Addition of CART-19 to Ibrutinib Yields Deep, Durable Remissions in CLL

The addition of CART-19 to ibrutinib (Imbruvica) resulted in frequent, durable, and deep remissions for patients with chronic lymphocytic leukemia (CLL), according to findings from an early phase 1 trial (NCT02640209) published in Blood.

Treatment with the combination yielded a 48-month progression-free survival (PFS) rate of 70% (90% CI, 46%-85%) and the median PFS was not reached. Patients who received ibrutinib in the first-line compared with those who had relapsed or refractory disease did not have a significantly different PFS (P = .15).

A total of 20 patients enrolled on the trial, 1 of whom did not receive the humanized binding CART-19 (hu-CART-19) because incurrent lung adenocarcinoma and coincident discovery of Richter transformation. Patients received the infusion at a median of 60 days from enrollment. The median age was 62 years, and patients had undergone a median of 2 prior lines of therapy. Median marrow CLL burden was 20%. A history of poor-risk cytogenetic or molecular abnormalities was observed in 15 patients.

After receiving previous CAR T-cell therapy, 3 patients had relapsed, and 2 were known to have ibrutinib-resistance mutations. The median follow-up was 42 months for 18 patients who received huCART-19 and survived at least 1 month.

When huCART-19 infusion occurred, patients had been receiving ibrutinib for 7 to 50 months. During infusion, 14 patients stopped ibrutinib during last follow-up and 5 remained on ibrutinib. Discontinuation most commonly occurred as a result of ibrutinib-related toxicity (n = 6), patient and physician choice following undetectable disease (n = 5), progression of CLL with a Bruton tyrosine kinase mutation (n = 1), chemotherapy for second malignancy (n = 1), and unknown reasons (n = 1).

At 3 months, 7 of 16 patients achieved complete response (90% CI, 23%-67%), and at 12 months, 7 of 14 were continued to be in CR (90% CI, 26%-74%). At 12 months, 3 patients had undetectable minimal residual disease (MRD), but this was not considered for having CR by the International Working Group of CLL because of residual adenopathy of over 1.5 cm in 1 axis. In 13 of 18 patients evaluable for response, MRD was undetectable at 12 months.

The overall survival (OS) probability at 48 months was 84% (90% CI, 63%-93%), but the median OS was not reached. Investigators did not find a significant difference between patients who had first-line ibrutinib vs those with relapsed or refractory disease (log-rank test, P = .35).

During follow-up, 1 responder had relapsed and died from progressive disease, 1 non-responder was alive and receiving next line therapy, 1 patient had died of infection during remission, and 1 had developed a secondary malignancy and their CLL status was not evaluable. Additionally, 13 patients remained alive and in remission, of whom 4 continue to receive ibrutinib.

Of 15 patients with undetectable MRD at 3 or 6 months, 1 patient had relapsed and died of progressive disease at 12 months, and 1 relapsed at 41 months and was on next-line therapy 58 months after infusion.

In total, of 3 patients who previously received CAR T cells, 1 did not respond and 2 were MRD-positive with a CR that lasted 54 months and 31 months, respectively. All 6 patients who received huCART-19 after first-line ibrutinib remained in remission.

Notable grade 3/4 AEs included neutropenia in 7 patients, thrombocytopenia in 10, and neurotoxicity in 1. On day 10 after infusion, 1 patient died following grade 4 cytokine release syndrome and immune effector cell–associated neurotoxicity. Another died of infection while receiving ibrutinib.

Reference

Gill SI, Frey NV, Hexner E, et al. Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia. Blood Adv. Published Online March 29, 2022. doi:10.1182/bloodadvances.2022007317