A phase I study of bexarotene, a retinoic X receptor agonist, in non-M3 acute myeloid leukemia.
OBJECTIVE
Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML).


METHODS
We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m(2) until evidence of disease progression or unacceptable adverse events occurred.


RESULTS
Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m(2)), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m(2). Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to <or=5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived >1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome.


CONCLUSIONS
The recommended dose of bexarotene for future studies is 300 mg/m(2)/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.
Tsai
Donald E
DE
Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. detsai@mail.med.upenn.edu
Luger
Selina M
SM
Andreadis
Charalambos
C
Vogl
Dan T
DT
Kemner
Allison
A
Potuzak
Melissa
M
Goradia
Ami
A
Loren
Alison W
AW
Perl
Alexander E
AE
Schuster
Stephen J
SJ
Porter
David L
DL
Stadtmauer
Edward A
EA
Goldstein
Steven C
SC
Thompson
James E
JE
Swider
Cezary
C
Bagg
Adam
A
Mato
Anthony R
AR
Carroll
Martin
M