Key Points Preinfusion dim CD19 expression and rare CD19– events in B-ALL do not affect relapses or responses to CD19-directed CAR T-cells. Prior blinatumomab treatment increases the rate of failure to achieve MRD– remission and CD19– MRD and relapse.
PURPOSE CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.
PURPOSE To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC ( P < .001), but persistence was not different ( P = .73). Event-free and overall survival were worse in the HTBC ( P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively ( P = .18). CONCLUSION Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
CAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may decrease T cell exhaustion, thereby improving CAR T cell function and persistence. We report our single institution experience of the use of PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T cell therapy. Methods: Patients treated with CD19-directed CAR T cell therapy (murine CTL019 or humanized CTL119) at the Children's Hospital of Philadelphia who demonstrated repeated early CAR T cell loss or partial/no response to CAR T cell therapy received a PD-1 inhibitor starting no sooner than 14 days after CAR T cell infusion and after resolution of cytokine release syndrome (CRS) symptoms, with the possibility of repeated doses up to every 3 weeks. Results: Fourteen patients, ages 4-17 years, with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1), were treated with CD19-directed CAR T cell therapy (CTL019, n=4; or CTL119, n=10) in combination with pembrolizumab (n=13) or nivolumab (n=1). Three of 6 patients treated with CD19 CAR T cells in combination with a PD-1 inhibitor for early B cell recovery re-established B cell aplasia (a reflection of CAR T cell function) for 5-15 months, 2 of whom have persistent B cell aplasia with ongoing pembrolizumab therapy. Four patients started pembrolizumab for bulky extramedullary disease unresponsive to or relapsed after CAR T cells, with 2 partial and 2 complete responses seen. In one patient, significant CAR T cell proliferation was measured within days of starting pembrolizumab and in temporal correlation to radiographic disease response. In 4 patients who failed to achieve disease remission with initial CAR T cell infusion, no CRs were achieved with the addition of pembrolizumab, although partial responses were seen, and one patient progressed with CD19-dim/negative disease. CRS symptoms and fever typical of CAR T cell proliferative responses were observed in 3/14 patients within 2 days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation, and including 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 patients with grade 3-4 cytopenias. No grade 5 toxicities or graft-versus-host disease flares occurred. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both patients relapsed/progressed with CD19+ disease a few weeks after discontinuation. Discussion: T cell exhaustion or activation induced CAR T death (AICD) has been suspected to contribute to poor persistence of CAR T cells. We hypothesized that the PD-1 checkpoint pathway may be involved in CAR T cell exhaustion in some cases, which may be overcome by checkpoint inhibition. Here, promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease. In contrast, PD-1 inhibition had partial, but no durable, effect in the four B-ALL patients with poor initial marrow response to CAR T cell therapy alone, suggesting a different mechanism such as AICD may be responsible for poor initial responses. No unexpected or fatal toxicities were seen. This cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T cell effect and persistence. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Callahan:Novartis Pharmaceuticals Corporation: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.