BCMA CAR-T induces complete and durable remission in refractory plasmablastic lymphoma

Abstract

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options.

Keywords: Immunotherapy; Pediatrics; Receptors, Chimeric Antigen.

Figure 1

PET whole body and lower extremity. (Aa) Pre-PBSCT. Minimal FDG of pleural-based lesion, SUV <2. (Ab) Hypermetabolic lesion in proximal left tibia, SUV 14. (Ba) Relapse at day 60 post PBSCT. No abnormal FDG uptake in chest. New uptake in liver, SUV 15.6. (Bb) Numerous areas of abnormal intake including right humerus, right sacrum and ilium, right proximal femur, right distal femur, and left mid-tibia. (Ca) Day 108 post PBSCT. Increase in size of hepatic lesion, two new hepatic lesions. (Cb) Innumerable, multifocal, hypermetabolic lesions throughout the axial and appendicular skeleton including proximal left tibial lesion; SUV 14.5. (Da) Pre-BCMA CAR-T. New patchy ground-glass opacities in the right upper lobe, SUV 4.4; no abnormal FDG in the abdomen/pelvis. (Db) Persistent residual disease in the left tibia. (Ea) Post-BCMA CAR-T: no abnormal FDG uptake in the chest/abdomen/pelvis. (Eb) Near complete resolution of FDG uptake in the left proximal tibia. (Fa) Fourteen months post-BCMA CAR-T: normal PET/CT. CAR-T, chimeric antigen receptor T cell; PBSCT, peripheral blood stem cell transplant; PET, positron emission tomography; FDG, fluorodeoxyglucose; SUV, standardized uptake value; Red arrows, identify certain hypermetabolic lesions.

Figure 2

(A) Ferritin and ALC following BCMA CAR-T demonstrate a moderate elevation in ferritin following CAR-T and a robust response in ALC with a peak on day 12, demonstrating successful CAR-T expansion. (B) BCMA directed CAR-Ts expanded in vivo, peaking on day 15, and were detectable until day 29 by flow cytometry. At the time of peak expansion, the CD4:CD8 ratio was 1.2 and CD8 cells were effector memory phenotype. (C) Minimal residual disease by next-generation sequencing of B-cell receptor clones throughout his clinical course, showing no residual sequences detected since BCMA CAR-T. ALC, absolute leukocyte count; BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T cell.