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

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). All products met release criteria, with a median 1.9 log (range: 1 - 2.6) CD4+CD25hi Treg depletion. For patients in DL0 (n=18), DL1 (n=6), and DL2 (n=1), the median number of IPI doses was 3 (range: 1-8), 3 (range: 1-6), and 1, respectively. During IPI dose-escalation, the first patient treated at DL2 had fatal GVHD. At de-escalated DL1, delayed-onset AEs (IPI colitis, GVHD requiring prolonged immune suppression, or respiratory failure) were noted, resulting in DL0 as MTD. Among all treated patients, 5 (20%) developed aGVHD (2 grade III-IV), and 7 (28%) developed cGVHD (6 moderate-severe). There was no association between GVHD prior to trial therapy and development of GVHD following therapy (p=0.41 aGVHD; p=0.53 cGVHD). The most common AEs were neutropenia (13/25, 52%), anemia (11/25, 44%), and increase in liver enzymes (18/25, 72%). The major SAEs among all patients included: GVHD in 5/25 (20%), and IPI-related inflammation (20%): hepatitis, encephalitis, polymyositis, pneumonitis, and Guillain-Barre syndrome. All IPI-related SAE were responsive to prednisone and/or IVIG therapy. At DL0, 9/18 (50%) experienced grade 3 SAE. Among all patients, median OS and PFS from the time of DLI was 23 months (95%CI: 5.9, 33) and 19.5 months (95%CI: 5.9, 25), respectively. Best response to therapy was CR in 12/25 (48%). Among patients with TP53 mutated disease, only 1/7 (14%) attained CR as best response but relapsed within 3 months of therapy. Among those without TP53 mutation, 11/18 (61%) attained CR. In patients attaining CR, 5/11 (45%) attained measurable residual disease negativity with NGS. Conclusions Treg-depleted DLI plus IPI is a novel combinatorial therapy for myeloid disease relapse following HCT that is tolerable despite risk for GVHD and IPI-related AEs. Among patients with non-TP53 mutated disease, the treatment shows promising evidence of efficacy and should be explored further.