JCAR014 and cyclophosphamide/fludarabine lymphodepletion showed a high level of antitumor activity, with an acceptable toxicity profile.— Cameron Turtle, MBBS, PhD
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Researchers from Fred Hutchinson Cancer Research Center in Seattle reported early results from a small study of their chimeric antigen receptor (CAR) T-cell product (JCAR014) in chronic lymphocytic leukemia (CLL) at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition. Their findings included bone marrow clearance by flow cytometry in 88% of patients and by immunoglobulin heavy chain variable region (IGH) sequencing in 50%.1
All 24 patients had previously received treatment with ibrutinib (Imbruvica), and all but one had high-risk features, such as del(17p) and/or complex karyotype. Six were refractory to venetoclax (Venclexta).
“We were able to manufacture a product for all patients. JCAR014 and cyclophosphamide/fludarabine lymphodepletion showed a high level of antitumor activity, with an acceptable toxicity profile,” said Cameron Turtle, MBBS, PhD.
Engineered at Fred Hutchinson, JCAR014 is a second-generation CAR T-cell product that comprises a murine single-chain variable fragment antibody against CD19, with a 4-1BB FMC63 costimulatory domain. These CAR T cells are distinct in that they are a mix of CD8-positive–derived and CD4-positive–derived CAR T cells, which provided optimal potency in a preclinical model, he said. The investigators believe the composition of the product is critical and the equal mix of CD4-positive and CD8-positive T cells in JCAR014 produces a better therapeutic index.
Dr. Turtle presented results for 24 CLL patients who are being treated within a larger study of patients with B-cell malignancies. Phase I of the study established the maximum tolerated dose for CLL patients at 2 × 106/kg and the preferred lymphodepleting regimen as cyclophosphamide plus fludarabine, which these patients received. The addition of fludarabine to cyclophosphamide abrogated immune CAR T-cell rejection and dramatically increased early CAR T-cell expansion and late persistence, the researchers explained.
The CAR T-cell product was successfully manufactured for all 24 patients, and 75% were treated as outpatients.
Of 19 restaged patients who received the optimal lymphodepletion regimen and CAR T-cell dose, 14 (74%) achieved a lymph node response, including 4 (21%) who had a complete response by computed tomography scan (International Workshop on Chronic Lymphocytic Leukemia [IWCLL] 2008) at the 4-week assessment. Of the 17 patients with bone marrow disease at baseline, 15 (88%) were negative by high-resolution flow cytometry at 4 weeks. For 11 patients with disease that was positron-emission tomography (PET)-avid, 64% had a complete response at 4 weeks, with 1 additional patient becoming PET-negative 8 weeks later.
Progression-free survival and overall survival (time from first infusion) were both longer in high-risk patients who demonstrated a lymph node response to cyclophosphamide/fludarabine lymphodepletion and JCAR014. Median progression-free survival was 9.7 months for complete responders and was not reached for partial responders but was only 1 month in nonresponders (P = .002). Median overall survival was not reached for complete or partial responders but was only 4.1 months for nonresponders (P = .0004). Survival for partial responders by IWCLL criteria was not inferior to that of complete responders. No patients underwent allogeneic transplantation after responding to JCAR014 therapy.
IGH deep sequencing of the bone marrow may identify patients with a lower risk of disease progression after JCAR014 infusion, according to the study’s findings. Of 17 patients who cleared their bone marrow by flow cytometry, 14 underwent bone marrow IGH sequencing, and in 7 (50%), the malignant index clone was not detected. For these 7 IGH sequencing–negative patients, median progression-free was not reached, compared with 8.5 months in IGH sequencing–positive patients (P = .0253). Median overall survival was not reached in either group, Dr. Turtle reported.
“Deep-marrow clearance by IGH sequencing after JCAR014 provides early signs of durable responses, with 100% progression-free and overall survival,” he said.
Participants with the highest number of CAR T cells in their blood after infusion had a reduced risk of progression or death (hazard ratio = 0.56, 95% confidence interval = 0.34–0.93, P = .025). JCAR014 expansion directly correlated with bone marrow and lymph node tumor burden, he added.
Cytokine-release syndrome (all grades) developed in 20 patients (83%) but was limited to grade 1 or 2 in 75%. Neurotoxicity (all grades) was observed in eight patients (33%). Six patients (25%) received tocilizumab (Actemra) and dexamethasone for cytokine-release syndrome and neurotoxicity, and two received vasopressors. One patient died from grade 5 cerebral edema and severe cytokine-release syndrome. The side effects experienced by other patients in the study were temporary.
Biomarkers of Toxicity
The researchers are also evaluating potential biomarkers of cytokine-release syndrome and neurotoxicity, which could help predict susceptibility to these complications and facilitate mitigation strategies. Specifically, their univariate analysis has shown that levels of interleukin (IL)-15, IL-6, IL-8, IL-10, soluble tumor necrosis factor receptor type 1, and interferon-gamma were significantly higher at day 1 after CAR T-cell infusion in patients who developed grade 3 to 5 cytokine-release syndrome. Similar observations have been made for the development of neurotoxicity, Dr. Turtle reported in a poster at the ASH meeting.2
He said that biomarkers could prove to be different for the different CAR T-cell products, “but I think the general principles will remain the same, with early identification and treatment of patients at high risk of subsequent toxicity being important factors in management.”
Jose F. Leis, MD, PhD
Session moderator Jose F. Leis, MD, PhD, of the Mayo Clinic in Phoenix, commented on the promise of CAR T-cell therapy for chronic lymphocytic leukemia. “As someone who works in bone marrow transplant, I look at CAR T-cell therapy as eventually replacing allogeneic transplant in this malignancy,” he said. ■
Disclosure: Dr. Turtle disclosed financial relationships with Juno Therapeutics and Seattle Genetics. Dr. Leis reported no potential conflicts of interest.
2. Turtle CJ, Hay KA, Juliane G, et al: Biomarkers of cytokine release syndrome and neurotoxicity after CD19 CAR-T cells and mitigation of toxicity by cell dose. 2016 ASH Annual Meeting. Abstract 1852. Presented December 3, 2016.