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Get a CLLue: Updates on CLL Biology and Therapy

December 18, 2022
Anupama Kumar, MD, and Ah-Reum (Autumn) Jeong, MD

Dr. Ah-Reum “Autumn” Jeong (@AutumnJeong) is an alum of Cornell University where she went for undergrad studies. A San Diego native, she returned to the West Coast and attended University of Southern California for medical school and residency, and UC San Diego for her fellowship. Today she is assistant clinical professor in the Division of Medicine, Department of Blood and Marrow Transplantation, at Moores Cancer Center at UC San Diego Health in La Jolla, California. Her interests include myeloma, CAR-T therapy, and bone marrow transplantation. This is Dr. Jeong’s second year on the board of ASH News Daily, having served as a Junior Author in 2021. “I did Taekwondo during college and competed regionally,” she informed us.

Dr. Anupama Deepa Kumar (@anupamakumar05) is a fellow at UC at Moores Cancer Center of UC San Diego Health. Focusing on all things malignant hematology, Dr. Kumar is an alum of Cornell University as well as Tufts University School of Medicine and Tufts Medical Center, where she completed medical school and residency, respectively. Her hometown is lovely Palo Alto, California.

The chronic lymphocytic leukemia (CLL) space experienced remarkable advances at #ASH22. This year, we learned about optimal combination therapies for newly diagnosed patients, new targeted therapies, and the best options for relapsed/refractory patients with CLL.

The small molecule inhibitors targeting Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) have revolutionized treatment for CLL/small lymphocytic lymphoma (SLL). We are now moving away from conventional chemotherapy to oral medications, which are well-tolerated and exhibit remarkable efficacy. The current goal is to find the optimal combination therapy and learn how to sequence therapy using available options. Dr. Nitin Jain from University of Texas MD Anderson Cancer Center discussed updated results from a phase II trial combining ibrutinib and venetoclax in patients with CLL with one or more high-risk features (deletion 17p, mutated TP53, deletion 11q, unmutated IGHV, or age > 65 years). After a median follow-up of 48.8 months, 72 percent of patients achieved bone marrow measurable residual disease (MRD) negativity as best response, with a four-year progression-free survival (PFS) of 94.5 percent, and overall survival (OS) of 96.6 percent. A triplet regimen is also under investigation, and Dr. Henriette Huber from Städtisches Klinikum Karlsruhe reported results from the CLL2-GIVe trial examining obinutuzumab, ibrutinib, and venetoclax in high-risk patients with CLL. Dr. Huber’s team demonstrated that 32 (78%) of 41 patients achieved peripheral blood MRD negativity and reported a PFS of 79.9 percent at 36 months, while median PFS was not reached. Unsurprisingly, the most frequent grade 3 or higher adverse events were cytopenias and infections. Will triplet therapy be the new standard of care in the future, or are we reserving options for the relapsed setting? We eagerly await follow-up results to answer these important questions.

In the Late-Breaking Abstracts session, Dr. Jennifer Brown of the Dana-Farber Cancer Institute (pictured left) presented final results of the ALPINE phase III trial comparing ibrutinib versus zanubrutinib in patients with relapsed/refractory CLL/SLL. After a median follow-up of 29.6 months, superior PFS was demonstrated in patients treated with zanubrutinib (hazard ratio, 0.65; median PFS, not reached in the zanubrutinib arm vs. 35 months in the ibrutinib arm). Zanubrutinib also demonstrated lower rates of grade 3 or higher adverse events, including atrial fibrillation and flutter. Therefore, zanubrutinib may represent the new standard of care in BTK inhibitor–naïve relapsed/refractory CLL/SLL.

Novel BTK inhibitors include pirobrutinib, which in contrast to the currently approved BTK inhibitors, is a highly selective noncovalent/reversible BTK inhibitor with equal potency against both wild-type and C481-mutated BTK. At #ASH22, updates on the phase I/II BRUIN study, which utilized pirobrutinib in relapsed/refractory CLL/SLL, were presented by Dr. Anthony Mato from Memorial Sloan Kettering Cancer Center. The overall response rate (ORR) was 74 percent in this heavily pretreated population with median PFS of 19.4 months. In addition, Dr. Nirav Shah of the Medical College of Wisconsin discussed the safety and efficacy of pirobrutinib in patients with Richter’s transformation. ORR was 54 percent, with a median duration of response of 8.6 months, which is remarkable for this heavily pretreated population with aggressive disease.

Another novel therapy under investigation is lisaftoclax, a specific BCL-2 inhibitor. Dr. Mathew Davids from the Dana-Farber Cancer Institute demonstrated that lisaftoclax as monotherapy, or in combination with acalabrutinib or rituximab in relapsed/refractory CLL/SLL, was associated with encouraging response rates. The ORR was 65 percent in the monotherapy group and 87-98% as combination therapy. Furthermore, lisaftoclax had an acceptable safety profile.

On the basic science front, Dr. Erin Michelle Parry and co-investigators from the Dana-Farber Cancer Institute sought to improve our understanding of the dismal outcomes associated with Richter’s transformation. They performed matched whole-exome and whole-genome sequencing of patients with Richter’s transformation and CLL and demonstrated that the transformation was clonally related 87 percent of the time. Alterations in MYC signaling, epigenetics, and interferon/inflammatory signaling as well as cell cycle deregulation and immune evasion occurred at the time of transformation. Furthermore, Richter’s transformation cases had genetically distinct signatures compared to diffuse large B-cell lymphoma. We hope these discoveries lead to early identification of those at high risk of transformation to prevent and combat this aggressive disease.

Don’t forget to access the #ASH22 virtual meeting platform to review any missed presentations on CLL from the comfort of your home.

Dr. Kumar and Dr. Jeong indicated no relevant conflicts of interest.

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