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

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 1-29, 74 (32%) were categorized as high-risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall CR rate was 94%, with no difference between strata. There was no difference in relapse free survival (RFS, p=0.8112), with 2-year RFS for the high-risk group of 63% (95%CI 52-77). There was similarly no difference seen in OS (p=0.5488) 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 (HR 0.70, 95%CI 0.21-2.90, p=0.7040), 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=0.0434). 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.

Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against <i>FLT3</i>- mutant acute myeloid leukemia and <i>KMT2A</i>-rearranged acute lymphoblastic leukemia

“…We hope that ongoing and future studies will shed further light upon the potential of FLT3CART to treat or perhaps even prevent these presently universally-fatal lineage-switch relapses. 15,17 Expanding upon the clinical potential of FLT3CART for patients with relapsed/refractory KMT2A-R ALL, we also report successful development of bispecific CD19xFLT3CART immunotherapy with at least equivalent preclinical activity to that of monovalent CD19CART and FLT3CART. Recent data from clinical phase 1 studies have demonstrated exciting promise of bispecific CD19xCD22 and CD19xCD20 CAR T cell immunotherapies for patients with relapsed/refractory B-ALL or lymphoma.…”

“…However, given recent reporting of FLT3i resistance mechanisms in patients with FLT3-mutant AML, such TKI-based therapies may not be curative for all patients. 36 Patients with KMT2A-R ALL are also known to be at particularly high risk of lymphoid-tomyeloid lineage switch following CD19CART immunotherapy 15,17 when compared to conventional chemotherapy or immunotherapy with the CD19xCD3 bispecific T-cell engager blinatumomab. 37 This lineage switch predilection presents a unique barrier to cure of these highrisk patients via CD19CART, as well as an opportunity for alternative therapeutic approaches.…”

“…Patients with KMT2A-R ALL are at increased risk for lineage switch to AML following CD19CART versus those with non-KMT2A-R ALL. 15,17 To assess the activity of FLT3CART in this setting, we created a pair of ALL and AML PDX models from an adolescent with primary chemotherapy-refractory KMT2A-AFF1 B-ALL who developed lineage-switched CD19-negative KMT2A-AFF1 AML approximately three weeks after tisagenlecleucel administration and was resistant to all further chemoimmunotherapy. In these preclinical studies, FLT3CART equipotently inhibited leukemia proliferation in vivo in both KMT2A-R ALL (Figure 4A) and AML (Figure 4B) PDX models, despite a marked reduction in FLT3 surface antigen density after lineage switch (Figure 4C).…”

“…Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CD19CART) or CD22 (CD22CART) has proven highly successful in patients with relapsed/refractory B-ALL, [11][12][13][14] including infants. 15 Despite high rates of initial remission, approximately 50% of patients treated with CD19CART will relapse again within two years, often due to target antigen loss and/or lineage switch in KMT2A-R ALL. 13,[15][16][17] This phenomenon has led to appreciable interest in alternative strategies that may prevent target antigen escape and increase long-term cure rates, including CAR T cells directed at alternative leukemia cell surface antigens (e.g., TSLPR, BAFFR) and bispecific CAR T cells that recognize and target multiple antigens simultaneously.…”

“…15 Despite high rates of initial remission, approximately 50% of patients treated with CD19CART will relapse again within two years, often due to target antigen loss and/or lineage switch in KMT2A-R ALL. 13,[15][16][17] This phenomenon has led to appreciable interest in alternative strategies that may prevent target antigen escape and increase long-term cure rates, including CAR T cells directed at alternative leukemia cell surface antigens (e.g., TSLPR, BAFFR) and bispecific CAR T cells that recognize and target multiple antigens simultaneously. 18 Initial studies of dual-targeting CD19xCD22 CAR T cells demonstrated robust anti-leukemia activity in preclinical B-ALL models, 19 and current clinical phase 1 trials of these bispecific immunotherapies (NCT03241940, NCT03289455, NCT03330691, NCT03448393) have reported exciting early results.…”