Advances in Hematologic Malignancies Issue 5, Fall 2016
— Matthew S. Davids, MD, MMSc
Matthew S. Davids, MD, MMSc
Patients with hematologic malignancies who relapse after allogeneic transplantation have few effective therapeutic options and generally have a poor prognosis. An important factor contributing to relapse may be that donor lymphocytes from the graft become dormant and are unable to recognize and kill tumor cells. We hypothesized that immune checkpoint blockade with the anti-CTLA-4 antibody ipilimumab (Yervoy) would re-awaken these dormant donor lymphocytes, thereby restoring anti-tumor immunity.
We conducted a phase 1/1b study of ipilimumab for patients with hematologic malignancies who relapsed after allogeneic transplantation. We partnered with the Cancer Therapy Evaluation Program (CTEP) from the NCI, who provided the study drug, and with the
Blood Cancer Research Partnership (BCRP), a multicenter clinical research consortium led by Dana-Farber and funded through the Leukemia and Lymphoma Society. Our study included patients with a diverse array of disease histologies, including
acute myeloid leukemia (AML), higher-risk
myelodysplastic syndromes (MDS),
Hodgkin lymphoma and
multiple myeloma, and others. We modeled our dosing regimen after that used for ipilimumab in melanoma, with doses given every 3 weeks for 4 cycles (induction) followed by doses given every 12 weeks for 4 cycles (maintenance), with a starting dose of 3 mg/kg.
In the 3 mg/kg cohort, we did not see significant toxicity or efficacy, so we escalated the dose in a second cohort treated with 10 mg/kg of ipilimumab. In the 22 patients treated at this dose level, we observed immune-related adverse events in 6 patients (21 percent) and graft vs. host disease that precluded further dosing in 4 patients (14 percent). About 60 percent of patients had signs of anti-tumor activity, and 32 percent of patients achieved clinicopathological response by formal disease-specific criteria. Twenty-three percent of patients achieved complete remission, all of whom had AML, including all 3 patients with leukemia cutis (see figure for a representative patient). Several of these complete responses have been durable. We found that responses were associated with infiltration of activated CD8+ T cells at the site of disease and with a decrease in the number and activity of regulatory T cells in the blood.
Overall, our study found this new approach of immune checkpoint blockade to treat post allogeneic stem cell transplant relapse is feasible and worthy of further exploration. Building on this initial experience, we recently opened a new arm of this study to investigate using PD-1 blockade with nivolumab instead of ipilimumab. The eligibility criteria are broad, and patients with prior exposure to PD-1 blockade in the pre-transplant setting are not excluded. We would be grateful to see in consultation any patients with relapsed hematologic malignancies after allogeneic stem cell transplantation who might be eligible and willing to participate in this or other studies.
For more information about this study or to discuss a patient who may be eligible, please contact Matthew Davids, MD, MMSc at
Reference: Davids, et al., N Engl J Med, 2016;375:143-53.