A Multicenter Phase I Study of CTLA-4 Blockade with Ipilimumab for Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Cell Transplantation

• Published in: Blood 2014-12, Vol.124 (21), p.3964-3964
• Main Authors: Davids, Matthew S., Kim, Haesook T., Costello, Caitlin L., Avigan, David, Chen, Yi-Bin, Armand, Philippe, Alyea, Edwin P., Hedlund, Jacquelyn, McSweeney, Peter A., Liguori, Rebecca, Ritz, Jerome, Ball, Edward D., Bashey, Asad, Soiffer, Robert J
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.3964.3964

The prognosis for patients with hematologic malignancies (HM) who relapse after allo-HCT is dismal, and more effective treatments are urgently needed. Immune checkpoint modulation was previously explored in a pilot study of a single low dose of the anti-CTLA-4 monoclonal antibody ipilimumab in patients relapsed after allo-HCT, and durable anti-tumor activity was seen in lymphoid malignancies without inducing clinical GVHD (Bashey et al., Blood, 2009). Here, we report for the first time on the results of a phase I study of ipilimumab given for multiple doses over an extended time course for patients with relapsed HM after allo-HCT. The primary objectives were to determine the MTD and evaluate safety. Secondary objectives included preliminary evaluation of efficacy and changes in immune cell phenotype. Patients were required to be off all immune suppression for > 4 weeks prior to study entry, with no history of grades 2-4 acute or extensive chronic GVHD. Ipilimumab was given at 3 mg/kg or 10 mg/kg IV every 3 weeks for 4 cycles of induction, followed by maintenance dosing every 12 weeks up to 1 year. The DLT observation period was the 12 week induction period. Standard response criteria for each disease were assessed at the mid-point (7 weeks), end of induction (13 weeks), and throughout maintenance. Immunophenotyping was performed by 8-color flow cytometry and analyzed by FACSDiva. This study is sponsored by CTEP (protocol 9204) and run through the Blood Cancer Research Partnership (BCRP) of the Leukemia & Lymphoma Society. Thirteen patients were enrolled, with 6 patients at dose level 1 (3 mg/kg) and 7 patients in dose level 2 (10 mg/kg). The median age at time of transplant was 52 (range 20-70), and the median time from allo-HCT to study enrollment was 19.3 months (range 6.2 - 49.3). The median number of prior therapies was 7 (range 2-11), and 9 patients had received prior therapy for their post transplant relapse, including 4 patients with prior DLI. Seven patients had related donors and 6 patients had unrelated donors. Histologies included cHL (n=4), NHL (n=3), AML (n=2), and 1 patient each had MM, MDS, MPN, and ALL. In the safety analysis, there was no acute GVHD and one case of chronic GVHD (liver, mild) at 3 mg/kg, which was the only DLT. Immune-related adverse events (irAEs) were observed in 2 patients, and included grade 3 thrombocytopenia due to ITP (n=1), grade 2 pneumonitis (n=2), and grade 2 diarrhea (n=1), all of which were rapidly reversible w