Chronic lymphocytic leukemia (CLL) presents as an accumulation of monoclonal, mature, CD5+ B-cells in secondary lymphatic organs where cancer cells engage in molecular and cellular interactions disrupting the adaptive immune response. Promising advances in therapy options for patients with CLL, targeting these molecular interactions, were discussed in a review published in The New England Journal of Medicine.1
Since the introduction of these novel therapeutics, the use of chemoimmunotherapy has drastically declined. “We have moved away from using chemotherapy for most patients, just over the last 5 years”, Jan Burger, MD, PhD, of the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston, told Hematology Advisor.
“We now have good alternatives to chemotherapy that, in the end, have better survival rates for our patients” Dr Burger, who is the author of the review paper, continued. “The reason why we were able to make this big step forward in treatment was to some extent [serendipitous]. These new kinase inhibitors became available at a time when there was more basic research which emphasized how important these molecules are in leukemia cells.”
Kinases and Apoptosis in CLL
CLL cells mimic B cells through the formation of pseudofollicles, allowing for activation by monocyte-derived macrophages, T cells, and stromal cells. This, in turn, activates the downstream targets spleen tyrosine kinase, Bruton tyrosine kinase (BTK), and phosphatidylinositol 3-kinase. These molecules transmit homing signals causing retention of CLL cells in secondary lymph organs. Due to deletions of miR-15a or miR-16-1,CLL cells commonly overexpress the antiapoptotic protein B-cell lymphoma 2 (BCL2), which maintains cell survival.
BTK inhibitors (ibrutinib and acalabrutinib) form a covalent bond with BTK at cysteine 481 and interrupt the CLL cell homing signal, halting migration and causing a redistribution of CLL cells to the peripheral blood.
Ibrutinib was the first successful BTK inhibitor. During clinical trials, the 7-year progression-free survival rate among patients without previous CLL treatment was 83% and 34% among patients with refractory or relapsed CLL. Ibrutinib was approved by the U.S. Food and Drug Administration (FDA) after outperforming ofatumumab (overall survival, 67.7 vs 65.1 months) and chlorambucil (60-month overall survival, 83% vs 68%) in clinical trials.1,2-5
Acalabrutinib was the second BTK inhibitor to receive FDA approval. Acalabrutinib differs from ibrutinib in that it is more BTK selective and does not interfere with unintended targets such as epidermal growth factor receptor (EGFR), interleukin-2-inducible T-cell kinase. At clinical trial, acalabrutinib demonstrated superior 30-month overall survival (94%) compared with obinutuzumab plus chlorambucil (90%).6
The BCL2 antagonist (venetoclax) counteracts BCL2 overexpression to promote cell lysis. In a phase 1 clinical trial (MURANO; ClinicalTrials.gov Identifier: NCT02005471), the median progression-free survival among patients with refractory or relapsed CLL treated with venetoclax was 25 months. When used in combination with rituximab, the 2-year progression-free survival rate was 84.9% compared with 36.3% for patients treated with bendamustine plus rituximab. The MURANO trial is currently in phase 3.