Lymphodepleting Alemtuzumab Earns FDA Orphan Drug Status in R/R B-ALL

The FDA previously granted orphan drug designation to UCART22 for treating patients with ALL in June 2024.

The FDA has granted orphan drug designation to the investigational agent alemtuzumab (CLLS52) in the treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to a press release from the developer, Cellectis.¹

Investigators evaluated treatment with alemtuzumab as part of a lymphodepleting regimen used in combination with UCART22 for the aforementioned population as part of the phase 1 BALLI-01 trial (NCT04150497).

“We are excited that the FDA granted alemtuzumab [orphan drug] designation status,” Mark Frattini, MD, PhD, chief medical officer at Cellectis, stated in the press release.¹ “The importance of adding alemtuzumab to the lymphodepletion regimen has been demonstrated in Cellectis’ BALLI-01 study, where the addition of this lymphodepletion agent to the fludarabine and cyclophosphamide regimen was associated with sustained lymphodepletion and significantly higher UCART22 cell expansion allowing for greater clinical activity.”

Updated findings from the BALLI-01 trial were presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition and published in Blood.²

Among 18 patients who received dose level 3 of the lymphodepleting regimen plus UCART22 process 1, investigators observed 1 complete response (CR), 4 CRs with incomplete hematologic recovery (CRi), and morphologic leukemia-free states (MLFS) in 2 patients. Among those who received UCART22 process 2 (n = 3), responses occurred in 67% (n = 2/3). One patient who received UCART22 process 2 had a minimal residual disease (MRD)–negative CR for more than 84 days following infusion, while another had MRD-negative MLFS lasting until day 40.

Treatment with UCART22 process 2 following lymphodepletion appeared to be well tolerated. Investigators reported no dose-limiting toxicities or immune effector cell-associated neurotoxicity syndrome (ICANS), although cytokine release syndrome (CRS) occurred in 67% (n = 2/3) of evaluable patients. Data showed 1 instance of serious grade 5 sepsis at day 40 of treatment; this was considered to be related to treatment with UCART22 process 2 and lymphodepletion.

“These data support the safety and preliminary efficacy of UCART22 [process 2] in this poor-risk [relapsed/refractory] B-ALL population,” Nitin Jain, MD, professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, and coauthors wrote.² “The study continues to enroll [patients[ treated with UCART22 [process 2] at dose level 2 [2.5 x 10⁶ cells/kg], and updated data will be presented.”

In the BALLI-02 trial, patients first underwent lymphodepletion with fludarabine at 30 mg/m² for 3 days plus cyclophosphamide at 0.5 g/m² for 3 days and alemtuzumab at 20 mg per day for 3 days. Following lymphodepletion, patients were assigned to receive UCART22 process 2 at escalating doses starting at 1 x 10⁶ cells/kg compared with the highest studied dose, dose level 3, of 5 x 10⁶ cells/kg associated with UCART22 process 1. UCART22 process 1 was developed by a CMO, whereas process 2 was manufactured by Cellectis.

Patients 15 to 70 years old with relapsed/refractory B-ALL expressing CD22 were eligible for enrollment on the trial.³ Having prior therapy with at least 1 line of standard chemotherapy and at least 1 salvage regimen was another requirement for study entry. Those who received prior cellular therapy or an investigational cellular or gene therapy within 60 days of enrollment were ineligible for entry.

The trial’s coprimary end points were safety, tolerability, and the maximum-tolerated dose or recommend phase 2 dose of UCART22. Other end points included the anti-leukemic activity and expansion associated with UCART22.

The FDA previously granted orphan drug designation to UCART22 for treating patients with ALL in June 2024.⁴

References

1. FDA grants orphan drug designation to Cellectis’ CLLS52 (alemtuzumab) for ALL treatment. Cellectis. August 1, 2024. Accessed August 5, 2024. https://tinyurl.com/2cs42cpm
2. Jain N, Chevallier P, Liu H, et al. Updated results of the phase I BALLI-01 trial of UCART22 process 2 (P2), an anti-CD22 allogeneic CAR-T cell product manufactured By Cellectis Biologics, in patients with relapsed or refractory (R/R) CD22+ B-cell acute lymphoblastic leukemia (B-ALL). Blood. 2023;142(suppl 1):4847. doi:10.1182/blood-2023-187252
3. Phase 1/​2 study of UCART22 in patients with relapsed or refractory CD22+ B-cell acute lymphoblastic leukemia (BALLI-01). ClinicalTrials.gov. Accessed August 5, 2024. https://tinyurl.com/3f5tn63v
4. Cellectis receives orphan drug designation for UCART22, its allogeneic CAR T product for patients with acute lymphoblastic leukemia. News release. Cellectis. June 4, 2024. Accessed August 5, 2024. https://tinyurl.com/2ph242tz