Induction of Graft-Versus-Leukemia Effect with Treg-Depleted DLI Plus Ipilimumab for Myeloid Disease Relapse after HLA-Matched Transplant

• Published in: Blood 2024-11, Vol.144, p.4833-4833
• Main Authors: Shapiro, Roman M., Kim, Haesook T., Terral, William H, Ho, Vincent T., Gooptu, Mahasweta, Romee, Rizwan, Gibson, Christopher J., Kelkar, Amar H., Cutler, Corey S., Antin, Joseph H., Maurer, Katie, Wu, Catherine J., Zeiser, Robert, Ritz, Jerome, Soiffer, Robert J., Nikiforow, Sarah, Koreth, John
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-194102

Background Myeloid disease relapse following allogeneic hematopoietic cell transplantation (HCT) has poor prognosis. We previously reported that the CTLA-4 inhibitor ipilimumab (IPI), at maximum tolerated dose (MTD) of 10mg/kg, can augment the graft-versus-leukemia (GvL) effect to treat relapse after HCT. In another phase 1 trial (NCT00675831) of T regulatory cell (Treg)-depleted donor lymphocyte infusion (DLI) for treating relapse after HCT, at MTD of 3 x 107 CD3+ cells/kg, we documented a median overall survival (OS) of 12.7 months. Together, these observations motivated the combination of Treg-depleted DLI with IPI as a novel therapy to treat post-HCT relapse of MDS and AML. Methods In this phase 1 clinical trial (NCT03912064), patients with at least 8/8 HLA matched donor and relapse of myeloid disease following HCT without any active GVHD were eligible. The target cell count for DLI on day +1 was 3 x 107 CD3+ cells/kg after Treg (CD4+CD25hi) depletion, with < 0.5% Treg in the released product. At the target DLI cell count, the IPI dose levels (DL) 0, 1, and 2 were 1, 3 and 10 mg/kg, respectively, administered q3 weeks for 4 doses starting on day +1, with q3 month x 4 maintenance in responders. Dose level -1 (DL-1) was 1 x 107 CD3+ cells/kg with IPI 1mg/kg. Dose-limiting toxicities (DLT) evaluated within 6 weeks of DLI included severe cytopenia (ANC < 500/uL and/or plts < 20,000/uL), grade ≥3 acute GVHD without improvement to grade ≤2 within 14 days of treatment, and CTCAE v5.0 grade ≥3 non-neurologic immune adverse events unresponsive to corticosteroids. SAEs were evaluated until 90 days from the last IPI dose. Treatment response was assessed with standard morphologic criteria and next-generation sequencing (NGS). Results A total of 25 patients were treated, including 19 with AML, 5 with MDS, and 1 with MDS/MPN. Seven patients (28%) had TP53-mutated disease. The median age at the time of therapy was 64 years (range: 20 - 77 years). Nine patients (36%) were female, 22/25 (88%) were Caucasian and 23/25 (92%) were non-Hispanic. Eleven patients (44%) had prior acute or chronic GVHD before trial therapy, although no patient had any active GVHD requiring immune suppression at the time of DLI. The median time from disease relapse to DLI was 77 days (range: 28 - 478 days). Fourteen patients (56%) received bridging therapy (chemotherapy, radiation, or surgery) prior to DLI. The median number of CD3+ cells infused was 2.9 x 107 cells/kg (range: 2.2-3.2 x 107). A