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.
10511 Background: CNS relapse of B-ALL is difficult to treat after cranial radiation or multiple relapses. Durable remissions of relapsed/refractory (r/r) B-ALL have been seen with CD19 CAR T cells; however, most trials excluded patients with active CNS disease. As we observed CAR trafficking into the CSF, we hypothesized that CD19 CAR T cells could control CNS B-ALL. Methods: We identified children and young adults with r/r CNS B-ALL treated on 4 clinical trials of CD19 CAR T cells, CTL019 or CTL119. NCT01626495 and NCT02435849 excluded active CNS disease, while the former in an amendment as well as NCT02374333 and NCT02906371 permitted active CNS disease controlled on therapy. All trials permitted CNS disease that cleared and excluded bulky intracranial disease that did not improve. We analyzed outcomes (CR, RFS) and safety. Results: We identified 65 patients 1-29y (median 10y) with r/r CNS B-ALL (CNS+) of 182 treated with CTL019/CTL119. There were no differences in age, sex, history of SCT or neurologic comorbidities in the CNS+ and CNS- cohorts. CNS+ patients were more likely to be in ≥2nd relapse (74% vs 46%, p < 0.01), to have received cranial radiation (58% vs 11%, p < 0.01), to have detectable CNS disease (p = 0.02) and less bone marrow disease pre-infusion (p < 0.01). At 1 mo post infusion, 62 (95%) CNS+ and 110 (94%) CNS- patients were in CR; 1 in each cohort died of sequelae of CRS and was inevaluable for response. All patients with CNS disease detected pre-infusion cleared by mo 3, including 9 in the CNS+ cohort [5 CNS2 ( < 5 CSF WBC with blasts), 4 CNS3 ( > 5 CSF WBC with blasts or exam/imaging evidence)] and 8 in the CNS- cohort (isolated CNS2 status pre-infusion). There was no difference in RFS (p = 0.28) in the CNS+ and CNS- cohorts [24-mo RFS: 61% (95% CI 46-73%) and 60% (95% CI 48-70%)]. There were 4 CNS relapses in the CNS+ cohort, and 1 in the CNS- cohort. Encephalopathy rate and grade was similar in the CNS+ and CNS- cohorts (52% vs 40% any grade; 12% vs 11% grade 3/4; p = 0.41). There were no deaths due to neurotoxicity (NT) and no statistically significant differences in incidence or severity of any NT or CRS in the CNS+ and CNS- cohorts. Conclusions: The CD19 CAR T cell therapies CTL019/CTL119 are effective at clearing CNS disease and inducing durable remissions in children and young adults with r/r CNS B-ALL. CNS relapse rates are low ( < 3%). Most CD19 CAR T cell trials excluded patients with active CNS disease, primarily due to the risk of NT. We show that patients with r/r CNS B-ALL that is adequately controlled prior to infusion can be safely treated with CD19 CAR T cells, with no increased risk of NT. Clinical trial information: NCT01626495, NCT02435849, NCT02374333, NCT02906371.
Background: CAR-modified T cells targeting CD19 have produced remarkable responses in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL); however, relapse continues to be a substantial challenge. CD19+ relapses, which account for 33-78% of relapses, are associated with loss of CAR T-cell surveillance due to short persistence. Thus, strategies to improve functional persistence to prevent and treat CD19+ relapsed disease are crucial. Here, we report our experience administering reinfusions of murine or humanized 4-1BB CD19 CAR T cells in an effort to prolong persistence in patients with demonstrated short persistence to mitigate relapse risk, treat CD19+ relapsed disease, and produce responses after nonresponse to initial CAR infusion. Methods: This analysis included patients aged <30 years treated with a murine CD19 CAR construct, either investigational CTL019 (NCT01626495, NCT02906371) or commercial tisagenlecleucel, or a humanized CD19 CAR construct, huCART19 (NCT02374333), who received ≥1 reinfusion of the same CAR product due to: 1) clinical signs of poor persistence within 6 months (mos) of initial infusion, including peripheral B-cell recovery (BCR) or CD19+ hematogones in the bone marrow, 2) new CD19+ minimal residual disease (MRD) or relapse, or 3) nonresponse to initial infusion. The huCART19 trial included patients who had previously received a CAR T cell product (CAR-exposed), whereas all patients reinfused with CTL019/tisagenlecleucel were CAR-naïve at initial infusion. The primary outcome was complete response (CR) at day 28 after reinfusion, defined as complete remission with establishment or maintenance of B-cell aplasia. Secondary outcomes included CRS incidence, cumulative incidence of relapse (CIR) and overall survival (OS). Results: Among 229 CAR-naïve and 33 CAR-exposed patients treated with CD19 CAR between 2012-2020, 81 received ≥1 reinfusion (investigational CTL019, n=44; commercial tisagenlecleucel, n=11; huCART19, n=13 CAR-naïve and n=13 CAR-exposed). In addition, 18 patients received PD-1 blockade after their first (n=11) or subsequent (n=7) reinfusions. Indications for first reinfusion were peripheral BCR (CAR-naïve, n=32; CAR-exposed, n=6), hematogones (CAR-naïve, n=21; CAR-exposed, n=4), CD19+ MRD/relapse (CAR-naïve, n=10, CAR-exposed, n=0), and nonresponse to initial infusion (CAR-naïve, n=5, CAR-exposed, n=3). CRS grade ≥2 (Penn scale) occurred in 19 patients (grade 2, n=13; grade 3, n=4; grade 4, n=2). Grade 3-4 events only occurred in patients with active disease at time of reinfusion. Twenty-two patients had an inpatient admission within 30 days of first reinfusion, of which 7 required intensive care unit admission Among the 63 patients reinfused for relapse prevention, 33 (52%) had a CR at day 28. With a median duration of follow-up of 38 mos, 13 experienced a subsequent relapse (7 CD19+, 4 CD19-, 2 CD19-subset negative), 4 received alternative therapy or allogeneic hematopoietic stem cell transplantation (HSCT) in remission, and 16 remain in remission without further therapy at a median of 39 mos after first reinfusion. The median duration of B-cell aplasia was 8 mos (IQR 2-35) after reinfusion. Of the 30 with no response (NR), 10 had a subsequent CD19+ relapse, 15 received alternative therapy or HSCT, and 5 remain in remission without further therapy at a median of 43 mos after reinfusion. CIR and OS were not statistically significantly different between patients with CR or NR (CIR, p=0.26; OS, p=0.25) (Figure A-B). However, at 24 mos after reinfusion, CIR was 29% (95% CI, 11-44%) for CR compared to 61% (95% CI, 24-80%) for NR; OS was 90% (95% CI, 80-100%) for both groups. Of the 10 patients reinfused for relapse, 5 (50%) had a CR; 2 subsequently experienced a CD19+ relapse, 2 received an HSCT in remission, and 1 remains in remission without further therapy at 18 mos after reinfusion. Of the 8 patients reinfused for nonresponse to initial infusion, 7 were evaluable; none had a CR, and all died at a median of 2.5 mos after reinfusion. Conclusions: Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may prolong B-cell aplasia in patients with short CAR persistence and reduce relapse risk, and can induce remissions in patients with CD19+ relapsed disease. Thus, reinfusion may provide an alternative to HSCT for short persistence. However, reinfusion is not effective for patients with nonresponse to initial CAR infusion. Figure 1 Figure 1. Disclosures Callahan: Novartis: Speakers Bureau. Rheingold: Optinose: Other: Spouse's current employment; Pfizer: Research Funding. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; Novartis: Patents & Royalties; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Maude: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Wugen: Consultancy.
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