Optimization of Tisagenlecleucel-Associated-Pancytopenia in a Transfusion-Free Medicine Patient with Diffuse Large B-Cell Lymphoma

Introduction

Tisagenlecleucel (Tisa-cel), a CD-19 directed autologous chimeric antigen receptor T-cell (CAR-T) product, is highly effective in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and post-infusion pancytopenia are common adverse events associated with Tisa-cel. The management of Tisa-cel associated-pancytopenia remains a challenge, particularly in transfusion-free medicine patients given the lack of standardized guidelines and limited evidence.

Case Presentation

An 80-year old Jehovah's Witness female with stage IV Germinal Centre B-Cell like DLBCL with involvement of splenic hilum, left kidney, and retroperitoneum is initiated with 6C of mini-RCHOP. Her disease underwent histologic transformation to double expressor phenotype DLBCL. Treatment then followed with bendamustine and abdominal radiation which resulted in partial response, and subsequent epcoritimab without significant response. She was then considered for Tisa-cel at the Pennsylvania Hospital Center for Transfusion-Free Medicine (CTFM) for further care.

Prior to leukapheresis, she had an Eastern Cooperative Oncology Group (ECOG) score of 0, hemoglobin of 11.5g/dL, platelets of 213x10^3/uL, and white blood cell (WBC) count of 3.5x10^3/uL. Her CD-3 count and Absolute Lymphocyte Count (ALC) pre-leukapheresis were 366 and 450 respectively. Following leukapheresis, she underwent bridging therapy with 1C of rituximab/polatuzumab throughout which her blood counts remained stable. Prior to re-infusion, her immunoglobulin (Ig) G, M and A levels were 317, <20, and 40 mg/dL, respectively. She received 60,000 units of prophylactic erythropoietin (EPO) and 300mg of intravenous iron for 3 days prior to Tisa-cel reinfusion. For closer monitoring, she was hospitalized for lymphodepleting chemotherapy (LDc) with brentuximab and Tisa-cel reinfusion. Count nadirs occurred on day 21 with a hemoglobin of 6.5g/dL, platelets 17x10^3/uL, and WBC of 1.0x10^3/uL with lowest ANC being 210THO/uL. Her course was complicated by G1 CRS and one episode of G1 ICANS, both of which were conservatively management. She was briefly treated with broad spectrum antibiotics, sulfamethoxazole-trimethoprim and levofloxacin prophylaxis, 300mcg of filgrastim for 5 days, and 11 days of aminocaproic acid. Her WBC improved to 11x10^3/uL and her platelets improved beyond 50x10^3/uL. Her course was also complicated by cytomegalovirus (CMV) gastritis and esophageal candidiasis treated with fluconazole and ganciclovir. Approximately 30 days after reinfusion, her hemoglobin was 6.7g/dL, platelet was 139x10^3/uL, and her WBC was 2.6x10^3/uL. Her IgG, M, and A levels were <75, <20, and 16 respectively, and she was discharged after optimization of her nutrition status and management of nausea. Unfortunately, 30-day post PET scans showed progression of disease.

Discussion

Our case highlights many challenges of CAR-T for bloodless medicine patients. These include managing rapidly progressing and refractory disease while awaiting cell engineering, and prolonged cytopenias following LDc without transfusion support. Our patient's age, ECOG status, and goals of care were factored prior to proceeding with CAR-T. At her lowest counts, our patient experienced grade-3 anemia with a hemoglobin of 6.5g/dL per common terminology criteria for adverse events (CTCAE), grade-4 CTCAE thrombocytopenia with platelets at 17x10^3/uL, and grade-3 CTCAE neutropenia with a WBC at 1.2x10^3/uL. Although this patient's pancytopenia was predicted, our case highlights the role of cell adjuncts such as EPO, intravenous iron, aminocaproic acid, and filgrastim, a strategy that is previously been established among our CTFM patients undergoing autologous stem cell transplantation. Our case may suggest possible hemoglobin thresholds to achieve prior to LDc, and the considering the use of thrombopoietin to manage anemia and thrombocytopenia. CAR-T treatment modifications may also include stem cell boosts to encourage hematopoiesis for persistently profound cytopenias, and tailoring lines of chemotherapy as to avoid LDc-specific agents prior to CAR-T to maintain tumor-sensitivity. Our single-center experience at the CTFM supports the safety of CAR-T in bloodless medicine patients with DLBCL.

Tomasulo:AstraZeneca: Consultancy; Sanofi: Consultancy; Abbvie: Consultancy.