Dr. Andrew Brunner, an oncologist at Massachusetts Cancer Center was recently interviewed by Targeted Oncology. The discussion centered around a phase 1b clinical trial (NCT03066648) investigating sabatolimab together with hypomethylating agents (HMAs) decitabine and azacytidine. Participants in the study had been diagnosed with acute myeloid leukemia (AML) or high-risk myelodysplastic leukemia (MDS).
Exploring a New Regimen
Dr. Brunner explained the motivations for exploring a new regimen. He said that the medical community has proven that immunotherapy can play a role in treating leukemia in the long term as well as having success in transplantation. However, the search is still on for new therapies to treat these patients.
The doctor said that targeting TIM-3 is one option to use to treat newly diagnosed patients with high-risk MDS, AML, and CMML.
The National Institute of Health acknowledges that T-cell immunoglobulin mucin-3 (TIM-3) is an important cancer immune checkpoint.
Dr. Brunner explained that the medical community now has a better understanding of TIM-3’s role in connection with malignant and normal tissues. He sees TIM-3 as being responsible for blasts (cancers) in the leukemic population. (Dr. Brenner describes TIM-3 as a “marker”). He said if they can disrupt TIM-3 they would be able to develop long-awaited therapeutic options.
About Checkpoint Inhibitors
A drug used to block proteins is called a checkpoint. It is generally made by T cells and/or cancer cells. The checkpoints regulate immune responses, preventing them from gaining strength or preventing T cells from performing their mission to destroy cancer cells. Blocking checkpoints with checkpoint inhibitors allows T cells to carry out their intended mission, which is to kill cancer cells.
Doctor Brunner spoke about the challenges of introducing traditional immune-oncology therapies for the treatment of MDS, AML, and other malignancies. He said that they have learned through transplantation and various other accomplishments that immunotherapy plays an important role in controlling leukemia in the long term. However, there is a constant search for new targets.
High on the list of challenges is the identification of young leukemic cells that lead to blood cancers.
The term progenitor cells and stem cells are at times interchangeable.
About the Study Design
There were several arms (groups) of patients in the study. Dr. Brenner initially focused on patients who were newly diagnosed with AML and had not received HMA therapy previously. Patients in the other arms had high risk MDS or chronic myelomonocytic leukemia (CMML). Other groups consisted of patients who had cancer that relapsed or was refractory (resisting treatment).
Some patients were treated with standard HMA therapy for five days of decitabine or seven days of azacytidine. The study drug, sabatolimab, was administered on the eighth day and again on the twenty-second day of the two-week cycle. Other patients were on a four-week cycle. Those patients received sabatolimab on the eighth day of the cycle.
Most of the patients in the study were around seventy years old with slightly more males in all groups.
Out of forty-one patients, twenty-five had MDS classified as high risk with sixteen patients out of forty-one having very-high-MDS. AML patients were divided at a medium risk of forty-four percent while fifty-six percent had adverse risk.
When asked what he felt was a take-away from the trial, Dr. Brenner referenced the low blood counts experienced by MDS patients and frequent trips to the hospital for transfusions that have an impact on a patient’s quality of life.
He added that sabatolimab does not cause a high degree of myelosuppression (decrease in the bone marrow’s inability to produce blood cells). Dr. Benner emphasized the importance in managing side effects in the first few months of treatment until patients experience a response.
Dr. Brenner said he was encouraged by patients responding not only with a satisfactory marrow response, but MDS patients were able to see their blood counts at a level that does not require frequent visits to a clinic.
Since some studies of immunotherapies in AML and MDS had toxicities that raised a red flag; safety was a prioritized goals of the current study. This holds true due to the higher number of older patients with MDS and AML and especially due to double or even triple therapy combinations. Dr. Brenner believes that sabatolimab is safe when combined with azacytidine or decitabine.
He went on to mention side effects of the drugs. They included fever, anemia, neutropenia (low neutrophils) and thrombocytopenia (low platelets). Dr. Brenner said that these side effects were typical of azacytidine therapy.
The researchers did see some adverse events that could be related to sabatolimab. He said that they were low grade and easily treatable. It is noteworthy that only a few patients discontinued treatment due to side effects.
The immediate goal of the researchers is to conduct a single-arm study now that they have identified a typical population that would benefit in an outpatient setting.
Dr. Brenner’s Analysis
Currently the field has many promising agents that can be combined with azacytidine. This translates into flexible planning by the oncologist. When an oncologist suspects that the patient is beginning to relapse, a new target agent can be added or a new plan can be substituted to maintain the patient’s remission. Dr. Brenner is pleased that sabatolimab will be playing a role along with other active agents in expanding overall survival and quality of life.
Results of the trial were presented at the 2020 ASH Annual Meeting.