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Top Advances in CLL Treatment Over the Past Decade

Top Advances in CLL Treatment Over the Past Decade

Top Advances in CLL Treatment Over the Past Decade


Over the past decade, the FDA has approved multiple new targeted therapies for chronic lymphocytic leukemia (CLL) that are encouraging a move toward chemotherapy-free treatment. Medical professionals have seen that patients are living longer under these treatments, often with a higher quality of life.

These treatment advances have also included a more comprehensive understanding of the prognostic role of several somatic gene alterations. Additionally, novel agents have encouraged researchers to rethink the role of minimal residual disease (MRD) tracking in CLL.

Prior to several novel targeted agents becoming available for CLL treatment, chemotherapy-based therapies were at the forefront. It was noted that, particularly for high-risk patients, the median survival was only about 2 to 3 years from the time of diagnosis.

In 2014, Bruton tyrosine kinase (BTK) inhibitors entered the treatment field. This form of oral medication targets and binds to BTK to suppress its activity. This blocks B-cell receptor signaling, which prohibits further growth of B-cell malignancies. While this form of treatment demonstrated improvement over chemotherapy, some patients had to stop treatment due to intolerable toxicities.

Along with the higher rates of progression-free survival (PFS) over chemoimmunotherapy, various BTKs also bring a substantial risk for atrial fibrillation and hypertension. Since 2014, improvements have been made to this form of treatment, and numerous patients now tolerate these drugs well and continue them until they die of other causes.

Following BTKs, the first BCL2 inhibitor earned FDA approval in 2016 as another therapy for treating CLL. The major difference between the two treatment forms is duration. With a BCL2 inhibitor as a first-line treatment, patients stay on the medication for one year. In the relapsed setting, patients stay on the medication for 2 years. Initially, this therapy carried a risk of tumor lysis syndrome. Close monitoring of patients during this time is recommended, and once their target dose is reached, the treatment is well tolerated.

Around the time the first BCL2 inhibitor was approved, two PI3 inhibitors were also granted FDA approval. Although PI3 inhibitors are effective drugs, they are less often used due to their adverse effect profile.

The past decade has also provided better tools for making a more detailed diagnosis. Several mutations in CLL cells have been researched further, providing clinicians with a deeper understanding of patient outcomes.

Two common mutations within CLL are mutated TP53, found in about 10% of patients, and del(17p), found in about 7% of patients. Each are associated with poor prognosis along with a poor response to chemotherapy treatment. Although these mutations may lead to less durable response with time-limited novel-agent–based regimens, further research demonstrates high rates of PFS among patients who have these mutations and who are on uninterrupted therapy with BTK inhibitors.

Another well-researched mutation of CLL is NOTCH1, which occurs in approximately a quarter of patients. Largely due to their association with an increased risk for Richter transformation, these mutations do suggest a more aggressive disease biology, with patients requiring close monitoring.

An additional prognostic marker in CLL is immunoglobulin heavy chain variable region (IGHV) status. IGHV can either be mutated, which poses a lower risk for the patient, or unmutated, which poses a higher risk. Mutated IGHV may be one of the few settings in which oncologists offer chemotherapy with FCR as an option. Data demonstrate that patients with mutated IGHV have the best chance for long-term remission after this treatment.

As CLL exists as either a slowly or rapidly growing cancer that is often linked to the above genetic mutations, it has yet to be fully examined. A recent study published in Nature Genetics examined how a newly constructed map of the landscape of genetic changes in this disease could lead to more accurate prognoses for patients, improved diagnostics, and novel treatments.

To construct this new map, investigators analyzed variations in genetic sequences, gene-expression patterns, and chemical modifications to DNA—or genomic, transcriptomic, and epigenomic data—from approximately 1,150 patients. Key findings from this study revealed 202 genes—109 of which were novel. When mutated, these genes could potentially drive CLL, and researchers refined the characterization of subtypes of CLL with distinct genomic characteristics and prognoses.

Moving forward, researchers are examining next-generation BTK inhibitors. For patients who develop resistance to targeted therapy, researchers are looking to CAR-T cell therapy for CLL—an approach that has made a major impact in many other blood cancers treatments.



10 Years in CLL: Top Advances From 2012-2022. Article. Targeted Therapies in Oncology. April 2, 2022. Volume 6. Accessed August 29, 2022.

Molecular Map Reveals Insights Into the Genetic Drivers of CLL. Article. The ASCO Post. August 16, 2022. Accessed August 29, 2022.