ARI-0001 CAR T-Cell Treatment Shows Promise in R/R CLL, Small Study Shows

ARI-0001, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, is feasible, safe, and efficacious in patients with relapsed or refractory (R/R) high-risk chronic lymphocytic leukemia (CLL) and Richter transformation, according to analysis results presented at the EBMT- EHA 4th European CAR T-Cell Meeting.

The analysis looked at 9 patients treated on the CART19-BE-01 trial (NCT03144583) or through a compassionate use program. Seven patients responded by International Workshop on CLL criteria, including complete responses in 6 patients. One patient had a response last- ing 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. At a median follow-up of 5.6 months (range, 1.2-45.3), 2 patients with Richter transformation experienced a CD19-negative relapse in their lymph nodes 2.1 months and 3 months after cell infusion, respectively. 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.

ARI-0001 is constructed of an anti-CD19 single-chain variable fragment with a CD8 hinge and 2 signaling domains: 4-1BB and CD3z.

Before their ARI-0001 cell infusion, patients were given 90 mg/m2 fludarabine each day plus 900 mg/m2 of cyclophospha- mide on days 6, 5, and 4. 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 0orsplitupby10%,30%,and60%on3days separated by 24 hours each.

Successful CAR T-cell production was achieved in all 11 patients who underwent apheresis and cell production but were still alive at the time of infusion. However, infusion is still pending for 2 patients.

Of the 9 evaluable patients, the median age was 58 years (range, 47-74) and 33% were female. Patients had received 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.

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 observed rate of cytokine release syndrome (CRS) in the 9 patients was 89% with a grade 3 or higher CRS rate of 11%. 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.

“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,” Valentín Ortiz-Maldonado, MD, of the Department of Hematology at the Hospital Clínic de Barcelona, Spain, said during his presentation. “On the other hand, there [were] no cases of ICANS [immune effector cell-associated neurotoxicity syndrome] or related mortality.”

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}