The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions

Abstract

The transformation of acute promyelocytic leukemia (APL) from an often fatal to highly curable cancer with long-term survival exceeding 90% is one of the greatest and most inspiring successes in oncology. A deeper understanding of the pathogenesis of APL heralded the introduction of highly effective therapies targeting the mutant protein that drives the disease, leading to the chemotherapy-free approach to cure almost all patients. In this review, we discuss the paradigm of treatment of APL in 2023, reinforce the high risk of early death without prompt initiation of treatment at first clinical suspicion, and dedicate a special focus to novel agents and future directions to improve cure rates and quality of life in patients affected by APL.

Keywords: acute promyelocytic leukemia; all-trans retinoic acid (ATRA); arsenic trioxide (ATO); coagulopathy; differentiation syndrome; disseminated intravascular coagulation (DIC); oral arsenic.

Figure 1

Summary of key agents used in the treatment of APL. APL, acute promyelocytic leukemia; WBC, white blood cell count; ATRA, all-trans retinoic acid; ATO, arsenic trioxide; GO, gemtuzumab ozogamicin; PPX, prophylaxis; DS, differentiation syndrome; 6-MP, 6-mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction.

Figure 2

Mechanism of action of key agents. Left: In APL, the PML-RARα fusion protein causes a block in differentiation and drives malignant promyelocytic proliferation. Right: The mutated retinoic acid receptor on the cell surface is targeted and bound by ATRA (all-trans retinoic acid) and ATO (arsenic trioxide), which promotes terminal differentiation, degradation of oncogenic proteins, and apoptosis. GO (gemtuzumab ozogamicin) is an antibody-drug conjugate which binds CD33 on the cell surface and when endocytosed releases the chemotherapeutic agent calicheamicin, causing cell death.