Lessons from the Treatment of APML

By Martin Carrol, M.D.

The Ham-Wasserman lecture will be held today from 12:30 p.m. – 1:30 p.m. It will be delivered by Dr. Zhen-yi Wang of the Shanghai Institute of Hematology in Shanghai, China. Dr. Wang is being honored for his seminal contribution to the treatment of acute promyelocytic leukemia (APML). Dr. Wang and his colleagues were the first to report the efficacy of both all trans retinoic acid (ATRA) and arsenic trioxide (As2O3) for the treatment of APML. Today, Dr. Wang will take the opportunity to review the lessons learned in the last 15 years from the treatment of APML and deliver an overview of ongoing studies on molecularly targeted therapy for other forms of acute leukemia.

APML is often cited as an example of “rational therapeutics”, but it is important to recall that the bedside lead the bench in these endeavours. Dr. Wang and his colleagues tested ATRA based on previous clinical observations, not because of the molecular target. The t(15;17) translocation typically associated with APML was only identified as containing the retinoic acid receptor alpha (RARa) after the clinical observations by Dr. Wang. The clinical success of ATRA is well known and ATRA in combination with chemotherapy is now the accepted standard for treatment of this disease. Dr. Wang will review two categories of therapeutic agents: (1) differentiation agents and (2) apoptosis or programmed cell death inducing agents. Large numbers of such compounds have been tested on myeloid cell lines and found to be cytotoxic. Few of these, however, have made their way successfully into clinical trials. Dr. Wang proposes that studies with ATRA and STI-571 in CML suggest that developing targeted and effective therapy for AML will require identifying specific molecular mechanisms involved in the pathogenesis of different forms of AML. Drugs can then be tested and developed to target these exact mechanisms of transformation. This raises a challenge to researchers in the field whether to pursue general differentiation inducing agents or to better define the exact steps in the pathogenesis of each form of AML. Dr. Wang proposes that the latter approach will allow for development of further specific and molecularly targeted therapeutics. Perhaps, traditional Chinese medicine will yield more compounds with such specific, educational and therapeutic effects.