Clinical study of 9-cis retinoic acid (LGD1057) in acute promyelocytic leukemia.
The use of all-trans retinoic acid (RA) for remission induction markedly increases survival of patients with acute promyelocytic leukemia (APL) compared to patients treated solely with cytotoxic chemotherapy. However, clinical resistance to this agent develops rapidly, which has been associated with a progressive decline in plasma drug concentrations. Previous studies suggested that 9-cis RA, a retinoid receptor 'pan agonist' did not induce its own catabolism to the same extent as all-trans RA. Therefore, we conducted a dose-ranging study of this compound in patients with both relapsed and newly diagnosed APL. We treated 18 patients with morphologically diagnosed APL (13 relapsed, five newly diagnosed). The daily dose of 9-cis RA ranged from 30 to 230 mg/m2/day given as a single oral dose. Four of 12 (33%) relapsed patients (three of whom were previously treated with all-trans RA) and four of five (80%) newly diagnosed patients achieved complete remission. The sole failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translocation had substantial hematologic improvement. The drug was generally well tolerated; headache and dry skin were the most common adverse reactions. Three patients were treated with corticosteroids for signs of incipient 'RA syndrome.' These preliminary data suggest that 9-cis RA is an effective agent for remission induction and deserves further investigation in patients with retinoid-sensitive APL.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Cornell University Medical College, New York, NY 10021, USA.
S L
SL
Soignet
F
F
Benedetti
A
A
Fleischauer
B A
BA
Parker
J A
JA
Truglia
M
M
Ra Crisp
R P
RP
Warrell
D000293:Adolescent; D000328:Adult; D000368:Aged; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12; D002899:Chromosomes, Human, Pair 9; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010976:Platelet Count / Q000187:drug effects; D012008:Recurrence; D014178:Translocation, Genetic; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D000077556:Alitretinoin; D014212:Tretinoin