Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL

Abstract

Purpose: CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined.

Methods: We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables.

Results: Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease-negative by flow cytometry. Utilization of fludarabine/cyclophosphamide-based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non-fludarabine/cyclophosphamide-based lymphodepletion (2/8, 25%; P = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease-negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8).

Conclusion: We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696).

Conflict of interest statement

Nirali N. ShahResearch Funding: Lentigen Daniel W. LeeEmployment: Karyopharm TherapeuticsConsulting or Advisory Role: Harpoon Therapeutics, Amgen, CelgeneResearch Funding: Kite/GileadPatents, Royalties, Other Intellectual Property: CAR T cell for pediatric and adult high-grade gliomas and other tumorsTravel, Accommodations, Expenses: Kite/Gilead Pamela L. WoltersStock and Other Ownership Interests: Bristol-Myers Squibb Crystal L. MackallStock and Other Ownership Interests: Lyell Immunopharma, Alimera Sciences, Apricity HealthConsulting or Advisory Role: Bryology, Vor Biopharma, Apricity Health, TPG, Alimera Sciences, PACT Pharma, Nektar, Lyell Immunopharma, NeoImmuneTechPatents, Royalties, Other Intellectual Property: I am an inventor on numerous patents related to chimeric antigen receptor therapeutics and received royalties from NIH for the CD22-CAR patent licensed to Juno therapeutics.Travel, Accommodations, Expenses: NeoImmuneTech, Roche, NektarOther Relationship: Lyell ImmunopharmaNo other potential conflicts of interest were reported.

Figures

FIG 1.

Response to CD19.28ζ CAR T-cell therapy. (A) Rate of those with MRD-positive or MRD-negative CR and those who had SD or PD among those with acute lymphoblastic leukemia. (B) Fraction of CR (MRD-positive and MRD-negative) according to patient demographics, disease characteristics, and treatment course. Squares represent the observed CR rate with the lines representing the 95% CIs for the difference of proportions from the reference category. The forest plots are based on the fraction and a Clopper-Pearson exact two-tailed 95% CI. (C) Duration in continuous remission among those who achieved a CR, indicating those who remain alive in remission, when HSCT was performed, the time of relapse, and those who experienced TRM. (D) Flow cytometric analysis of the CSF in patient 45 showing progressive CAR T-cell expansion (green) along with leukemia regression (red) in a patient with extensive CNS disease. (E) Brain magnetic resonance imaging findings from before, during, and after CAR T-cell infusion corresponding with patient 45, whose concurrent flow cytometry samples are shown in (D). Top panel (postcontrast axial fluid-attenuated inversion recovery) shows the evolution of intraparenchymal edema related to the leptomeningeal involvement to encephalomalacia. Bottom panel shows the evolution of widespread patchy white matter injury or edema involving the cerebrum and cerebellum with extensive involvement of the left temporal lobe (pretreatment). At day +10, neurologic symptoms included encephalopathy and right gaze preference. Necrosis had developed in the portion of the left temporal lobe that was most edematous. Diffusion-weighted images (not shown) demonstrated restricted diffusion corresponding to the area that is dark on fluid-attenuated inversion recovery. By day +76, the necrosis in the left temporal lobe had evolved to encephalomalacia (not ex vacuo expansion of the left temporal horn). B-ALL, B-cell acute lymphoblastic leukemia; CR, complete remission; HSCT, hematopoietic stem-cell transplant; MRD, minimal residual disease; PD, progressive disease; SD, stable disease; TRM, transplant-related mortality.

FIG 2.

(A) Median and interquartile range of CAR T-cell expansion (as a percentage of T cells that were CAR T-cell–positive) in the bone marrow at day 28 (± 4 days) post-CAR T-cell infusion, stratified by those who achieved a CR and those who did not (lower limit of CAR T-cell detection by flow cytometry is 0.05% of CD3+ T cells). (B) Median and interquartile range of peak CAR T-cell expansion (as a percentage of T cells that were CAR T-cell–positive) in the peripheral blood within the first 28 days (± 4 days) post-CAR T-cell infusion, stratified by those who achieved a CR and those who did not. (C) Median and interquartile range of peak CAR T-cell expansion (as a percentage of T cells that were CAR T-cell–positive) in the peripheral blood within the first 28 days (± 4 days) post-CAR T-cell infusion, stratified by those who had grade 0, grade 1/2, and grade 3/4 CRS. (D) Percentage of CAR T cells positive for PD1, TIM3, or LAG3 as stratified by CD4 and CD8 populations with red indicating those who achieved a CR and blue indicating those who did not. (E) Proportion of the CD4+ CAR T-cell product that are naïve T cells; T (CM), T (EM), and T (TE). (F) Proportion of the CD8+ CAR T-cell product that are naïve T cells; T (CM), T (EM), and T (TE). (G) Peak IFNγ values stratified by CRS grade 0-2 versus CRS grade 3-4 in those who achieved a CR. (H) Peak IL-6 values stratified by CRS grade 0-2 versus CRS grade 3-4 in those who achieved a CR. (I) Peak IL-8 values stratified by CRS grade 0-2 versus CRS grade 3-4 in those who achieved a CR. CR, complete remission; CRS, cytokine release syndrome; EM, extramedullary; IFN, interferon; IL, interleukin; PD, progressive disease; T (CM), central memory T cells; T (EM), effector memory or effector T cells; T (TE), terminal effector T cells.

FIG 3.

Continuous remission, OS, and EFS. (A) OS and EFS among patients with B-cell acute lymphoblastic leukemia, starting from CAR infusion at day 0. (B) OS, (C) EFS among patients who received Flu/Cy–based pre-CAR T-cell lymphodepletion versus those who did not. (D) OS, (E) EFS among patients who had an M2 marrow (≥ 5% marrow disease) or higher compared with those who had an M1 marrow (