Ipilimumab shows promise for patients who relapse following HSCT

Ipilimumab induced complete responses among patients with hematologic malignancies who relapsed following allogeneic hematopoietic stem cell transplantation, according to the results of a study published in The New England Journal of Medicine.

Further, responses appeared durable for several histologic subtypes, including extramedullary acute myeloid leukemia. However, researchers also noted the occurrence of immune-mediated toxic effects and graft-versus-host disease (GVHD).

“Patients with hematologic malignancies that had relapsed after allogeneic transplant are usually excluded from clinical trials of novel agents. The prognosis for these patients is particularly poor, and I wanted to develop a more effective way to treat them,” Matthew D. Davids, MD, MMSc, instructor in the hematologic oncology department at Harvard Medical School, told HemOnc Today. “We worried going into the study that we would see significant GVHD that would limit our ability to give the drug to this patient population, but only four of the 28 patients developed GVHD that precluded further dosing, which suggested to us that it is feasible to give ipilimumab to patients in the post-transplant setting.”

Because Davids and colleagues hypothesized that CTLA-4 blockade may induce a graft-versus-tumor effect, they evaluated ipilimumab (Yervoy, Bristol-Myers Squibb), a monoclonal antibody that blocks CTLA-4.

Researchers evaluated the safety and efficacy of ipilimumab in 28 patients (57% men; median age, 58 years) with relapsed hematologic cancer after allogeneic HSCT. Twelve patients had acute myeloid leukemia, seven had Hodgkin lymphoma, four had non-Hodgkin lymphoma and two had myelodysplastic syndrome. There was one case each of multiple myeloma, myeloproliferative neoplasm and acute lymphoblastic leukemia.

Six patients received induction 3 mg/kg IV ipilimumab every 3 weeks for four doses. However, based on the safety profile and previous evidence, researchers expanded induction dosage to 10 mg/kg for the remaining patients. Those who did not experience disease progression or unacceptable toxic events received maintenance therapy every 12 weeks for up to 60 weeks.

The median time from transplant to initial ipilimumab treatment was 675 days (range, 198-1,830), and the median time from relapse to ipilimumab was 97 days (range, 0-1,415).

No patients who received 3 mg/kg responded to treatment.

Of those who received 10 mg/kg, five patients experienced a complete response, four of whom had extramedullary acute myeloid leukemia and one myelodysplastic syndrome that developed into acute myeloid leukemia. Two other patients achieved a partial response and six demonstrated decreased tumor burden.

At a median follow-up of 15 months, the 1-year survival rate was 49%. The median duration of response had not been reached; however, researchers noted four patients had a durable response for more than 1 year.

Researchers then conducted exploratory studies to evaluate the association between clinical outcomes and immunological response to ipilimumab in the site of disease and in the blood. Results showed responses were associated with in situ infiltration of cytotoxic CD8–positive T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood.

Immune-related adverse events occurred in two patients who received 3 mg/kg — including grade 2 pneumonitis and grade 2 diarrhea — and three patients in the 10-mg/kg cohort, which included grade 2 immune thrombocytopenia, grade 3 colitis, and grade 2 and grade 4 pneumonitis. One patient with grade 3 colitis and grade 4 pneumonitis died after receiving the initial dose of ipilimumab.

Four patients experienced GVHD that precluded further ipilimumab, three of which occurred in the 10-mg/kg cohort.

“Because we did see some toxicities at 10 mg/kg of ipilimumab, we are currently evaluating a cohort being treated at 5 mg/kg to see if that may optimize the balance between efficacy and safety,” Davids said. “Our next step will be to explore targeting one of the other key immune checkpoint molecules, PD-1. We are poised to launch a phase 1 study of the PD-1–blocking antibody nivolumab (Opdivo, Bristol-Myers Squibb) in this same patient population later this year, and we are hopeful that this will be a well-tolerated and effective strategy for post-transplant relapse.” – by Nick Andrews

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Matthew S. Davids , MD, MMSc , can be reached at matthew_davids@djci.harvard.edu.

Disclos ure: Davids reports grant support from ASCO, Pasquarello Tissue Bank, NIH/NCI and Leukemia & Lymphoma Society during the conduct of the study. He also reports grant support and personal fees from Genentech, Infinity, Pharmacyclics and TG Therapeutics, and personal fees from AbbVie, Gilead, and Janssen unrelated to this study. Please see the full study for a list of all other researchers’ relevant financial disclosures.