August 2016, Vol. 5, No. 6
CAR T-Cell Therapy Produces High Response Rates in Refractory B-Cell Malignancies
A durable complete response (CR) was achieved in a high proportion of adult patients with refractory B-cell malignancies who were treated with CD19+ chimeric antigen receptor (CAR) T cells made up of a defined 1:1 ratio of CD8+ and CD4+ cells.
The data were presented by Cameron John Turtle, MBBS, PhD, Attending Physician, Seattle Cancer Care Alliance, at the 2016 ASCO Annual Meeting.
In the phase 1/2 study, 90 patients with refractory or resistant acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) underwent leukapheresis to produce autologous CAR T cells. Lymphodepleting chemotherapy was followed 2 to 4 days later by infusion with 1 of 3 CAR T-cell dose levels (2 × 105, 2 × 106, and 2 × 107 cells/kg).
The highest CR in the study was achieved in ALL patients. Thirty-six patients with ALL were treated, and in one-third allogeneic stem cell transplantation had failed. Thirty-two of the 34 patients (94%) who completed a response assessment had a bone marrow CR, and 2 had minimal residual disease. In vivo CAR T-cell expansion and toxicity correlated with bone marrow blast count and infused dose of defined composition CAR T cells.
CAR T-cell expansion and persistence were dramatically increased in a subset of patients who underwent lymphodepletion with cyclophosphamide and fludarabine, compared with those who did not receive fludarabine. “In addition to improving the CAR T-cell kinetics in vivo, we also saw a marked improvement in the disease-free survival [DFS] in the patients who received cyclophosphamide/fludarabine depletion,” said Dr Turtle. At 18 months, a DFS rate of approximately 60% was observed in the patients receiving optimized lymphodepletion compared with <10% of those receiving cyclophosphamide only (P = .0005).
Forty-one patients with NHL were treated in the study, 66% of whom had received at least 4 prior lines of therapy.
The objective response rate (ORR) was 80% (16 of 20 patients) among NHL patients receiving 2 × 105 cells/kg CAR T-cell infusion with cyclophosphamide/fludarabine lymphodepletion, 50% of whom achieved a CR. With this preferred regimen, the median progression-free survival (PFS) and overall survival for those who achieved a CR had not yet been reached.
Thirteen patients with CLL were treated, most of whom had high-risk disease as defined by 17p deletion and/or complex karyotype. All patients had prior ibrutinib therapy: 54% were ibrutinib refractory and 15% were ibrutinib intolerant. The ORR in the cyclophosphamide/fludarabine-depleted patients was 91%, with 45% achieving a CR. “One of the observations from the CLL patients was the high rate of marrow clearance in these individuals,” he said. Ten of 11 (91%) cleared disease from the bone marrow with CAR T-cell therapy. The index clone was not detected in all 4 patients in whom IgH deep sequencing of the bone marrow was performed.
In the CLL patients with optimized lymphodepletion, the median PFS had not yet been reached.
The percentage of patients with high-grade cytokine release syndrome was 26% for ALL patients who received the preferred lymphodepletion and risk-adapted CAR T-cell dosing regimen, 10% for NHL patients who received preferred lymphodepletion with level 2 CAR T-cell dosing, and 23% for patients with CLL. Neurotoxicity was experienced by 26%, 10%, and 3% of these 3 groups, respectively.
“Although the toxicities of CAR T cells can be significant, they are in general manageable,” said Dr Turtle. The evidence is the number of days patients spent in the hospital for their entire treatment cycle, he said, which ranged from 5 to 8 days.
Chimeric antigen receptor T-cells (CAR-T) have saved lives in some patients with acute lymphoblastic leukemia (ALL) who had run out of other treatment options. This type of immunotherapy is making inroads in other hematologic malignancies as well, but it is still being studied in very sick patients.The downside of CAR-T [ Read More ]
A multitargeted RAF inhibitor demonstrated activity in several types of advanced solid tumors associated with different mutations in the RAF family of genes, results of a preliminary clinical trial showed. Of 29 evaluable patients, 3 had confirmed partial responses to treatment with BGB-283, 1 had an unconfirmed response, and 14 [ Read More ]