ADJUVANT TREATMENT WITH CYCLOSPORINE-A INCREASES THE TOXICITY OF CHEMOTHERAPY FOR REMISSION INDUCTION IN ACUTE NONLYMPHOCYTIC LEUKEMIA

P-glycoprotein (Pgp)-related multidrug resistance (MDR) is frequently observed in acute non-lymphocytic leukemia (ANLL) and is associated wi th a poor response to standard chemotherapy. Cyclosporin A (CsA) is an effective down-modulator of Pgp-related MDR in vitro and has already been tested for that purpose in vivo also. Since Pgp is expressed in s everal normal cells and tissues, the modulation of Pgp can also modify total body exposure to antileukemic drugs and can alter and increase the toxicity of the antileukemic treatment. We report here the results of a study where 46 consecutive adult patients with ANLL were assigne d to receive the same standard chemotherapy regimen of arabinosyl cyto sine and idarubicin (IDA) for remission induction or consolidation, wi thout or with CsA. Twenty-eight patients received 36 courses of chemot herapy without CsA and 18 patients received 32 courses of chemotherapy with CsA. CsA dose was 10-12.5 mg/kg/day and was given as a continuou s i.v. infusion for 72 h, Whole blood CsA steady-state concentration r anged between 0.61 and 1.14 mu M. The IDA area-under-the-curve was abo ut twice as high in the cases that received CsA than in the other case s. CsA had no detectable effects on renal function and fluid balance, but significantly increased systemic blood diastolic pressure and conj ugated bilirubine concentration. Furthermore, CsA-treated patients had greater, and more severe, oral and intestinal mucosal toxicity, with more severe adverse events, including more cases of gram-negative bact eremia, and with a delayed hemopoietic recovery. In conclusion, this s tudy showed that an attempt at an effective downmodulation of Pgp-medi ated MDR would substantially increase the hemopoietic and mucosal toxi city of antileukemic treatment and that the increase is accounted for, at least in part, by an increase of total body exposure to IDA.