Checkpoint inhibitors such as Opdivo and Yervoy are showing promise in treating MDS and AML.
Multiple studies are currently assessing new combination strategies for checkpoint inhibitors to move forward the treatment for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), according to Naval Daver.
“We have a lot of work going on in this area, to see what the expression of these checkpoint are and how we can clinically use them,” said Daver, assistant professor, Department of Leukemia, MD Anderson Cancer Center. “The next step, like with most leukemias, is how can we combine them with approved agents for these disease.”
Early research into the viability of checkpoint inhibitors in hematologic malignancies focused heavily on identifying which checkpoints might have the greatest activity. In these studies, DNA methyltransferase (DNMT) was found to upregulate PD-L1 and PD-1, which was linked to resistance to therapy and worse outcomes.
Clinical activity, specifically for those with AML, was first demonstrated in a phase 1/1b study assessing the CTLA-4 inhibitor Yervoy (ipilimumab) for relapsed hematologic malignancies following allogeneic stem cell transplantation. Across 12 patients with AML treated with Yervoy at 10 mg/kg, the complete response (CR) rate was 42 percent.
Additionally, a separate phase I study assessed the combination of the hypomethylating agent azacitidine with the PD-1 inhibitor Opdivo (nivolumab) for patients with relapsed/refractory AML. After a median follow-up of 8.3 months across 35 patients, the CR and CR with incomplete hematologic recovery (CRi) rate was 18 percent. The overall response rate (ORR) was 32 percent.
Although the data were still immature and the patient population was small, there was a strong trend toward improved overall survival (OS), according to Daver. The median OS with azacitidine plus Opdivo was 9.3 months, which compared favorably with a historical OS of 4.7 months for this population.
Overall, 12 patients in the study experienced a grade 2 to 4 adverse event (AE), which included pneumonitis (11 patients), nephritis (five patients), skin rash (two patients) and colitis (two patients). A majority of the AEs occurred within the first six weeks of treatment and all toxicities responded rapidly to treatment with steroids.
“The toxicity has been a learning curve for me and for my group, since leukemia doctors have not yet been using these drugs,” said Daver. “The pattern and profile of toxicities seems to be different than what was seen for solid tumors. The majority of toxicities have been pneumonitis, and the others have been colitis and skin related.”
When looking at T cell subpopulations before and after Opdivo /azacitidine, the number of CD3+ cells and the ratio of CD8+ cells to Tregs predicted response to treatment. In these early observations, PD-L1 expression did not appear to impact results. “There were some hints that baseline immune infiltrate is able to predict for response,” added Daver.
A study assessing immunotherapies for MDS demonstrated similar promise. In this trial, patients received single-agent Opdivo (15 patients), azacitidine plus Opdivo (13 patients), or Yervoy (13 patients). The combination demonstrated an ORR of 68 percent and responses were still pending for Yervoy. Monotherapy with Opdivo did not elicit a response.
A second study is looking at the combination of the killer-cell immunoglobulin-like receptors (KIR) inhibitor lirilumab and azacitidine. In early data from three patients treated with the combination, the ORR was 100 percent and there were no unexpected toxicities. This phase 1/2 study is currently enrolling patients with AML to receive azacitidine plus lirilumab in a dose finding cohort followed by a phase 2 portion utilizing the maximum tolerated dose. Further results from the study will be presented at the 2016 ASH Annual Meeting.