Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) — the clonal proliferation of myeloid precursor cells, which accumulate in the marrow and displace normal blood-cell production. What defines APL is a translocation, an exchange of material between two chromosomes: t(15;17) fuses PML on chromosome 15 with RARA on chromosome 17 and produces the PML::RARA fusion protein. APL accounts for about 7% of childhood AML, which makes it uncommon, but it is the subtype that looks least like any other childhood leukemia in the way it is treated — and the one that can kill a child by bleeding before any chemotherapy has been given.
The fusion protein holds the promyelocyte short of maturation
The promyelocyte is an immature stage on the way to becoming a neutrophil. RARα is a retinoic acid receptor, and the PML::RARA fusion acts as a transcriptional repressor — it switches off the genes the cell needs to move on — so the myeloid precursor is held at the promyelocyte stage. The cells cannot mature, so they accumulate, and they accumulate full of the granules and Auer rods — needle-shaped cytoplasmic inclusions of fused azurophilic granules — that give APL its morphological signature.
Coagulopathy comes before treatment does
Almost every child with APL has a coagulopathy at diagnosis. The promyelocyte granules and Auer rods release procoagulant material: tissue factor on the blast surface activates the coagulation cascade, and annexin II drives fibrinolysis (the breakdown of clots) at the same time. The result is a picture of disseminated intravascular coagulation, in which clotting is activated throughout the circulation and platelets and clotting factors are used up: thrombocytopenia, prolonged prothrombin and partial thromboplastin times, raised D-dimers and low fibrinogen. It can worsen in the first days of treatment. Bleeding and thrombosis appear together, and early deaths in APL are usually hemorrhagic.
That timing sets a rule. Any child with a new acute leukemia and abnormal clotting is treated as if they have APL until cytogenetics or molecular testing say otherwise: platelets and fibrinogen are replaced before bleeding starts, and all-trans retinoic acid (ATRA) is started on morphological suspicion rather than after the translocation result. A lumbar puncture at diagnosis waits until the coagulopathy has resolved.
Some children are at greater risk than others. A high white cell count, a low platelet count, abnormal coagulation studies, a high body mass index and a FLT3 internal tandem duplication (a duplicated stretch within the FLT3 gene) all mark the children at greatest risk of a coagulopathic complication.
Differentiation therapy instead of cytotoxic chemotherapy
The defining feature of APL is that it can be treated without conventional cytotoxic chemotherapy — a statement that is true of almost no other acute leukemia.
The modern backbone is all-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO), with chemotherapy reserved for high-risk presentations such as a high white cell count. The two agents attack the same fusion protein in different ways:
- ATRA binds the RARα portion and releases the transcriptional repression the fusion imposes, so the promyelocytes resume the maturation program they were arrested in — they differentiate into neutrophils rather than being killed.
- ATO binds the PML portion and triggers degradation of the PML::RARA protein through sumoylation (tagging with small ubiquitin-like modifier proteins) and the proteasome, the cell’s protein-degrading machinery.
Differentiation and degradation together remove the driver, and most patients are cured without classical cytotoxic chemotherapy.
Differentiation syndrome and QT prolongation
Making the leukemic cells mature is not free of harm. The treatment brings two toxicities of its own: one from the maturation it produces, and one from arsenic trioxide itself.
Differentiation syndrome. The same maturation that makes the therapy effective can produce fever, dyspnea, weight gain, pleural or pericardial effusions, pulmonary infiltrates and hypotension — the cells release cytokines as they differentiate, and the capillaries leak. It is treated with dexamethasone, started at the first suspicion.
QT prolongation — a lengthening of the QT interval on the electrocardiogram — is added by arsenic trioxide, so electrocardiograms and potassium and magnesium monitoring are part of the treatment plan.
Risk groups and treatment in children
The randomized comparison of ATRA plus ATO against ATRA plus chemotherapy, published in 2013, is what established the chemotherapy-free combination in adults with low- and intermediate-risk disease.
In children, the combination has been taken a step further. High-risk APL is defined by a white cell count of 10 × 10⁹/L or above; children present at or above that threshold — and with the microgranular morphological subtype — more often than adults do. The Children’s Oncology Group AAML1331 trial gave tretinoin (the drug name for ATRA) and arsenic trioxide without cytotoxic chemotherapy to standard-risk children, and the same two drugs plus 4 doses of idarubicin during induction to high-risk children; it reported 3 relapses and 1 death among 154 children, with no significant difference in outcome between the risk groups.
Prognosis
Cure rates for APL with ATRA and ATO are high — above 90% in the trial data for adults — and the same approach has transformed pediatric APL from the most lethal subtype to one of the most treatable. Relapse after remission induction occurred in about 2–4% of children in the pediatric trials, and with tretinoin- and arsenic trioxide-based therapy high-risk disease no longer carries a clearly worse outcome.
What makes that possible is a driver that two drugs can remove. Neuroblastoma, the embryonal tumor of the sympathetic nervous system, has no single driver of that kind to take out: its treatment is built on age, stage and biology instead, and it is a different problem from the leukemias in almost every respect.