Findings could optimize use of CLL drug

Scientists have discovered new markers that could identify which patients would receive maximum benefit from the pan-Bcl-2 inhibitor ABT-737 (also known as Navitoclax).

Initially, researchers were uncertain why ABT-737 was effective in some patients with chronic lymphocytic leukemia (CLL) and not others. But a study recently published in Blood has defined a Bcl-2 expression index that can help predict patients’ responses to the drug.

The study began with Alex Almasan, PhD, of the Cleveland Clinic, and his colleagues collecting blood samples from 57 CLL patients (and 6 healthy donors for comparison). The team isolated primary CLL cells from patients’ peripheral blood and examined the effects of ABT-737 on these cells.

ABT-737 elicited apoptosis in the majority of the CLL samples, but there was a wide range of sensitivity to the drug. Roughly 58% of the samples were considered sensitive to ABT-737, with cell viability less than 40%. About 26% had intermediate sensitivity, with viability ranging from 40% to 65%. And approximately 16% of the samples were resistant to ABT-737, with cell viability greater than 65%.

Analysis revealed that Bcl-2, Mcl-1, and Bfl-1 expression were higher in cells sensitive to ABT-737, with Bcl-2 expression being the highest. In the intermediately sensitive samples, Mcl-1 and Bfl-1 levels were higher than Bcl-2. But in the resistant group, Mcl-1 and Bfl-1 expression were much higher than Bcl-2.

Furthermore, the relative ratio of Mcl-1 and Bfl-1 to Bcl-2 expression provided a highly significant linear correlation with ABT-737 sensitivity (r=0.6, P<0.001).

To be certain of this, Dr Almasan and his colleagues validated the (Mcl-1 + Bfl-1)/Bcl-2 ratio in a panel of leukemic cell lines subjected to genetic and pharmacologic manipulations. Their results suggest this Bcl-2 expression index can predict CLL’s response to ABT-737.

Dr Almasan concluded, “Follow-up studies on patients that have been treated with Navitoclax, particularly those that are poor responders, could determine whether the Bcl-2 family genes examined in this study may also be important for development of resistance to this agent.”

This study was prepublished online July 19 in Blood.

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