Axicabtagene ciloleucel for CD19+ plasmablastic lymphoma
Authors: Ruben Raychaudhuri, Julianne Qualtieri, Alfred L. Garfall
Journal: American Journal of Hematology (2019)

To the Editor: Plasmablastic lymphoma (PBL) is an uncommon, high-grade B cell neoplasm. While recognized by the WHO classification as a subset of large B-cell lymphoma, its plasma cell-like immunophenotype, morphology, and association with HIV and EBV reactivation distinguish PBL from typical diffuse B-cell lymphoma.1 Current guidelines suggest initial therapy with dose-adjusted infusional etoposide, vincristine and doxorubicin with bolus cyclophosphamide and prednisone (DA-EPOCH), reflecting its classification as a large B-cell lymphoma.2 Median overall survival with this approach is disappointing, reported as 15 months in HIV-positive patients, and likely worse in HIV-negative patients.3, 4 PBL is challenging to differentiate from plasma cell myeloma, and several reports have suggested improved survival with addition of anti-myeloma agents such as bortezomib and lenalidomide.5 Despite these advances, PBL remains a highly aggressive malignancy and new approaches are necessary. We report here a case of relapsed/refractory CD19+ PBL treated with axicabtagene ciloleucel (axi-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy approved by the FDA for large B-cell lymphoma that is relapsed or refractory after two or more lines of systemic therapy. Our patient was a previously healthy 31-year-old female who presented with fatigue and back pain. Initial laboratory evaluation was remarkable for a hemoglobin of 5 g/dL and serum calcium of 18 mg/dL. A CT scan demonstrated a pulmonary embolism, multiple pathologic rib fractures, widespread bony lucencies, diffusely enlarged kidneys, and bilateral, large pleural effusions. Pleural fluid cytology revealed a malignant B lymphoid neoplasm with plasmacytic features. HIV serology and EBV in situ hybridization were negative. A bone marrow biopsy demonstrated 100% replacement by large cells (Figure 1A). The Ki67+ fraction approached 100%. On flow cytometry, the cells were lambda-restricted, expressing CD10, CD19, CD38(bright), CD45(dim),CD138 (dim), and negative for CD5, CD20, CD23, CD34, and CD56 (Figure 1B, left). Fluorescent in situ hybridization identified gain of 1q21 and was negative for MYC re-arrangement. Her serum protein electrophoresis was negative for a monoclonal spike, and her serum free lambda and kappa light chains were 133 and 20 mg/L respectively. She was diagnosed with PBL and began therapy with DA-EPOCH. After two cycles she was switched to ifosfamide, carboplatin, and etoposide (ICE) due to progressive disease. PET/CT performed after her first cycle of ICE demonstrated widespread disease, with nearly confluent fluorodeoxyglucose (FDG) uptake throughout her skeleton and kidneys (Figure 1C). A lumbar puncture showed no disease involvement of her central nervous system by cytology and flow cytometry. She began salvage treatment with carfilzomib, lenalidomide, daratumumab, and dexamethasone. Her symptoms and lambda FLCs level improved, but her cytopenias persisted and repeat bone marrow biopsy performed 2 months after initiation of this regimen demonstrated 70% involvement of her PBL and reconfirmed CD19 expression. The patient underwent autologous leukapheresis for axi-cel manufacturing while continuing her prior regimen during the manufacturing process. About 6 months from her initial presentation, she received cyclophosphamide and fludarabine for lymphodepletion followed by axi-cel. After axi-cel infusion, she developed grade 2 cytokine release syndrome with high fevers, a peak ferritin of 18 330 ng/mL and grade 2 neurologic toxicity (grade determined based on ASTCT consensus scheme). She did not receive tocilizumab or steroids. At her 6 week follow-up, her cytopenias had resolved, her lambda FLCs had decreased from a pre-treatment level of 91.3 to <1.5 mg/L, and her pain had significantly improved. At 4 months after axi-cel, a PET/CT showed a complete metabolic response (Figure 1C). Unfortunately, a bone marrow biopsy performed 5 months post-treatment to assess depth of response found 50% involvement by residual/recurrent CD19+ PBL. One month later, at 6 months post-treatment, the patient developed severe thrombocytopenia and spontaneous tumor lysis; she was found to have circulating PBL cells and elevated lambda FLC at 142.1 mg/L. She was admitted for stabilization and initiation of salvage blinatumomab, which was chosen given her preserved CD19 expression (Figure 1B). She tolerated blinatumomab well but did not show any evidence of immediate response. Shortly after discharge she was re-admitted with septic shock and disease progression and passed away shortly thereafter, 13 months after her initial diagnosis. Regarding mechanism of resistance, 2 months after axi-cel administration, her circulating CD19+ cell count (as assessed by flow cytometry) was 0, suggesting active anti-CD19 immune surveillance. When her relapsed was identified, circulating CD19+ cell count had risen to 412/uL, suggesting loss of CAR T cell activity. CD19 expression was retained on her residual/recurrent PBL cells. These data suggest loss of in vivo axi-cel activity, and not loss of CD19 expression, as the cause of treatment failure. PBL is classified by the WHO as a subtype of large B cell lymphoma, which allowed our patient to be considered within the FDA's labeled indication for axi-cel. However, PBL patients were not included in the pivotal studies that led to approval of either axi-cel or tisagenlecleucel for relapsed/refractory large B cell lymphomas (Kite Pharma, personal communication, March 5, 2019; Stephen Schuster, University of Pennsylvania, personal communication, March 11, 2019). This report provides useful evidence that PBL can respond favorably to axi-cel when CD19 is expressed. Here, the response was short-lived but clinically meaningful. Our patient's pain and transfusion-dependent cytopenias resolved, and her performance status normalized. Longer in vivo persistence of axi-cel activity may have enabled more durable response. As noted above, PBL is often indistinguishable from aggressive PCM unless certain PBL-specific features are present such as HIV infection, EBV reactivation, or initial presentation with oropharyngeal lesions. Our patient exhibited many features of multiple myeloma including osteolytic bone lesions, hypercalcemia, and + 1q on FISH analysis; indeed, this patient met IMWG diagnostic criteria for PCM.6 Several features of this case were atypical for PCM, however, including our patient's young age, presence of extramedullary disease at diagnosis, expression of CD19 and CD10, and very high fraction of Ki67+ cells. Our patient was treated initially along a large cell lymphoma treatment pathway but later responded, however transiently, to drugs typically used in treatment of PCM. Our experience suggests that a diagnosis of PBL and axi-cel therapy should be considered in cases classified initially as plasmablastic PCM if CD19 expression is present. ALG acknowledges support from the Conquer Cancer Foundation of ASCO and is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. RR contributed to patient care and wrote the manuscript. JQ edited the manuscript, analyzed/obtained pathology specimens/images and flow cytometry data. ALG contributed to patient care and edited the manuscript. ALG reports research support from Novartis, Janssen, Amgen, and Tmunity; consulting fees from Tmunity, Surface Oncology, Janssen, Surface Oncology, and Kite Pharma; inventorship and royalties on patents in the field of CAR T cell therapy.