By Michael Choi, M.D.
Chronic Lymphocytic Leukemia (CLL) has been described as a relentless accumulation of leukemic cells due to an imbalance of excessive cell proliferation and defective cell death. In other words, CLL cells have both “pro-survival” and “anti-death” mechanisms. In a previous article, we described the pathways on the pro-survival side, such as the B-cell receptor associated tyrosine kinases, and clinical trials of agents that block those pathways. In this article, we will focus on the opposite side of the equation: the mechanism by which CLL cells escape cell death, and how new therapies can overcome it.
Cell death is normally tightly regulated by proteins in the B-cell lymphoma/ leukemia 2 (BCL-2) family. BCL-2 sequesters and disables the proteins BAX and BAK, which when left free of BCL-2, signal a cell to die. When normal cells or their DNA are damaged, BCL-2 is bound and occupied by other signals, thus freeing BAX and BAK to trigger cell death. CLL cells (and other cancerous cells) have extremely high levels of BCL-2, to the point that its grasp on BAX and BAK cannot be overcome.
In recent years, therapies that inhibit BCL-2 have been designed and largely pioneered by our group and collaborators in the CLL Research Consortium. The pharmaceutical company Abbott has developed and refined drugs that inhibit BCL-2, including ABT-737, ABT-263, and ABT-199. In a phase 1 study treating patients with relapsed CLL, ABT-263 was strikingly effective: 90% of patients experienced a significant decrease in lymphocyte counts and the median progression-free interval was over 2 years. (Roberts, Seymour, Brown, Wierda, Kipps, et al. JCO, 2011)
Although very well tolerated overall, the most common adverse effect of ABT- 263 was a decrease in platelet counts due to the inhibition of one particular BCL-2 family member that is important for platelet function. Due to this, ABT-199 was developed to avoid this effect on platelets. Trials of this oral drug are ongoing, both alone and combined with other agents. Although these are early phase studies (phase 1 and 2), our years of experience with Abbott compounds and the clinical proof that blocking BCL-2 is an effective treatment make us confident that these new agents will represent a significant step towards our goal of curing this disease.