fludarabine v cladribine

A new look at Cladribine has been published in Blood. It is perhaps a neglected drug, being very similar to fludarabine, which is usually preferred. I first heard about it from Gunner Julliussen who was obtaining it cheaply from Poland. I gather someone there was manufacturing it as a cottage industry. More recently it has been championed by Dr Robak from Poland. Although similar to fludarabine it has an extra activity in that it is able to alter the mitochondrial membrane potential, which produces caspase-dependent apoptosis in a TP53 independent way. However, There seem to be only 4 fludarabine-refractory patients who have responded to cladribine and 2 cladribine-refractory patients who have responded to fludarabine.

There is a head-to-head comparison between cladribine and fludarabine as front-line therapies for CLL, which showed a significantly longer progression-free survival for cladribine (25 v 10 months), but that seems a very short pfs for fludarabine (more jiggery-pokery from the pharmaceutical companies?).

There is one study which suggests that cladribine does better fludarabine in del 17p cases, but the fludarabine patients in the comparison were of a more advanced stage and the p value was only 0.112.

The major side effect of cladribine is cytopenia, which can be severe and persistent. CD4 lymphopenia is a problem as it is with fludarabine, requiring PCP prophylaxis. Secondary MDS occurs in 1.6% of patients treated with cladribine. The combination of cladribine and an alkylating agent increased the risk of lung cancer. Autoimmunity is no commoner than with chlorambucil. Rare toxicities reported include, Stevens-Johnson syndrome, stroke, tumor lysis syndrome and Transfusions associated GVHD.

All in all cladribine is very similar to fludarabine and the only reason for using it in preference to fludarabine would be if it were substantially cheaper.