Rationale for CAR-T to Treat R/R MCL

Javier Munoz, MD, MS, FACP: The course of mantle cell lymphoma is many times convoluted. This is an aggressive disease. The median overall survival when incorporating intensive therapy is 8 to 10 years, and shorter survival times are seen with less intensive therapy. For the relapsed/refractory setting of mantle cell lymphoma, there are 3 BTK [Bruton tyrosine kinase] inhibitors currently FDA approved: ibrutinib, acalabrutinib, and zanubrutinib. Other options include bortezomib, the immunomodulator lenalidomide, and the BCL2 inhibitor, venetoclax.

Patients who are relapsed or refractory after a BTK inhibitor have a very ominous prognosis, with a survival of maybe 13 months. Hence, several trials have been conducted trying to salvage this population of patients. The inclusion criteria for ZUMA-2 was for patients with relapsed or refractory mantle cell lymphoma after up to 5 previous therapies, and all patients needed to have received a previous BTK inhibitor. Needless to say, these patients face an unmet need in lymphoma, and the ZUMA-2 trial did allow patients with high-risk features to enroll, including patients with high MKI67, TP53 abnormalities, high MIPI [Mantle Cell Lymphoma Prognostic Index] scores, and blastoid or pleomorphic histologies. These patients are the sickest of the sick and have historically done very poorly with standard chemotherapy.

We know that chimeric antigen receptor, or CAR, T-cell therapy, such as axicabtagene ciloleucel, or axi-cel for short, has displayed efficacy in patients with relapsed or refractory aggressive B-cell lymphomas. This includes diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. KTE-X19 is an anti-CD19 CAR T-cell therapy, meaning you are re-educating those T cells to target cells that express CD19, which is present across the board in multiple B-cell malignancies including mantle cell lymphoma. The KTE-X19 data in the ZUMA-2 trial was recently presented by Dr Michael Wang at medical conferences. Furthermore, KTE-X19 is particular in the way that it’s produced in a manufacturing process that removes circulating CD19-expressing malignant cells that could potentially be present in patients with leukemia or lymphomas. The removal of these CD19 malignant cells decreases the chances of exhaustion of anti-CD19 CAR-T cells during the manufacturing process, making it more seamless.

ZUMA-2 was a phase 2 trial that analyzed data for 74 patients enrolled. The results showed 93% of patients had an objective response, and 67% of patients had a complete response. KTE-X19 was manufactured for 71 patients and administered to 68 patients. Hence, when you look at the intention-to-treat analysis, the objective response was 85% and complete response was 59%, which is still impressive.

At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Very similar to the CAR T cells previously approved for aggressive B-cell lymphomas, serious and life-threatening toxic effects were consistent with those reported with those of other constructs. The main toxicities for CAR T-cell therapies, in general, are cytokine release syndrome and neurological events. Grade 3 or higher cytokine release syndrome and neurological events occurred in 15% and 31% of patients, respectively, when KTE-X19 was used.

Transcript edited for clarity.

Case: A 66-Year-Old Woman With Mantle Cell Lymphoma

History

• A 66-year-old woman diagnosed with mantle cell lymphoma in 2017
• She was treated with rituximab, dexamethasone, cytarabine + carboplatin followed by autologous stem cell rescue; achieved PR;
  • Continued on rituximab maintenance therapy
• In 2019 she experienced clinical relapse and was started on acalabrutinib; achieved SD
   

Currently

• She complains of a 3-month history of intermittent fatigue, nausea and dyspnea on exertion
• PMH: DM, medically controlled
• PE: bilateral submandibular lymphadenopathy; otherwise unremarkable
• Labs: WBC 12 X 109/L, hemoglobin 9.8 gm/dL, plt 90,000/u, LDH 410 U/I, ANC 3100/mm3
• Lymph node biopsy: IHC; cyclin D1+, CD10+, CD20+, CD43+; FISH: t (11;14)
• C/A/P CT scan: widespread lymphadenopathy including bilateral submandibular (2.9 cm, 3.4 cm), 2 left-sided axillary lymph nodes (3.7 cm, 4.1 cm), and lumbar region (5.1 cm)
• PET/CT shows diffuse uptake of 18F-FDG in the submandibular, axillary and lumbar lymph nodes
• Beta-2-microglobulin 4.2 µg/L
• Ann Arbor stage IV; MIPI score 6.6, high risk; ECOG PS 0
• Treatment was started with fludarabine + cyclophosphamide, followed by a single infusion of CAR transduced autologous T cell