Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells

Abstract

Relapse following chimeric antigen receptor (CAR) T-cell therapy directed against CD19 for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) remains a significant challenge. Three main patterns of relapse predominate: CD19 positive (CD19pos) relapse, CD19 negative (CD19neg) relapse, and lineage switch (LS). Development and validation of risk factors that predict relapse phenotype could help define potential pre- or post-CAR T-cell infusion interventions aimed at decreasing relapse. Our group sought to extensively characterize preinfusion risk factors associated with the development of each relapse pattern via a multicenter, retrospective review of children and young adults with r/r B-ALL treated with a murine-based CD19-CAR construct. Of 420 patients treated with CAR, 166 (39.5%) relapsed, including 83 (50%) CD19pos, 68 (41%) CD19neg, and 12 (7.2%) LS relapses. A greater cumulative number of prior complete remissions was associated with CD19pos relapses, whereas high preinfusion disease burden, prior blinatumomab nonresponse, older age, and 4-1BB CAR construct were associated with CD19neg relapses. The presence of a KMT2A rearrangement was the only preinfusion risk factor associated with LS. The median overall survival following a post-CAR relapse was 11.9 months (95% CI, 9-17) and was particularly dismal in patients experiencing an LS, with no long-term survivors following this pattern of relapse. Given the poor outcomes for those with post-CAR relapse, study of relapse prevention strategies, such as consolidative hematopoietic stem cell transplantation, is critical and warrants further investigation on prospective clinical trials.

Graphical abstract

Figure 1.

Categories of relapse phenotype and overall outcomes following relapse. (A) Categories of relapse phenotype. (B) CONSORT flow diagram. Figure made using BioRender. Unknown relapse category due to unavailable immunophenotype at time or relapse. ∗Includes 2 patients who had rapid emergence of LS at first restaging timepoint. (C) Overall survival following relapse (n = 166). Median OS was 11.9 months (95% CI, 9.0-17.0). The 6-, 12-, and 24-month OS rates were 69.8% (95% CI, 62.0% to 76.3%), 49.4% (95% CI, 41.1% to 57.2%), and 34.0% (95% CI, 25.7% to 42.5%), respectively.

Figure 2.

Outcomes stratified by relapse immunophenotype. (A) CIR stratified by relapse immunophenotype. Corresponding data in supplemental Table 2. (B) Median time to relapse, stratified by relapse immunophenotype. (C) OS following relapse, stratified by relapse immunophenotype. Median OS for CD19^pos relapse was 18.9 months (95% CI, 11.2-27.0). Median OS for CD19^neg relapse was 9.7 months (95% CI, 6.9-15.9). Median OS for LS was 3.7 months (95% CI, 1.2-7.0). (D) BCA at time of relapse, stratified by relapse immunophenotype. BCA, and loss thereof, was based on local assessment and was generally defined by 1 of the following parameters: (1) >1% bone marrow CD19+ hematogones; (2) >1% increase in CD19⁺ cells in bone marrow or peripheral blood; or (3) >3% CD19⁺ B cells of total peripheral blood lymphocytes or >50 CD19⁺ cells/μL, verified by 2 consecutive timepoints.

Figure 3.

Outcomes for patients with KMT2Ar ALL. (A) Intersection graph showing association between KMT2Ar, infant ALL diagnosis and lineage switch. (B) Flow diagram showing overall outcomes of patients with KMT2Ar ALL following CD19 CAR. ∗2 patients died of CAR toxicity; ^ˆ1 died of post-HSCT TRM. CR, complete remission; NE, nonevaluable; NR, nonresponse (including partial response, stable disease, and progressive disease). (C) Relapse phenotype of non-KMT2Ar patients. (D) Relapse phenotype of KMT2Ar patients. (E) Outcomes for individual patients with KMT2Ar ALL.

Figure 4.

Overall and event-free survival in patients with KMT2Ar and infant ALL. (A) EFS KMT2Ar vs non-KMT2Ar. EFS for KMT2Ar patients at 6, 12, and 24 months was 55.3% (95% CI, 38.3% to 69.3%), 52.5% (95% CI, 35.6% to 66.9%), and 43.8% (95% CI, 27.6% to 58.8%), respectively, with a median EFS of 14.1 months (95% CI, 2.2 NE). EFS for non-KMT2Ar patients at 6, 12, and 24 months was 69.5% (95% CI, 64.6% to 73.9%), 58.0% (95% CI, 52.9% to 62.7%), and 47.0% (95% CI, 41.7% to 52.2%), respectively, with a median EFS of 20.2 months (95% CI, 13.9-28.4). P = .47. (B) OS KMT2Ar vs non-KMT2Ar. OS for KMT2Ar patients at 6, 12, and 24 months was 71.1% (95% CI, 53.9% to 82.8%), 57.7 (95% CI, 40.5% to 71.5%), and 51.9% (95% CI, 34.9% to 66.5%), respectively, with a median OS of 25.3 months (95% CI, 7.9 NE). OS for non-KMT2Ar patients at 6, 12, and 24 months was 85.6% (95% CI, 81.6% to 88.7%), 76.3 (95% CI, 71.7% to 80.3%), and 65.9% (95% CI, 60.6% to 70.7%), respectively, with a median OS of 51.9 months (95% CI, 42% NE). P = .02. (C) EFS infant ALL vs noninfant ALL. EFS for infant patients at 6, 12, and 24 months was 55.2% (95% CI, 35.6% to 71.0%), 55.2% (95% CI, 35.6% to 71.0%), and 50.9% (95% CI, 31.5% to 67.5%), respectively, with a median EFS not reached. EFS for noninfant patients at 6, 12, and 24 months was 69.2% (95% CI, 64.3% to 73.5%), 57.7% (95% CI, 52.6% to 62.5%), and 46.5% (95% CI, 41.2% to 51.6%), respectively, with a median EFS of 19.5 months (95% CI, 13.9-27.0). P = .88. (D) OS Infant ALL vs noninfant ALL. OS for infant patients at 6, 12, and 24 months was 69% (95% CI, 48.8% to 82.5%), 58.2% (95% CI, 38.3% to 83.8%), and 54.1% (95% CI, 34.2% to 70.3%), respectively, with a median OS of 35.8 months (95% CI, 5.6 NE). OS for noninfant patients at 6, 12, and 24 months was 85.4% (95% CI, 81.5% to 88.5%), 75.8 (95% CI, 71.2% to 79.8%), and 65.4% (95% CI, 60.2% to 74.2%), respectively, with a median OS of 49.1 months (95% CI, 42.0 NE). P = .15.