Hematopathologic Correlates of CAR T-Cell Therapy

Key points

Introduction

CD19 is a key B-cell lineage marker that is expressed almost universally on immature and mature lymphoid neoplasms. ¹ CD19-targeting chimeric antigen receptor (CAR) T-cell products, tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, are approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL), ^2 , 3 respectively. CAR T cells are under active investigation for the treatment of other hematological malignancies (eg, acute myeloid leukemia [AML], myeloma), solid tumors, and nonmalignant diseases. ^4 , 5

Although 70% to 95% of patients with relapsed/refractory B-ALL go into a complete morphologic remission following CD19-targeting CAR T-cell therapy, a subset of patients relapses with CD19-negative or CD19-positive leukemia. 6789 The cause and treatment of relapse varies depending on the CD19 status and immunophenotype of the relapse.

Various clinical laboratory professionals play an important role in the collection, administration, and follow-up of patients treated with CAR T-cell therapy. The blood bank is involved in the apheresis of the initial T cells, and the stem-cell laboratory is vital for administration of CAR T-cell products. Peripheral blood, bone marrow, and cerebrospinal fluid (CSF) cell counts from the hematology laboratory are important in the monitoring of patients undergoing CAR T-cell therapy. Peripheral blood B-cell and T-cell counts assessed by flow cytometry are necessary for monitoring of CAR T-cell function. Cytokine panels from the immunology laboratory aid in the evaluation of cytokine release syndrome (CRS) postinfusion. Bone marrow biopsies, tissue biopsies in conjunction with immunophenotyping, and genetic studies are necessary for characterization of responses and relapses. This review focuses on hematopathology correlates of CD19-targeted CAR T-cell therapy of B-ALL but can be extended to other targeted antigens in other hematologic malignancies.

Discussion

CD19-directed CAR T-cell therapy was first approved by the FDA for relapsed/refractory B-cell leukemia and lymphoma based on the results from the global, phase 2 ELIANA trial for ALL, ⁷ and the JULIET trial for axicabtagene ciloleucel. ¹⁰ In the initial trials, patients with B-ALL were candidates for CAR T-cell therapy if they were refractory to chemotherapy, immunotherapy, or had experienced second or greater relapse, including post-stem cell transplant. ^9 , 11 Newer studies are investigating the use of CD19-targeted CAR T cells earlier in therapy for specific patient populations with high-risk leukemia. The NCHOP Basket trial (CT04276870) is investigating the use of tisagenlecleucel in pediatric and young adult patients with hypodiploid or t(17;19) B-ALL, infants with very high-risk KMT2A -rearranged B-ALL, and patients with central nervous system (CNS) relapse. The COG AALL1721 CASSIOPEIA trial ( NCT03876769 ) is investigating the frontline use of tisagenlecleucel in de novo high-risk pediatric and young adult B-ALL patients who are end-of-consolidation minimal residual disease positive.