Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL).
Sixteen adult patients with relapsed (7 patients) or refractory (9 patients) acute leukemia received mitoxantrone (10 mg/m2 per day for 3 days) and etoposide (200 mg/m2 per day for 3 days) with escalating dose of cyclosporin A (CsA) from a loading dose of 2 mg to 6.5 mg/kg per 2 h followed by 3 days continuous infusion of 5-15 mg/kg per day. The major toxicities were stomatitis and prolonged aplasia, occurring for 15 mg/kg per day of CsA. Transient conjugated hyperbilirubinemia occurred in all patients, and was CsA dose-dependent (r = 0.7). Adequate serum levels of CsA (> 1 microgram/ml) were obtained in 3/6 patients treated with 10 mg/kg per day and 4/4 patients with 15 mg/kg per day. The pharmacokinetic of mitoxantrone showed an unusual increase of carboxylic metabolites, parallel to CsA levels. We observed six responses (two complete and four partial remissions), and eight resistances. Two patients died at days 3 and 8 from sepsis. Before treatment, 7/16 patients tested for P-gp with C219 were positive (> 10% positive cells). 3/6 responders were P-gp-positive. At time of leukemic regrowth, cells expressing P-gp before therapy reverted to P-gp-negative cells.
Marie
J P
JP
Service d'Hématologie, Hôtel-Dieu, Paris, France.
Bastie
J N
JN
Coloma
F
F
Faussat Suberville
A M
AM
Delmer
A
A
Rio
B
B
Delmas-Marsalet
B
B
Leroux
G
G
Casassus
P
P
Baumelou
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000008:administration & dosage*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D005047:Etoposide; D016572:Cyclosporine; D008942:Mitoxantrone