Innovative clinical trials continue to change the treatment landscape of chronic lymphocytic leukemia (CLL). The AMPLIFY study was a practice-changing randomized phase 3 trial led by Jennifer Brown, MD, PhD. The study reported progression-free (PFS) and overall survival benefit of fixed-duration targeted triplet and doublet combinations compared to traditional chemoimmunotherapy in treatment-naïve (TN) CLL patients without TP53 aberration. The doublet combination investigated the Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax (AV), and in the triplet combination, the anti-CD20 antibody obinutuzumab was added (AVO). Both AVO and AV were given in a fixed duration of 14 cycles in AMPLIFY regardless of clinical response or minimal residual disease (MRD) status.
Additional data supporting the efficacy of AVO were released from a separate phase 2 study led by Matthew Davids, MD, MMSc. What set this investigator-sponsored study apart from the AVO arm of AMPLIFY was the utilization of MRD status to guide treatment duration and the inclusion of high-risk disease defined by TP53 aberration (63% of the study population). Treatment with MRD-guided AVO as initial therapy in CLL led to durable PFS, including for patients with TP53 aberration (4-year PFS: 70%). In February 2026, the U.S. Food and Drug Administration (FDA) approved AV as first-line therapy in CLL, making it the first all-oral targeted combination regimen with regulatory approval in the U.S. Both AV and AVO are also listed in the National Comprehensive Cancer Network guideline as preferred first-line therapy. Although the addition of obinutuzumab to targeted agents improves the efficacy, triplet regimens have been more frequently associated with infections compared to doublets in clinical trials. Selection of initial CLL treatment requires careful consideration of disease (e.g. TP53 status), patient (e.g. comorbidities), and treatment-related factors (e.g. toxicity profiles).
Despite the success of targeted agents, some CLL patients still present with an aggressive clinical course characterized by treatment resistance and histologic transformation. Double-refractory CLL refers to an emerging group of patients who develop resistance to two mainstream targeted agents, especially BTK and BCL2 inhibitors. In a recent analysis of the Dana-Farber CLL database, double-refractory CLL patients had short survival rates (median 2.2 years) and frequently developed Richter's transformation (RT, approximately 30%) despite frequent utilization of noncovalent BTK inhibitors and cellular therapy.
An ongoing first-in-human study of the BTK degrader BGB-16673 aims to improve the outcome of patients with treatment-resistant CLL. Unlike kinase inhibitors, degraders do not require an enzymatically active binding site and therefore, can overcome BTK mutations that alter the ATP-binding pocket of the protein and confer resistance to BTK inhibitors. Data from the phase 1 portion of this study were presented by Inhye Ahn, MD, reporting high rates of response (86%) among heavily pretreated CLL patients regardless of the BTK mutation status. A global phase 3 study providing a head-to-head comparison of BGB-16673 and pirtobrutinib in CLL is accruing at Dana-Farber (Dana-Farber 25-777; NCT06973187).
To develop an effective treatment for RT, Christine Ryan, MD, is leading a multicenter phase 2 study of glofitamab as monotherapy or in combination with pirtobrutinib, atezolizumab, or polatuzumab vedotin (Dana-Farber 23-429; NCT06043674). With the successful development of the CD20xCD3 bispecific antibody glofitamab in aggressive lymphomas, this ongoing study dedicated to RT holds promise for patients with this rare disease, which currently does not have any FDA-approved treatment. In parallel to this clinical trial, Erin Parry, MD, PhD, leads scientific laboratory efforts to better understand the biology of RT and its therapeutic vulnerabilities.
Research paves the way to a better understanding of CLL and an improvement in patient outcomes. To refer potential participants for clinical trials, please contact 877-DF-TRIAL (877-338-7425).
References
- Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. New England Journal of Medicine. 2025;392(8):748-762.
- Davids MS, Ryan CE, Lampson BL, et al. Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-naive chronic lymphocytic leukemia population enriched for high-risk disease. Journal of Clinical Oncology. 2025;43(7):788-799.
- National Comprehensive Cancer Network. (2026). Chronic lymphocytic leukemia/small lymphocytic lymphoma (Version 2.2026).
- Yoon JT, Zhou Y, Mikhaleva M, et al. Characteristics and outcomes of patients with double refractory and double exposed chronic lymphocytic leukemia. Blood Advances. 2025;9(11):2808-2817.
- Ahn I, Parrondo R, Thompson M, et al. Updated efficacy and safety results of the Bruton tyrosine kinase (BTK) degrader BGB-16673 in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) from the ongoing phase 1 CaDAnCe-101 study. Blood. 2025;146(Supplement 1):85-85.