High-dose chemotherapy followed by immunotherapy benefits patients with acute myeloid leukemia

A clinical trial conducted at the UNC Lineberger Comprehensive Cancer Center and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center found that a high dose of cytarabine followed by subsequent immunotherapy treatment with pembrolizumab was beneficial for patients with leukemia resistant or relapsing acute myeloid (AML), a very aggressive cancer.

The results were published in Blood Cancer Discovery, a journal of the American Association for Cancer Research.

The phase II trial included 37 patients under the age of 70. They received high dose cytarabine injections followed by intravenous pembrolizumab two weeks later to examine whether clinical responses could be improved with the addition of pembrolizumab. On the primary endpoint of the trial, 14 people (38%) had complete remission of their cancer.

These results compare favorably with the remission rates observed with high dose cytarabine and other chemotherapy regimens in resistant or relapsed AML. Best of all, in patients who had not received standard treatment and received high dose cytarabine followed by pembrolizumab in their second phase of overall treatment, 46% of trial participants achieved complete remission. with the one-two punch, suggesting that this treatment might be preferable early in their illness. Serious side effects were rare and limited.

Immunotherapy has led to a paradigm shift in cancer treatment, but AML lags behind other cancers despite ample evidence that it may be effective. Our study is the first clinical trial to investigate the role of pembrolizumab in combination with intensive chemotherapy in patients with relapsed AML or who are resistant to treatment. “

Joshua Zeidner, MD, associate professor of medicine, head of leukemia research at UNC Lineberger and corresponding author of this study

While the five-year survival for AML has increased from about 6% in 1975 to almost 30% today, survival in the later stages of the disease remains low. Patients whose cancer does not respond to aggressive treatment or becomes resistant to chemotherapy usually have a life expectancy measured in months, making the search for better therapies urgently needed.

“Overall, trial participants lived for a median of almost a year after their treatment, which is significant compared to the prior benefits seen with chemotherapy alone, which resulted in a median survival of six to seven months, ”Zeidner said.

In addition to finding a benefit for chemotherapy followed by immunotherapy, clinicians found that a specific type of cell in the immune system, known as a T cell, was prevalent prior to treatment. The benefit of treatment was correlated with the function of these T cells, as a certain population of T cells may have been invigorated by pembrolizumab. The presence of these T cells may be able to predict which patients will benefit from pembrolizumab in AML. In addition, different gene pathways were more common in leukemia cells in those that responded to pembrolizumab, suggesting that these genes could serve as potential biomarkers to predict the response.

“We hope that the results of this study will lead to a clinical trial of chemotherapy with or without immunotherapy. We also hope to identify robust biomarkers of immunotherapy response that can be incorporated into future study designs,” said Jonathan S. Serody, MD, Elizabeth Thomas Professor of Medicine, Cell Therapy Program Director at UNC Lineberger and one of the lead authors of the study. “In addition, we plan to incorporate our results into a larger multi-institutional analysis of predictive biomarkers and characteristics of the response to immunotherapy in AML.

In an accompanying commentary, James Allison, PhD, who received the Nobel Prize in 2018 for his research harnessing the immune system to attack cancer, and three colleagues from the University of Texas MD Anderson Cancer Center wrote: “ results of this assay demonstrate the potential of rationally designed combinations of cytotoxic chemotherapy with immune checkpoint blockade to treat historically refractory malignancies, including [relapsed and refractory] LAM. Although the combination appears to provide a benefit (shifts the survival curve to the right of the historical comparison), we still need to induce long-term sustainable responses similar to those seen in other indications to bring point therapy to the point. control in the foreground in the AML. “

This study is the result of a collaboration between clinical and translational researchers at UNC Lineberger, Johns Hopkins and Merck & Co., who supported the clinical trial and evaluations of tumor and immune cells in treated patients. with this therapy. “This type of collaborative research, where two outstanding cancer centers are working with a leading pharmaceutical company to rationally move therapies to the clinic, is critical to improving outcomes for patients with acute myeloid leukemia,” said Serody, who led the collaboration.

Studies are underway to explore the role of immunotherapies with another chemotherapeutic agent, azacitidine. Researchers could also explore the use of immunotherapy agents other than pembrolizumab in future studies.