In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. A11-A11
Abstract:
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with a peak incidence at 3-5 years of age. Despite the improved survival rate of 90% for newly diagnosed children with ALL, the outcome for patients with relapsed disease is poor with a less than 30% overall survival. CD19 CAR T-cell therapy has shown remarkable response rates in relapsed/refractory disease. Long-term survival analysis has shown that initial response rates exceed 80%. However, durable response rates at one year are closer to 40%. Little is known about factors predicting durable response to CAR T therapy. We hypothesize that patients with CD19 CAR T-cell resistant ALL have a distinct disease compared to responders to therapy that can be identified in pretreatment leukemia. Utilizing advanced genomic, epigenetic, proteomic, and single-cell (sc) techniques, we characterized patient bone marrow aspirates (BMA) to identify mechanisms of resistance. Patients enrolled in PLAT-02 at Seattle Children’s Hospital were categorized according to the durability of their response to CD19 CAR T therapy. To characterize the molecular and genomic alterations specific to the therapy-resistant ALLs, we performed comprehensive analyses on pre-treatment therapy-resistant and sensitive BMAs using whole-exome sequencing, RNA- BMAs seq, scRNA-seq, sc B cell receptor (BCR)-seq, methylation array, H3K27ac ChIP-seq, ATAC-seq, and CyTOF. Additionally, we developed murine patient-derived xenografts (PDXs) for future studies. Initial mutation analyses revealed 5 hotspot mutations (ABL1, 2 x KRAS, IKZF1, and EP300) and actionable fusion (2 ABL1, 2 ETV6, 2 ETV5, KMT2A). Interestingly, we identified a KMT2A-AFF1 fusion in a sensitive leukemia, which has been demonstrated to predispose patients to CD19 CAR T resistance through lineage switching. Additionally, we identified a novel CREBBP-fusion in leukemias resistant to CD19 CAR T-induced B-cell aplasia. Alterations of CREBBP have previously been associated with ALL that is refractory to conventional therapies. Integrated gene expression and epigenetic analyses are ongoing to identify genes or pathways associated with resistant disease. scRNA- and scBCR-seq data are being analyzed and integrated with CyTOF analyses to detect mixed lineage and gene expression-based heterogeneity that may predict clonal selection by CAR T pressure. Finally, we developed and genetically analyzed murine PDXs for 64% of the patient samples, establishing a valuable resource for future studies and developing novel therapies for resistant leukemias. This study is one of the most integrative and comprehensive genomic profiling approaches to identify the molecular traits of therapy-resistant ALL in patient samples. We hope to identify and develop crucial biomarkers predicting responsiveness to CAR T-cell therapy. Citation Format: Katherine E. Masih, Rebecca Gardner, Berkley E. Gryder, Abdalla Abdelmaksoud, Ashley Wilson, Serifat Adebola, Benjamin Z. Stanton, Young K. Song, Justin Lack, Chaoyu Wang, Xinyu Wen, Zachary Rae, Adam Cheuk, Gregoire Altan-Bonnet, Michael Kelly, Jun S. Wei, Michael C. Jensen, Rimas J. Orentas, Javed Khan. A comprehensive and integrative omic analysis of multiply relapsed refractory pediatric pre-B cell acute lymphoblastic leukemia predicts response to CD19 CAR T-cell therapy [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A11.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.PEDCA19-A11
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
