAR (n=40 CNS3; n=15 non-CNS EM). The median age at infusion in CNS cohort was 10 years (range <1-25) and the non-CNS EM cohort was 13 years (2-26). In patients with CNS disease, 88% (35/40) achieved a CR, versus only 66% (10/15) with non-CNS EM disease. Patients with CNS disease (both with and without marrow involvement) had comparable 24-month OS outcomes to non-CNS EM or BM only (p=0.41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM only patients (p=0.92). No increased toxicity was seen with CNS or non-CNS EM disease (p=0.3). Active CNS disease at time of infusion did not impact outcomes. Isolated (iCNS) disease trended towards improved OS when compared to combined CNS and BM (p=0.12). R/R EM disease can be effectively treated with tisagenlecleucel with toxicity, relapse rates and survival rates comparable to patients with BM only. Outcomes for iCNS relapse are encouraging.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

et al. 2022

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“…CNS disease may be another area where CAR therapies have increased efficacy. In a post-hoc analysis of 195 patients with r/r CD19 + ALL with and without CNS disease who received CD19 CAR T-cells, the same proportion of patients achieved CR at 28 days after infusion [138]. Additionally, CRS and ICANs rate were identical across those with and without CNS disease.…”

Section: Target Population For Aml Carsmentioning

confidence: 90%

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

Marvin-Peek

Savani

Oluwole

et al. 2022

Cancers

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The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR T-cell therapy has been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs has posed a larger challenge. AML not only creates an immunosuppressive tumor microenvironment that dampens CAR T-cell responses, but it also lacks many unique tumor-associated antigens, making leukemic-specific targeting difficult. One advantage of CAR T-cell therapy compared to alternative treatment options is the ability to provide prolonged antigen-specific immune effector and surveillance functions. Since many AML CAR targets under investigation including CD33, CD117, and CD123 are also expressed on hematopoietic stem cells, CAR T-cell therapy can lead to severe and potentially lethal myeloablation. Novel strategies to combat these issues include creation of bispecific CARs, CAR T-cell “safety switches”, TCR-like CARs, NK CARs, and universal CARs, but all vary in their ability to provide a sustained remission, and consolidation with an allogeneic hematopoietic cell transplantation (allo-HCT) will be necessary in most cases This review highlights the delicate balance between effectively eliminating AML blasts and leukemic stem cells, while preserving the ability for bone marrow to regenerate. The impact of CAR therapy on treatment landscape of AML and changing scope of allo-HCT is discussed. Continued advances in AML CAR therapy would be of great benefit to a disease that still has high morbidity and mortality.

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Sequencing antigen‐targeting antibodies and cellular therapies in adults with relapsed/refractory B‐cell acute lymphoblastic leukemia

et al. 2023

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The recent approvals of four CD19‐or CD22‐targeted therapies for B‐cell acute lymphoblastic leukemia (B‐ALL) have transformed the treatment of relapsed/refractory (r/r) disease. Adults with r/r B‐ALL are usually eligible for all options, but there are no studies directly comparing these agents, and the treating physician must decide which to select. Each therapy has notable activity as a single agent but has limitations in particular settings, and the optimal choice varies. These therapies can be complementary and used either sequentially or concomitantly. Here, we review the current landscape of antigen‐targeted therapies for r/r B‐ALL and discuss considerations for their use.

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CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials

Cited by 67 publications

References 27 publications

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

Sequencing antigen‐targeting antibodies and cellular therapies in adults with relapsed/refractory B‐cell acute lymphoblastic leukemia

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