A clinical trial conducted at the University of North Carolina Lineberger Comprehensive Cancer Center and Johns Hopkins Sidney Kimmel Comprehensive Cancer Center found that high-dose cytarabine followed by subsequent immunotherapy treatment with pembrolizumab benefited patients with resistant or relapsed acute myeloid leukemia (AML), a highly aggressive cancer.
The findings (“Phase II Trial of Pembrolizumab after High Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia”) appear in Blood Cancer Discovery, a journal of the American Association for Cancer Research.
The Phase II trial enrolled 37 patients under age 70. They received high-dose injections of cytarabine followed by intravenous pembrolizumab two weeks later to examine whether clinical responses can be improved with the addition of pembrolizumab. At the primary endpoint of the trial, 14 people (38 percent) had a complete remission of their cancer.
“Immune suppression, exhaustion and senescence are frequently seen throughout disease progression in AML. We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg IV on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to two years,” write the investigators.
“Among thirty-seven patients enrolled, the overall response rate, composite complete remission rate (CRc; primary endpoint), and median overall survival (OS) were 46%, 38% and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS 13.2 and 11.3 months, respectively). Grade >3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T-cells expressing TCF-1 in the bone marrow prior to treatment.
“A multifaceted correlative approach of genomic, transcriptomic and immunophenotypic profiling offer insights on molecular correlates of response and resistance to pembrolizumab.
These results compare favorably to remission rates seen with high-dose cytarabine and other chemotherapy regimens in resistant or relapsed AML. Also, in patients who had not benefitted from standard therapy and received high-dose cytarabine followed by pembrolizumab in their second overall treatment phase, 46% of trial enrollees achieved complete remission with the one-two punch, suggesting this treatment might be best early in the course of their disease. Serious side-effects were rare and limited, according to the researchers.
“Immunotherapy has led to a paradigm shift in treating cancer, but AML has lagged behind other cancers despite extensive data that it may be effective,” said Joshua Zeidner, MD, associate professor of medicine, chief of Leukemia Research at UNC Lineberger and corresponding author of this study. “Our study is the first clinical trial to investigate the role of pembrolizumab in combination with intensive chemotherapy in patients with AML that relapses or is resistant to therapy.”
While five-year survival for AML has risen from about six percent in 1975 to nearly 30% today, survival at advanced stages of the disease remains poor. Patients whose cancer does not respond to aggressive treatment or becomes resistant to chemotherapy generally have life expectancies measured in months, making the search for better therapies a pressing need.
“Overall, trial participants lived for a median of nearly one year after their therapy, which is significant in comparison to previous benefits seen from chemotherapy alone, which resulted in median survival of six to seven months,” continued Zeidner.
In addition to finding benefit for chemotherapy followed by immunotherapy, the clinicians found that T cells were prevalent prior to treatment. The treatment benefit correlated with the function of these T cells as a certain population of T cells were possibly able to be reinvigorated by pembrolizumab. The presence of these T cells may be able to predict which patients derive benefit from pembrolizumab in AML.
Also, different gene pathways were more prevalent in leukemia cells in those who responded to pembrolizumab, suggesting that these genes could serve as potential biomarkers to predict response.
“We hope that these study results will lead to a clinical trial of chemotherapy with or without immunotherapy. We also hope to identify robust biomarkers of response to immunotherapy that can be incorporated into future study designs,” added Jonathan S. Serody, MD, Elizabeth Thomas Professor of Medicine, director of the Cellular Therapy Program at UNC Lineberger and one of the study’s senior authors. “Additionally, we are planning to incorporate our results into a larger, multi-institutional analysis of predictive biomarkers and characteristics of response to immunotherapy in AML.”
“The results of this trial demonstrate the potential of rationally designed combinations of cytotoxic chemotherapy with immune checkpoint blockade to treat historically refractory malignancies including [relapsed and refractory] AML,” wrote James Allison, PhD, who was awarded 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, in an accompanying commentary to the article. “While the combination appears to provide benefit (shifts survival curve right on historical comparison), we still need to induce long-term durable responses similar to those observed in other indications to bring checkpoint therapy to the forefront in AML.”
This study is the result of a collaboration between clinical and translational researchers at UNC Lineberger, Johns Hopkins, and Merck & Co., which supported the clinical trial and the evaluations of tumor and immune cells in patients treated with this therapy.