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Triplet Therapy Shows Promise in Phase 2 Study in Chronic Lymphocytic Leukemia

Dana-Farber researchers find that combining a BCL-2 inhibitor with two other targeted agents is active in previously untreated CLL patients

A clinical research team led by Dana-Farber Cancer Institute reports that a combination of three molecularly targeted drugs is active against chronic lymphocytic leukemia (CLL), a form of blood cell cancer that primarily affects older adults. The experimental triplet therapy — including a second-generation inhibitor of BTK (acalabrutinib), an inhibitor of BCL-2 (venetoclax), and a CD20 inhibitor (obinutuzumab) — was evaluated in a single-arm, phase 2 clinical trial of 37 patients with CLL who had not previously received treatment. As the researchers describe in Lancet Oncology, 86 percent of trial participants demonstrated a significant response over the course of the two-year study: no minimal residual disease (MRD) could be detected in these patients’ bone marrow using sensitive cellular tests, a key predictor of progression-free survival.

Matthew Davids, MD, MMScMatthew Davids, MD, MMSc

“This is the first published study to report on this three drug combination for the treatment of CLL,” said first co-author Matthew Davids, MD, MMSc, Director of Clinical Research of the Division of Lymphoma at Dana-Farber. “We’ve found that the regimen not only shows remarkable activity against this form of cancer, but in this study, the rate of side effects is also quite low. These are very encouraging results.”

CLL treatment has shifted dramatically over the last decade. The once-standard therapy, a cocktail of different traditional chemotherapy drugs, is ineffective for patients with higher risk forms of the disease and often difficult for older patients to tolerate because of significant side effects. Today, this approach is rarely used, thanks to a slate of new, molecularly targeted drugs.

These include the BCL-2 inhibitor venetoclax, which can be an effective CLL treatment on its own, but shows even more potency when combined with another drug, the CD20 inhibitor obinutuzumab. This two-drug combination is already approved for use in CLL patients. BTK inhibitors are another important class of targeted agents. Acalabrutinib is a second-generation BTK inhibitor already approved in CLL either with or without obinutuzumab, and recent clinical studies suggest it is better tolerated by CLL patients than the original BTK inhibitor, ibrutinib.

“These targeted drugs have sparked a revolution in CLL treatment,” said Davids. “But there is still room for improvement. Previous preclinical studies in our lab indicated that combining acalabrutinib and venetoclax together could have a meaningful impact for patients.”

Benjamin Lampson, MD, PhDBenjamin Lampson, MD, PhD

In 2018, Davids and his colleagues Benjamin Lampson, MD, PhD, and Jennifer Brown, MD, PhD, from Dana-Farber’s Center for CLL, with support from pharmaceutical company collaborators AstraZeneca and Genentech, launched a phase 2, single-arm clinical trial to evaluate acalabrutinib, venetoclax, and obinutuzumab (AVO) in patients with previously untreated CLL. Thirty-seven patients were enrolled in the study, and all of them received at least one cycle of the triplet combination therapy.

The drugs were administered in a series of 28-day cycles, beginning with a first cycle of acalabrutinib. Obinutuzumab was added in cycle 2 and venetoclax in cycle 4. The majority of patients underwent a 15- or 24-month course of therapy, depending on when they were found to have undetectable MRD in their bone marrow. MRD undetectability has increasingly been recognized to be the best predictor of a low risk of future CLL disease progression.

An important feature of this experimental triplet therapy is that it is intended to be time limited. The goal is for patients to stop therapy once their disease recedes beyond detection, rather than remain on continuous therapy for many years.

When examined across the full duration of the study, 86 percent of study participants were found to have undetectable MRD in the bone marrow. Thirty-eight percent met the primary endpoint, which was undetectable MRD at the start of cycle 16 and a complete remission. Moreover, the rate of significant side effects was low in light of a study published last year using ibrutinib instead of acalabrutinib in a similar triplet-based regimen.

Based on these results, Davids and his colleagues are accruing an additional group of patients in their study to examine the activity of this AVO triplet therapy against high-risk forms of CLL, such as those with mutations or deletions of TP53. In addition, a phase 3, randomized trial is now underway to test the therapy against other treatment combinations. If positive, this larger study could lead to the approval of AVO as a new standard of care for initial therapy of CLL.

“A time-limited treatment that is highly effective and well-tolerated by patients could be a significant advance for the field,” said Davids. “It’s exciting to think that we may be able to do better than the currently approved treatments, especially for older patients and those with high-risk disease.”

The study’s co-first author is Benjamin Lampson, MD, PhD, and additional authors include:  Svitlana Tyekucheva, PhD, Zixu Wang, MS, Jessica Lowney, BS, Samantha Pazienza, BS, Josie Montegaard, NP, Victoria Patterson, RN, Jennifer Crombie, MD, Samuel Ng, MD, PhD, Austin Kim, MD, Caron Jacobson, MD, MMSc, Ann LaCasce, MD, MMSc, Philippe Armand, MD, PhD,  David Fisher, MD, and Jennifer R. Brown, MD, PhD, of Dana-Farber; Matthew Weinstock, MD, and Jon Arnason, MD, of Beth Israel Deaconess Medical Center.

This work was supported by AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award, and the investigators are supported by the Leukemia and Lymphoma Society, as well as grants from the National Institutes of Health (NCI R01CA213442, NCI R01CA258924, and NCI P01CA206978).