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AML cells

NEW ORLEANS—A phase 4 study has revealed biomarkers that appear to predict the efficacy of treatment with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) in patients with acute myeloid leukemia (AML).

Researchers found that patients who remained in complete remission after 1 cycle of HDC/IL-2 experienced a significant reduction in effector memory T cells (TEM) and a concomitant increase in effector T cells (Teff) during therapy.

This “TEM to Teff transition” was associated with favorable leukemia-free survival (LFS) and overall survival (OS), especially among patients older than 60.

Frida Ewald Sander, PhD, of University of Gothenburg in Sweden, and her colleagues presented this research at the 2016 AACR Annual Meeting (abstract CT116*).

The study was supported by The Swedish Research Council, The Swedish Cancer Society, The Swedish Society for Medical Research, Meda Pharma, and Immune Pharmaceuticals, which markets HDC as Ceplene®.

The combination of HDC and IL-2 is currently approved in more than 30 countries to prevent relapse in AML patients. In this phase 4 study (Re:MISSION), the researchers set out to assess the immunomodulatory properties of this treatment and correlate potential biomarkers with clinical outcomes.

The study included 84 non-transplanted AML patients (ages 18 to 79) in first complete remission. The patients received HDC (0.5 mg SC BID) and human recombinant IL-2 (1MIU SC BID) in 3-week cycles for 18 months. The patients were followed for at least 2 years from the start of immunotherapy to evaluate survival.

The researchers collected blood from the patients before they began HDC/IL-2 therapy and at the end of the first treatment cycle. From these samples, the team assessed the frequency of CD8+ T cells, including naïve T cells (CD45RA+CCR7+), central memory T cells (CD45RO+CCR7+), TEM cells (CD45RO+CCR7-), and Teff cells (CD45RA+CCR7-).

The researchers found that non-relapsing patients experienced a significant reduction in TEM cells (P=0.001) and a significant increase in Teff cells (P=0.007) during cycle 1. However, this effect was not observed in patients who did relapse.

Further analysis revealed that the reduction in TEM cells was significantly associated with favorable LFS  and OS in the entire cohort (P=0.0007 and P=0.005, respectively) and among patients over 60 (P<0.0001 and P=0.002, respectively).

Likewise, the increase in Teff cells was associated with favorable LFS and OS in the entire cohort (P=0.07 and P=0.04, respectively) and among patients over 60 (P=0.004 and P=0.0001, respectively).

The concomitant reduction of TEM cells and induction of Teff cells—the TEM to Teff transition—was associated with superior LFS and OS in the overall cohort (P=0.0002 and P=0.002, respectively) and in the over-60 population (P<0.0001 for LFS and OS).

The researchers said these predictors of outcome remained significant when they adjusted for potential confounders (age, risk group classification, number of induction courses required to achieve complete response, and number of consolidation courses).

Therefore, the team concluded that the altered distribution of cytotoxic T cells during treatment with HDC/IL-2 can prognosticate LFS and OS in AML patients, particularly those over 60.

“We believe that the new data may allow a personalized approach to selection of patients who are most likely to benefit from Ceplene/IL-2 treatment in AML—in particular, the older patient population, who have demonstrated almost 100% survival when positive for the T-cell transition biomarkers,” said Miri Ben-Ami, MD, executive vice president of oncology at Immune Pharmaceuticals.

“In addition, current research is revealing the potential synergy between immune checkpoint inhibitors and Ceplene, which could open the possibility of additional therapeutic indications for this combination.” end hematology article

*Information in the abstract differs from that presented at the meeting.

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