Ipilimumab Induces Complete Responses in Patients Who Relapse After Allogeneic Transplantation

More than one-third of patients with hematologic malignancies who undergo allogeneic hematopoietic cell transplantation (alloHCT) will relapse, and treatment options for this patient population are limited. Previous research has shown that immune checkpoint blockade, specifically targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), could restore anti-tumor reactivity through graft-versus-tumor effect, without accelerating graft-versus-host disease (GVHD).

In a phase I/Ib, open-label, investigator-initiated, single-group, multicenter study, Matthew S. Davids, MD, of the Department of Medical Oncology at the Dana-Farber Cancer Institute and Harvard Medical School, and authors assessed the safety and efficacy of ipilimumab – a monoclonal antibody that blocks CTLA-4 – in patients with hematologic malignancies who have relapsed after alloHCT. The results, published in the New England Journal of Medicine, showed that treatment with ipilimumab led to remissions in some patients.

“We have shown for the first time that checkpoint blockade can induce durable complete response in myeloid malignancies that relapse after alloHCT, with toxicity that is manageable,” Dr. Davids told ASH Clinical News.

A total of 28 patients were enrolled from six sites between April 2013 and March 2015. Patients were eligible for inclusion if they had:

  • received a diagnosis of progressive or persistent leukemia, lymphoma, multiple myeloma (MM), or a neoplasm with myelodysplastic or myeloproliferative features ≥3 months after alloHCT
  • no immune suppression for at least 4 weeks
  • no history of grade 3/4 acute GVHD
  • ≥20% donor-derived CD3+ T-cell chimerism
  • no history of autoimmune disease
  • no active infection

Patient diagnoses included:

  • acute myeloid leukemia (n=12, including 3 with leukemia cutis and 1 with myeloid sarcoma)
  • Hodgkin lymphoma (n=7)
  • non-Hodgkin lymphoma (n=4)
  • myelodysplastic syndromes (MDS; n=2)
    MM (n=1)
  • myeloproliferative neoplasm (n=1)
  • acute lymphocytic leukemia (n=1)

Twenty-nine percent of patients (n=8) had grade 1/2 acute GVHD, and 57 percent (n=16) had previous chronic GVHD.

In the phase I dose-finding study, patients received escalating doses of ipilimumab (initial dose of 3 mg/kg, increased to 10 mg/kg if no more than one manifestation of dose-limiting toxicity occurred) to determine the maximum tolerated dose (MTD) of the drug.

In the phase Ib dose-expansion study, a total of 22 patients received the MTD dose of ipilimumab (10 mg/kg) over 90 minutes every 21 days for four treatment cycles – unless disease progression or toxic events occurred. Patients could continue to receive maintenance ipilimumab every 12 weeks for up to 60 weeks.

Patients were evaluated every week for the first three weeks, then every three weeks through week 12, and monthly thereafter.

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

Other than transplantation, patients received a median of three prior treatments (range = 1-14 treatments), and 71 percent (n=20) had previously received treatment for relapse after transplantation, including chemotherapy (61%; n=17), radiation (21%; n=6), and donor-lymphocyte infusions (21%; n=6).

Six patients (21%) experienced immune-related adverse events, including one death, the authors reported. Among the 22 patients in the 10 mg/kg cohort, dose-limiting toxic effects included two cases of chronic GVHD of the liver and one case of grade 2 acute GVHD of the gut, all of which resolved with glucocorticoids, but precluded further administration of ipilimumab.

The median number of doses received was four (range = 1-8). A total of 15 patients (54%) received the full course of induction therapy, and six patients (21%) received maintenance therapy. “Ipilimumab was discontinued because of dose-limiting toxic effects in five patients: four patients with GVHD and one patient with severe immune-related adverse events,” Dr. Davids and colleagues reported.

“Although no objective responses were seen at a dose of 3 mg/kg, seven of 22 patients (32%) who received 10 mg/kg met disease-specific criteria for response,” the authors noted. “This suggests that the antibody dose may be important after transplantation.”

Of the patients treated with 10 mg/kg:

  • 5 patients (23%) had a complete response (CR)
  • 2 patients (9%) had a partial response (PR)
  • 6 patients (27%) had stable disease
  • 9 patients (41%) had disease progression

The CRs occurred in four patients with extramedullary AML and one patient with MDS that transformed into AML.

“These observations suggest that CTLA-4 blockage may be effective after alloHCT by inducing a dormant graft-versus-tumor response,” the authors wrote.

After a median follow-up of 15 months (range = 8-27 months) for survivors, the one-year overall survival rate was 49 percent, for which the median duration of response had not been reached. Four patients had a durable response for more than one year.

“Responses were associated with an in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood,” the authors noted.

Treatment response was not associated with the patient’s age, intensity of the conditioning regimen, hematopoietic cell source, time since alloHCT, or prior donor-lymphocyte infusion.

However, the authors observed that all patients who had a CR or PR (n=7) had some prior GVHD, compared with 62 percent among those who did not have a response (p=0.08).

“CTLA-4 blockade was a feasible approach for the treatment of patients with relapsed hematologic cancer after transplantation,” the authors concluded. “Complete remissions with some durability were observed, even in patients with refractory myeloid cancers.”

The study is limited by its small patient population and short duration of follow-up. Dr. Davids discussed further limitations with ASH Clinical News. “Our original study focused solely on CTLA-4 blockade with ipilimumab and did not assess whether programmed death 1 blockade may also be feasible for these patients,” he said. “We have recently amended the protocol to add a cohort of patients treated with nivolumab monotherapy, and we are eager to open this new cohort this fall.”


Reference

Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375:143-53.

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