New advances in the treatment of acute promyelocytic leukemia

Abstract

Objective: Describe the treatment options of newly diagnosed and relapsed APL.

Induction: The fusion PML/RAR gene provided the rationale for using all-trans retinoic acid (ATRA) as differentiation therapy. The standard approach is antracycline + ATRA and no ARA-C.

Consolidation: Anthracycline based chemotherapy, no high dose ARA-C and perhaps no ARA-C. Maintenance seems to be important. Cure with ATRA + chemotherapy increased to 75% from 35% with chemotherapy alone.

Poor prognosis factors: WBC >10,000, age >55, platelets <40,000 and CD 56 expression. Achieving and maintaining a molecular remission (MCR) i.e. RT-PCR (-) for PML/RAR alpha expression, is the best predictor for cure. Conversion to PCR (+) will eventually result in relapse. PCR monitoring in the first 2 years and intervention during molecular relapse would be safer than treatment in clinical relapse. Molecular relapses have been treated successfully by ATRA plus BMT. Arsenic trioxide (ATO) or gentuzumab (mylotarg) are also being studied.

Relapse (induction): Patients after ATRA in first CR are less likely to respond to ATRA reinduction regardless of the time off ATRA and rarely achieve a molecular remission. Single-agent ATO induced in 52 relapsed patients CR of 87% (75% MCR) with low toxicity and no treatment related deaths (U.S. pivotal trial), confirmed in a NCI trial. Induction of relapsing patients with single agent ATO is preferable than ATRA + chemotherapy because the high molecular remission and lower toxicity.

Relapse (post remission): No standard approach and the role of chemotherapy is unknown. ATO alone: in the pivotal trial, 9/21 patients had long remissions without other therapy. BMT: Not indicated in 1st MCR. In young patients auto BMT with PCR (-) harvests could be done in subsequent CR. Allo BMT has a higher death rate without overall better results. In the pivotal trial 12 patients were transplanted in CR after ATO alone (9 allo BMT) and 11 still without disease. Possibly allo BMT is safer after a less toxic ATO induction.

Other: ATO plus ATRA +/- AntiCD33 conjugated with toxin (gentuzumab) or 131I; Synthetic retinoid (Am80); histone deacetylase inhibitors; oral tetra-arsenic tetra-sulfide and various combinations.