Current issues in the management of acute promyelocytic leukemia.
Slack JL, Rusiniak ME
Department of Medicine,
Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
James.Slack@RoswellPark.org
[Medline record in process]
Acute
promyelocytic leukemia (APL) is caused by one of four genetic lesions that
disrupt the alpha receptor for retinoic acid, RAR alpha. The fusion protein
responsible for greater than 99% of APL cases, PML-RAR alpha, inhibits
PML-dependent apoptotic pathways in a dominant negative fashion and blocks
myeloid differentiation by direct transcriptional inhibition of retinoic acid
target genes. This transcriptional inhibition is mediated by recruitment of
co-repressor proteins and resultant deacetylation of histones in the promoter
regions of genes (yet to be identified) that control promyelocyte development.
In the presence of high levels of all-trans retinoic acid (ATRA), both
PML-dependent apoptotic mechanisms and myeloid-specific gene expression programs
are reactivated. In the clinic, the combination of anthracycline-based
chemotherapy plus ATRA cures approximately 80% of APL patients, and a high
percentage of relapsed patients can achieve second remissions with arsenic
trioxide. With the publication of results from the European APL 93 trial, the
'standard-of-care' for induction treatment of APL now includes ATRA plus
concurrent anthracycline-based chemotherapy. The amount and type of
consolidation therapy necessary for an individual APL patient remains somewhat
of an open question, but at present should include at least two cycles of
chemotherapy. Based on recent trials that demonstrate a benefit of maintenance
ATRA ( low-dose chemotherapy), all APL patients should probably receive some
type of maintenance therapy. While the above approach currently cures the
majority of APL patients, future improvements in the treatment of this disease
will require risk-adapted protocols that incorporate real-time molecular
monitoring and appropriate introduction of novel therapeutic
agents.
