Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy.

TitleImpact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy.
Publication TypeJournal Article
Year of Publication2022
AuthorsLeahy ABarz, Devine KJ, Li Y, Liu H, Myers R, DiNofia A, Wray L, Rheingold SR, Callahan C, Baniewicz D, Patino M, Newman H, Hunger SP, Grupp SA, Barrett DM, Maude SL
JournalBlood
Volume139
Issue14
Pagination2173-2185
Date Published2022 Apr 07
ISSN1528-0020
KeywordsAntigens, CD19, Child, Cytogenetic Analysis, Humans, Immunotherapy, Adoptive, Infant, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Antigen, T-Cell, Recurrence, Young Adult
Abstract

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.

DOI10.1182/blood.2021012727
Alternate JournalBlood
PubMed ID34871373
PubMed Central IDPMC8990372
Grant ListK12 CA076931 / CA / NCI NIH HHS / United States
P01 CA214278 / CA / NCI NIH HHS / United States