CAR T-Cell Therapy Promising in R/R Chronic Lymphocytic Leukemia

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The CD19-directed chimeric antigen receptor (CAR) T-cell therapy ARI-0001has demonstrated efficacy in relapsed or refractory (R/R) high-risk chronic lymphocytic leukemia (CLL) and Richter transformation, according to a recent analysis of a small study.

Data from the analysis were presented at the EBMT- EHA 4th European CAR T-Cell Meeting, February 10-12, 2022, by Valentín Ortiz-Maldonado, MD, of the Department of Hematology at the Hospital Clínic de Barcelona, Spain. Investigators found that 2 patients with Richter transformation experienced a CD19-negative relapse in their lymph nodes 2.1 months and 3 months after cell infusion, respectively, at a median follow-up of 5.6 months (range, 1.2-45.3). The 2-year overall survival rate was 62.5% (95% CI, 32%-100%) from the ARI-0001 cell infu- sion and 51.4% (95% CI, 24%-100%) overall.

“Regarding specific toxicities, almost 90% of patients didn’t [experience] any major grade of CRS, but [there] were mild [cases of] CRS of grade 1 to 2,” Ortiz-Maldonado said during his presentation. “On the other hand, there [were] no cases of ICANS [immune effector cell-associated neurotoxicity syndrome] or related mortality.”

ARI-0001 is constructed of an anti-CD19 single-chain variable fragment with a CD8 hinge and 2 signaling domains: 4-1BB and CD3z. Investigators analyzed 9 patients treated in the CART19-BE-01 trial (NCT03144583) or through a compassionate use program.

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Median age was 58 years (range, 47-74) of 9 evaluable patients, 33% of which were female. Patients had a median of 5 prior lines of therapy (range, 2-9), including ibrutinib (Imbruvica) in 100%, venetoclax (Venclexta) in 55%, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in 55%, and allogeneic stem cell transplant in 22%. Six of the patients had Richter transformation and 8 had extra- medullary disease. Six patients had high- to very high-risk CLL, with 6 having TP53 alterations and 3 having complex karyotype.

Responses, by International Workshop on CLL criteria, were observed in 7 patients, with 6 complete responses. One patient had a response lasting more than 51 months. All 6 patients with Richter transformation responded. Measurable residual disease–negative complete response was documented in the peripheral blood and bone marrow of all patients analyzed.

Patients were given 90 mg/m2 fludarabine each day plus 900 mg/m2 of cyclophosphamide on days 6, 5, and 4 prior to ARI-0001 cell infusion. This was then followed by a dose of 1 × 106 CAR T-cells/kg for patients with CLL. Patients with Richter transformation were given a dose of 5 × 106 CAR T-cells/kg as a single infusion on day 0 or split up by 10%, 30%, and 60% on 3 days separated by 24 hours each.

All 11 patients that underwent apheresis alive at the time of infusion had successful CAR T-cell production. Infusion is pending for 2 patients.

All of the infused patients experienced absolute B-cell aplasia (ABCA), with active ABCA ongoing up to 4.2 years. Median peak ARI- 0001 cell expansion reached 5.7 copies/ng. Measurable CAR T cells were seen as far as 2.5 years.

The therapy was well-tolerated, although cytokine release syndrome (CRS) did occur in 89% of patients, 11% of these events were grade 3 or higher. The median time to CRS was 1 day (range, 0-3) and the median duration of CRS was 5 days (range, 1-17). Four patients required tocilizumab (Actemra) and 2 required steroids for CRS.

Three patients died during the trial, with 1 patient having died from their disease while waiting for infusion that was delayed due to the COVID-19 pandemic. One patient who responded to the treatment with stable disease progressed to diffuse large B-cell lymphoma and died after a CD19 relapse in 7 months, and another who had a partial response to treatment later progressed to plasmablastic lymphoma and died after 3.7 months. The patient with the highest CRS grade of 3 was alive and free of disease 4.2 months after treatment, and the lon- gest outcome was 45.4 months. Seven patients continued to be followed at the time of data cutoff.

Comparatively, Ortiz-Maldonado said that complete response rates for patients with R/R CLL treated with CD19-directed CAR T cells were between 19% and 45%. Overall response rates were between 19% and 82%.

“[In conclusion, our data seem] to be in line with other outcomes from academic or industry teams for a small cohort of [patients with] CLL. Our long tails [of the survival curves] have been able to show long-term remission in CLL, and further research in standalone therapy [is warranted],” Ortiz-Maldonado concluded.

REFERENCE

Ortiz-Maldonado V, Frigola G, Español-Rego M, et al. ARI-0001 CART19 cells in patients with relapsed/refractory chronic lymphocytic leukaemia and Richter’s transformation. Presented at: EMBT-EHA 4th European CAR T-Cell Meeting; February 10-12, 2022; virtual. Abstract BA03-6