Marrow Clearance With Concurrent CAR T-Cells, Ibrutinib in Resistant CLL

Saar Gill, MD

Concurrent treatment with CTL-119 cell therapy and ibrutinib (Imbruvica) led to complete marrow clearance of leukemic cells in 8 of 9 evaluable patients with heavily pretreated or genetically high-risk chronic lymphocytic leukemia (CLL), results of a pilot study showed.

The eight patients’ marrow remained clear of CLL during follow-up for as long as 12 months. All 9 patients developed tumor lysis syndrome (cytokine release syndrome, CRS), which was mostly grade 1/2 and did not require treatment with the interleukin-6 antagonist tocilizumab.

All of the patients had minimal or no response to ibrutinib after at least 6 months of treatment, a requirement of entry criteria for the study, according to a presentation at the 2017 ASCO Annual Meeting.

The preliminary results from the ongoing study continued the unfolding success story of chimeric antigen receptor (CAR) T-cell therapy in the treatment of hematologic malignancies. Acknowledging that CAR T-cell therapy has achieved high response rates in many patients with limited treatment options, study investigator Saar Gill, MD, said in an interview with OncLive that the early findings were not entirely unexpected.

“It’s not surprising, but it was important to show that there is nothing adverse about adding ibrutinib to the mix,” said Gill, an assistant professor of medicine at the University of Pennsylvania. “What this tells us is that we can get very deep responses, even in refractory patients. Most of these patients had failed multiple prior regimens, and 2 of the patients had already developed ibrutinib resistance mutations.”

The rationale for the study came from preclinical evidence of anticancer synergy with the combination of anti-CD19 CAR T-cells and the BTK inhibitor ibrutinib. Gill and colleagues hypothesized that treatment with ibrutinib before and during administration of CTL-119 cell therapy would enhance the rate of complete response in patients with pretreated and cytogenetically high-risk CLL.

Eligible patients had CLL associated with 1 or more mutations that identified them as high risk. The disease must have progressed or proven refractory to at least 1 regimen prior to starting ibrutinib, with the exception of patients who had 17p deletion or a TP53 mutation. Patients must have been on ibrutinib for at least 6 months prior to administration of CTL-119.

The CAR T-cell therapy began with lymphodepletion with fludarabine-cyclophosphamide or bendamustine one week prior to infusion of the cell therapy. Patients received up to 5 x 108 T cells transduced with a lentiviral vector encoding humanized anti-CD19 scFv, 4-1BB costimulation, and CD3zeta (CTL-119).

Investigators evaluated CLL burden in the marrow by means of nine-color flow cytometry and by next-generation deep sequencing for IgH gene rearrangements. They evaluated changes in patients’ lymph node and spleen size with CT imaging.

The treatment was well tolerated, as no patient required anti-cytokine therapy for CRS. Significant toxicity consisted of 1 case each of febrile neutropenia and confusion, in addition to the 1 patient who developed grade 4 tumor lysis syndrome.

In the 8 patients with no evidence of residual disease, the determination was made by flow cytometry and/or testing for minimal residual disease. Radiologic responses are less conclusive and require longer follow-up, said Gill.

Investigators plan to treat a total of 25 patients with the CTL-119/ibrutinib combination. Most of the patients who received the cell therapy remain on ibrutinib, and longer follow-up will be required to determine whether remissions are sustained after discontinuation of ibrutinib.

Looking ahead, the work could help set the stage for strategies that would allow for withdrawal of chronic therapy.

“It’s not necessarily surprising that you get deep responses in patients who are responding to a drug and then you add another drug to it,” said Gill. “This gives us the opportunity to talk about, in the future, withdrawing ibrutinib, maybe talk about eradicating disease, maybe eliminate the need for chronic, daily-dispensed therapy.”

“Another important aspect of what we showed in this study is the relative lack of toxicity,” he added. “Everyone gets CRS but no one gets severe CRS. No patient required tocilizumab. Some of these patients were treated exclusively as outpatients. It is an advance, as far as I see.”

Gill S, Frey NV, Hexner EO, et al. CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL. J Clin Oncol 35, 2017 (suppl; abstr 7509).