Ipilimumab Shows Impressive Activity After HSCT Failure

Alexander M. Castellino, PhD

July 13, 2016

The immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb Company) showed impressive activity in patients with hematologic malignancies who experienced relapse after receiving a hematopoietic stem cell transplant (HSCT). These patients have limited treatment options and a poor prognosis.

The new results come from a phase 1/1b study published online July 14 in the New England Journal of Medicine.

HSCT offers the best chance of a cure for some patients with hematologic malignancies. Unfortunately, more than one third of patients who undergo HSCT experience disease relapse, the authors explain. "The prognosis for these patients is poor; the majority die within 1 year after relapse despite salvage chemotherapy, donor-lymphocyte infusion, or retransplantation," they write.

In the new study, they report that ipilimumab elicited responses in 32% of patients. With a median follow-up of 15 months, the 1-year overall survival was 49%; the median duration of response has not been reached.

"This is the first time that targeting an immune checkpoint therapeutically has led to striking responses in patients with a broad range of hematologic malignancies who have relapsed following allogeneic transplantation," lead author Matthew S. Davids, MD, from the Dana-Farber Cancer Institute, Boston, told Medscape Medical News.

"In patients who relapse following transplantation, the use of ipilimumab may reawaken a dormant immune system and restore antitumor effects," he said.

Medscape Medical News contacted several experts who were not associated with this study and who employ HSCT in the treatment of patients with hematologic malignancies for their reaction to this report.

"This is an exciting and important study and impacts patients who are in a challenging situation," Gita Thanarajasingam, MD, hematologist at the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

Dr Thanarajasingam explained that patients who experience relapse after allogeneic transplant tend to do poorly.

"We have been reticent to use immunotherapy in patients who relapse following allogeneic transplantation," she said, citing concerns about toxicity. She noted that although immune-related adverse events and graft-vs-host disease (GVHD) occurred in some patients in the study, the clinical responses are impressive.

"Just as with the undertaking of an allogeneic transplant in the first place, immune checkpoint blockade after allogeneic transplant should be regarded as a treatment with the potential for high risk and high reward," Dr Thanarajasingam said.

Immune checkpoint blockade after allogeneic transplant should be regarded as a treatment with the potential for high risk and high reward. Dr Gita Thanarajasingam

Another expert, Alex Herrera, MD, assistant professor at the City of Hope Medical Center, Duarte, California, told Medscape Medical News: "The results are provocative, and, given the poor prognosis of these patients, further study of checkpoint inhibition after allogeneic transplant should be undertaken."

The new findings "represent a significant advance in the field, as they have demonstrated that checkpoint inhibition has the potential to revive graft-vs-tumor effects and induce responses across a range of diseases," he said.

Investigator-Led Study

Dr Davids conducted this investigator-initiated study with colleagues from the Leukemia and Lymphoma Society Blood Cancer Research Partnership (LLS/BCRP).

"It is challenging to run an investigator-initiated, multicenter study without per-patient pharmaceutical company funding," Dr Davids said. "The support we received from LLS/BCRP and the NCI Cancer Therapy Evaluation Program, who provided the study drug, were essential for allowing us to run this study," he added.

Dr Davids also noted the key role played by Robert J. Soiffer, MD, chief of hematologic malignancies at Dana-Farber Cancer Institute, who was the senior investigator on the study, in making the study a success.

The phase 1/1b study, which was conducted from 2013 to 2015, enrolled 28 patients with various hematologic malignancies who had experienced relapse following allogeneic transplant undertaken at six centers.

The patients had a variety of disorders ― myeloid leukemia (12 patients, including three with leukemia cutis and one with myeloid sarcoma), Hodgkin's lymphoma (seven patients), non-Hodgkin's lymphoma (four patients), myelodysplastic syndrome (two patients), and one patient each with multiple myeloma, myeloproliferative neoplasm, and acute lymphoblastic leukemia.

Patients had received prior treatment following relapse — 17 (61%) with chemotherapy, six (21%) with radiation therapy, and six (21%) with donor lymphocyte infusion. In addition, eight patients (29%) had prior grade 1 or 2 acute GVHD, and 16 patients (57%) had chronic GVHD.

Dose-limiting toxic effects were evaluated over a relatively long period of 12 weeks. "Many studies evaluate dose-limiting toxicities for 4 weeks, but we wanted to be able to capture any delayed immune-related adverse events as dose-limiting toxicities," Dr Davids said.

In the phase 1 portion of the study, an initial cohort of six patients received ipilimumab 3 mg/kg (one patient was not evaluable for toxicity owing to early progression, and one patient had dose-limiting liver toxicity) every 3 weeks for four courses.

With only one dose-limiting toxicity observed at 3 mg/kg, the protocol allowed for escalating the dose of ipilimumab in the phase 1b portion of the study. In this cohort, patients were treated with ipilimumab at 10 mg/kg given every 3 weeks for four courses unless disease progressed or patients experienced unacceptable toxicities.

Following the four courses, patients could continue receiving maintenance therapy with ipilimumab, also at 10 mg/kg given every 12 weeks for up to 60 weeks. This regimen was modeled on that used in earlier studies in metastatic melanoma, Dr Davids noted.

Patients received a median of four doses (range, one to eight). Fifteen patients (54%) completed induction therapy, and six (21%) received maintenance therapy.

Responses Seen Across Several Malignancies

Responses were seen only with the higher dose of immunotherapy, the researchers note. Patients receiving the lower dose of ipilimumab 3 mg/kg showed no responses.

Among the patients who received the higher dose of ipilimumab 10 mg/kg, complete responses were reported for five (23%); partial responses were seen in two patients (9%); and decreased tumor burden was seen in an additional six patients (27%).

