In this video, Dr. Sameer A. Parikh, MD, a CLL specialist at Mayo Clinic Cancer Center, in Rochester Minnesota, is interviewed by Dr. John Pagel, MD, PhD, the Chief of Hematology at Swedish Cancer Center, in Seattle, Washington. This video was recorded at the 61st Annual Meeting of the American Society of Hematology, in 2019, in Orlando, Florida. Dr. Pagel serves the CLL Society’s Medical Advisory Board and Board of Directors.
Approximately 70% of newly diagnosed chronic lymphocytic leukemia patients do not need immediate treatment. Patients who do not require therapy are actively observed by their physicians regularly. Active observation status is referred to as “Watch and Wait,” in layman’s terms. The 2018 International Workshop on CLL (iwCLL) guidelines recommend “close observation” of early-stage CLL patients who do not meet the criteria for therapy.
The question of whether patients at higher risk would benefit from earlier intervention is not new. In the past, attempts to intervene early failed to show benefit. These studies did not select only those patients at the highest risk of needing treatment. These studies used alkylating agents such as chlorambucil or combinations of chemo-immunotherapy; unfortunately, this approach showed no benefit but was associated with significant toxicities.
The introduction of ibrutinib (Imbruvica®), the first Bruton’s Tyrosine Kinase inhibitor (BTKi), has revolutionized the treatment of CLL with little difference in outcomes between patients at low or high risk. Researchers soon began to wonder if early intervention with a BTKi would benefit high-risk patients. They based this on the high rate of effectiveness of BTKi agents in high-risk patients. An additional benefit seen with the BTKi drugs is some improvement in immune function. These facts raised the question of whether earlier intervention with a BTKi might mitigate the increased risk of infections associated with immune suppression in CLL.
Dr. Parikh and his group established an “investigator-initiated trial” to evaluate the second-generation BTKi acalabrutinib, with or without obinutuzumab (Gazyva®) in patients at high and very high risk. To determine risk stratification, the group used the International Prognostic Score for Asymptomatic Early Stage CLL. This scoring system classifies patients into four risk categories, low, intermediate, high, and very high. This study is only enrolling patients at high and very high risk levels who have never been treated and don’t meet criteria for treatment. Patients in the treatment arms, (high or very high group), receive either acalabrutinib mono-therapy, (arm A), [which serves as the control arm], or acalabrutinib plus obinutuzumab, (arm B), [treatment arm]. A third arm, (arm C), includes low and intermediate risk groups, who are observed every six months for two years and then according to accepted clinical practice.
The primary endpoint desired in the treatment arms, (A & B), is to measure the achievement of undetectable minimal residual disease (uMRD), or complete remission, after two years of therapy. The primary endpoint for Arm C, is time to first therapy. Secondary endpoints for all arms are progression-free survival, overall survival, and safety.
Dr. Parikh explains that his group hopes to determine whether this early intervention defined treatment period is beneficial, how it impacts immune functioning, and whether patients develop any new genetic changes as a result of treatment.
The exploration of early intervention is a hot-topic in CLL research. This study carries the exciting possibility that early intervention in high-risk patients may mitigate some of immune issues, such as frequent infections associated with disease progression, and lessen the risk of death from infectious processes, one of the leading causes of mortality in CLL patients.
Early intervention has not been helpful in past trials with chemotherapy, but recent research with ibrutinib in a similar trial presented at EHA (European Hemology Assoc) 2019 Annual Congress, offered promising results. This trial will dig even deeper looking at cellular evolution and immune function.
For more information about this clinical trial, which is recruiting at the three Mayo Clinic locations (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ), go to https://clinicaltrials.gov/ct2/show/NCT03516617. To learn more about clinical trials, in general, go to https://cllsociety.org/clinical-trials.
This is important research with a big upside for patients, if proven to be helpful.
Stay strong; we are all in this together!
Thomas. E. Henry III, MBA, RPh, CPh