CAR T-cell Therapy Shows 6-Year Durability in CLL Patients

This article first appeared in Targeted Oncology.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy delivered durable responses and showed potential to cure a subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia cells cluster in blood flow: © LASZLO - stock.adobe.com

In the phase 1/2 study (NCT01865617), 49 patients received JCAR014, a novel CAR T-cell therapy, with (n = 19) or without (n = 30) concurrent ibrutinib (Imbruvica). At a median follow-up of 79.6 months (IQR, 60.5-87.5), the median progression-free survival (PFS) for all patients who received CAR T-cell therapy was 8.9 months (95% CI, 3.0-19.9), and the median overall survival (OS) was 25.0 months (95% CI, 11.5-62.1). The 6-year PFS rate was 17.8% (95% CI, 9.7%-32.8%), and the 6-year OS rate was 31.2% (95% CI, 20.3%-48.1%). The median duration of response (DOR) was 18.9 months (95% CI, 9.66-55.6) with a 6-year DOR estimate of 26.4% (95% CI, 14.8%-47.2%).

Worse PFS was associated with younger age, bulky disease before lymphodepletion, and maximum standardized uptake value before lymphodepletion. Moreover, better PFS was observed among patients who underwent lymphodepletion with both cyclophosphamide and fludarabine rather than only 1 of the agents.

A total of 33 patients had a complete response (CR) or a CR with incomplete hematologic recovery 28 days after leukapheresis. CAR persistence was observed up to or beyond 1 year after CAR T-cell infusion in 7 of 9 patients who had ongoing responses at the last follow-up, with the longest measured persistence of 86.0 months. Of 19 patients who experienced relapse or disease progression following CAR T-cell infusion, CAR persistence was observed in 18 (95%).

Experiencing a CR or minimal residual disease (MRD) negativity by day 28 was associated with longer PFS. Higher peak CD4-positive and CD8-positive CAR T-cell expansion and longer CAR persistence was also associated with longer PFS.

“We demonstrate that in a heavily pretreated, ibrutinib-refractory/intolerant population with high-risk cytogenetics, CD19 CAR T-cell therapy induced durable responses, with ∼25% of responders still in remission at 6 years. Our findings suggest that CD19 CAR T-cell therapy may be curative in a subset of responders with MRD-negative results,” study authors wrote.

Patients in the study had received heavy pretreatment before CAR T-cell therapy, with a median of 5 prior lines of therapy (IQR, 4-7). Purine analogs (29%), bendamustine (51%), and venetoclax (Venclexta; 39%) were some of the most common prior lines of therapy. Ibrutinib intolerance or resistance was observed in 96% of patients.

The median patient age was 61 years (IQR, 55-67), and 94% of patients (n = 46) had high risk cytogenic profiles, including a complex karyotype or 17p deletion. A prior history of Richter transformation was reported in 7 patients (18%), while 2 patients had a current Richter transformation.

Cytokine release syndrome (CRS) was reported in 40 patients (82%), with 7 patients (14%) experiencing grade 3 or higher CRS. One patient died from CRS with neurotoxicity. Sixteen patients (33%) experienced neurotoxicity, and 13 of those patients (27%) experienced neurotoxicity of grade 3 or higher. Adverse events that persisted 1 year or more after infusion included hypogammaglobulinemia (25%), secondary malignancy (20%), infection (20%), and neurologic disorders (10%).

Of patients who had a CR or partial response, 4 (9%) died after receiving CAR T-cell therapy, but the deaths were not attributed to the study treatment. The causes of death included diffuse alveolar hemorrhage and pulmonary aspergillosis, progressive multifocal leukoencephalopathy, myocardial infarction, and therapy-related myelodysplastic syndrome transformed to AML.