All three patients with leukemia cutis had complete responses, as did one patient with myeloid sarcoma involving lymph nodes and one patient with smoldering myelodysplastic syndrome.

Of the two patients with partial responses, one had Hodgkin's lymphoma, and one had multiple myeloma with lung plasmacytomas.

"We saw responses across a diverse array of hematologic malignancies (eg, acute myeloid leukemia, Hodgkin lymphoma, multiple myeloma), which suggests that there may be a shared mechanism of enhancing the graft-vs-malignancy effect," Dr Davids told Medscape Medical News. He noted that the approach seemed to work particularly well for extramedullary myeloid diseases, such as leukemia cutis.

"We are not certain why this is the case, but one hypothesis is that the extramedullary environment may be rich in antigens, and the tumor cells there may be more visible to the immune system," Dr Davids explained.

"These data show that ipilimumab may be used in patients who relapse on allogeneic transplants even with a prior history of grade 1 or 2 acute or chronic GVHD," Dr Thanarajasingam commented.

Ipilimumab Is Safe, and Clinical Responses Correlated With Immune Responses

Dose-limiting toxicities with ipilimumab 10 mg/kg included two cases of chronic GVHD of the liver and one case of grade 2 acute GVHD of the gut. All of these resolved with glucocorticoid treatment, but ipilimumab was discontinued in these patients.

Three patients experienced immune-related adverse events (grade 2 thrombocytopenia, grade 3 colitis, and grade 3 pneumonitis). These events were managed with glucocorticoids. Steroid was tapered in two patients, after which ipilimumab treatment was resumed. The third patient died 42 days after the initial dose of ipilimumab after experiencing grade 3 colitis and grade 4 pneumonitis.

The investigators note that it is difficult to differentiate GVHD from immune-related adverse events. They report that in two cases of colitis, histology on biopsy allowed them to differentiate between autoimmune colitis and GVHD of the gut.

"However, it is important to monitor patients for adverse events over time to determine if chronic GVHD or other potential sequelae of immune activation in the post-allogeneic transplant setting are higher in survivors," Dr Thanarajasingam told Medscape Medical News.

In an exploratory analysis, Dr Davids and his colleagues showed that clinical outcomes correlated with immunologic responses at the site of disease and in the blood. They did this by studying the histopathology and gene expression profiles of biopsy specimens before and after treatment and changes in T-cell subpopulations using flow and mass cytometry.

The figure above shows an imunohistochemical image of an activated donor CD8+ T-cell (red/brown stain) contacting multiple leukemic cells (blue stain), from a patient with leukemia cutis.

"The correlative studies have provided some initial clues about the mechanism of action that need to be validated in larger studies," Dr Davids said.

Dr Herrera pointed out that this exciting set of correlative studies supports the immunologic basis of the treatment responses observed.

Clinical Relevance of the Study

In patients who experience relapse after transplant, donor lymphocyte infusion is sometimes used to boost graft immune response, but there is a risk for GVHD. Will this study mean that ipilimumab may be used to accomplish the same goal but with less toxicity?

Dr Davids said that after he presented preliminary results from this study at the annual meeting of American Society of Hematology in December 2015, clinicians began contacting him about using ipilimumab off label when transplant patients with hematologic malignancies experience relapse.

When he and his team encounter patients who relapse following transplant, they enroll them into an expansion cohort of the same study. The protocol has been amended to allow accrual of patients to a separate study arm, where they receive a different immunotherapy, the programmed cell death (PD-1) inhibitor nivolumab (Opdivo, Bristol-Myers Squibb Company) as monotherapy.

Nivolumab is already approved for the treatment of classical Hodgkin's lymphoma following relapse after autologous transplant and treatment with brentuximab (Adcetris, Seattle Genetics, Inc).

Dr Herrera expressed excitement about these data. "I am convinced of the potential of checkpoint inhibitors in salvaging these patients who fail allogeneic stem cell transplantation ― so much so that we will now be participating in the next part of the study that will be starting later this year," he told Medscape Medical News.

There is a theoretical concern that PD-1 inhibitors may be associated with a higher rate of GVHD, Dr Davids pointed out. The concern arises from murine models showing higher GVHD with PD-1 blockade. "We don't know yet whether nivolumab or ipilimumab would be better for patients who relapse following allogeneic transplantation, or whether the combination would be tolerable and possibly even more efficacious," he said.

"This study is a critical first step to demonstrate safety and tolerability as well as efficacy of checkpoint inhibition in the allogeneic transplantation setting," Dr Herrera said.

"With the more favorable toxicity profile observed with PD-1 inhibitors relative to CTLA4 [cytotoxic T-lymphocyte-associated protein 4] blockade, there is a tremendous opportunity to evaluate whether PD-1 inhibitors can produce the same or better responses with less toxicity," he noted.

Finally, Dr Thanarajasingam noted that clinical trials of immune-activating therapies typically exclude patients who have received a transplant. "We now have a precedent not to preclude these patients from clinical trials of immune checkpoint blockade," she said.

The study was supported by grants from the National Institutes of Health, the Cancer Therapy Evaluation Program of the National Cancer Institute, the Leukemia and Lymphoma Society Therapy Accelerator Program, the Pasquarello Tissue Bank, and the Department of Medical Oncology and Center for Immuno-Oncology of the Dana–Farber Cancer Institute. Dr Davids and Dr Thanarajasingan have disclosed no relevant financial relationships. Dr Herrera has received research funding from Merck, Genentech/Roche, Pharmacyclics, Immune Design, and Seattle Genetics.

N Engl J Med. Published online July 14, 2016. Abstract


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