February 18, 2019
Treatment advances for CLL, the most common leukemia
BY Clayton R. Boldt, Ph.D.
Chronic lymphocytic leukemia (CLL), which originates in white blood cells known as lymphocytes, is the most common form of leukemia in adults. According to the American Cancer Society, more than 20,000 new cases of the leukemia will be diagnosed in the U.S. this year, and nearly 4,000 people will die from the disease.
Built upon the long-standing expertise of clinicians and researchers at MD Anderson, the CLL Moon Shot™ is working toward improved treatments for CLL through new immunotherapy approaches, a better understanding of CLL genetics, and novel targeted therapies. The effort is part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Varsha Gandhi, Ph.D., professor and chair ad interim of Experimental Therapeutics, is one of the leaders of the CLL Moon Shot’s focus on developing targeted therapies. She spoke with Cancer Frontline about this work.
Q: How has the CLL Moon Shot built on MD Anderson’s tremendous clinical and translational expertise to improve outcomes for patients with CLL?
Gandhi: We have long conducted translational research at MD Anderson, with extensive collaboration across multiple teams and departments. For many years, standard of care for patients with CLL was a combination of chemotherapeutic agents, such as fludarabine and cyclophosphamide, as well as the monoclonal antibody rituximab, which targets CD20 on leukemia cells. This chemo-immunotherapy combination, known as FCR, was developed by faculty here at MD Anderson through those collaborations.
FCR therapy was the standard of care when we launched the Moon Shot™, but we set out to improve upon the standard of care to eventually bring cures to more patients. For one subgroup of patients with CLL — those with mutations in the IGHV gene — FCR therapy resulted in disease-free survival for about 60% of patients. You can call that a cure. However, FCR didn’t work well for patients with unmutated IGHV and could be a harsh treatment, especially for elderly patients.
Therefore, one of our flagship projects for the CLL Moon Shot is directed at advancing new targeted therapies for all CLL patients, particularly those with unmutated IGHV. Together with Dr. William Plunkett and Dr. Michael Keating, I lead that effort.
Q: What are the advantages of targeted therapies?
Gandhi: In general, patients with CLL are in good physical health and have productive, active lives, even when inflicted with this cancer. They do not want to disrupt that with trips to the hospital for treatment or suffer the debilitating side effects of chemotherapy drugs. Further, patients don’t want to take on the risk of developing additional tumors that emanates from receiving highly genotoxic chemotherapies.
Targeted therapies provide practical solutions to these issues. Almost all current targeted therapeutics for CLL are oral — abolishing the need for frequent hospital visits. They are well-tolerated, allowing patients to maintain active and productive lives. Although not fully established, the general belief is that targeted therapies should not result in long-term and undesirable adverse events. In general, quality of life is not compromised for patients with CLL on targeted therapies.
Since the launch of the Moon Shot, several small-molecule targeted agents have been approved by the Food and Drug Administration (FDA) for the treatment of CLL: ibrutinib, idelalisib, duvelisib, and venetoclax. Ibrutinib targets Bruton’s Tyrosine Kinase (BTK), while idelalisib and duvelisib strike PI3-Kinase (PI3K). These enzymes are pivotal in the B-cell receptor (BCR) pathway, which is responsible for proliferation, survival, and migration of CLL cells. Venetoclax neutralizes the Bcl-2 protein, a culprit that is accountable for existence, maintenance, and survival of CLL lymphocytes.
The advent of targeted therapies has given us tools to treat patients for whom standard treatments aren’t effective, and we have focused our efforts to maximize the efficacy of these drugs, either alone or in mechanism-based combinations. Our aim is to increase the number of patients who achieve what we call “undetectable minimal residual disease (U-MRD).” This means we can’t detect evidence of leukemia cells in the bone marrow following treatment, and we know that patients with U-MRD often go on to have long-term remissions and cures.
Q: What are you doing now to advance these therapies?
Gandhi: Because we can easily isolate CLL cells from the peripheral blood of patients, we have a unique opportunity to make preclinical discoveries in patient samples that we can translate to the clinic. We have taken advantage of that potential and profiled malignant lymphocytes from patients on ibrutinib. Through this work, based on molecular changes we observed in the Bcl-2 family of proteins following ibrutinib treatment, we established that venetoclax is an optimal drug partner with ibrutinib.
Our clinical data provided additional justification for the combination of ibrutinib and venetoclax. These agents preferentially hit CLL cells in different niches and target distinct intracellular survival pathways. We therefore hypothesized that a sequential combination of ibrutinib and venetoclax would be highly effective.
To test such a postulate, I worked with Dr. Bill Wierda and Dr. Nitin Jain to design a protocol where patients received three courses of ibrutinib, followed by venetoclax. At the one-year mark, around 90% of previously untreated patients achieved complete remission, and >60% had U-MRD. Complete remission rates (96% at 18 months) and U-MRD stage (69% at 18 months) are further improving with time. This is a remarkable clinical outcome, as one year of treatment with ibrutinib or venetoclax alone mostly results in partial remissions and U-MRD standings are rare if any.
As a logical extension of this combination trial, we worked with the TRACTION platform, part of MD Anderson's Therapeutics Discovery division, to test the combination of a new and more selective BTK inhibitor, acalabrutinib, with venetoclax in a mouse model of CLL. Currently, we are working on a new clinical protocol to combine these two agents.
Q: Are there any other projects you’re particularly excited about?
Gandhi: During our investigations with ibrutinib alone, my laboratory recognized that, after one cycle of ibrutinib, we not only see a reduction in phospho-BTK protein, which is expected, but also a decrease in the total BTK protein. Because one molecule of ibrutinib is needed to neutralize one molecule of BTK protein, we postulated that ibrutinib doses could be lowered after one or two standard cycles of therapy.
This was the impetus for our ibrutinib 3-2-1 clinical trial, a pilot protocol that we designed with our clinical colleagues, Dr. Keating and Dr. Prithvi Bose. On this trial, patients received a standard dose (3 capsules, 420 mg/day) during first cycle (28 days), then 2/3 dose (2 capsules, 240 mg/day) during the second cycle, and finally 1/3 dose (1 capsule, 140 mg/day) during the third cycle.
Taking serial blood samples from each patient over these three cycles, Dr. Lisa Chen in my group demonstrated that BTK is fully (>95%) occupied by ibrutinib, a desired hallmark of this therapy. Biomarkers such as cytokines were equally impacted at all three doses.
We were excited at these results for several reasons. Not only did we validate our hypothesis, but a lower dose may result in decreased toxicity, open up additional prospects for combinations, and reduce the cost of therapy for patients. This was a prototype flagship project of science-driven patient care. With an integrated team of researchers and clinicians, we now are working to test this in a large prospective, randomized clinical trial to establish clinical efficacy of lower-dose ibrutinib.
Q: How has the Moon Shots Program made your work possible in a way that it was wasn’t previously?
Gandhi: With the unprecedented success of small-molecule targeted agents in CLL, grant revenues are not easily available for therapeutic approaches in this disease. Pharmaceutical companies are not attracted or enticed to a proposal where the investigator wants to test a reduced dose of the FDA-approved standard dose of their drug. Yet such studies are indispensable for optimal patient care and for future progress.
The CLL Moon Shot was vital, and the funding from the Moon Shots Program was instrumental in launching and completing our work in this area. Through our continued collaboration with colleagues and support of the Moon Shots platforms, we look forward to the strides we can continue to make for our patients.