Science
Acute promyelocytic leukemia (APL) is a unique acute myeloid leukemia (AML) subtype accounting for 5‑10% of AML cases. APL is a biologically and clinically distinct variant of AML caused by arrest of leukocyte differentiation at the promyelocyte stage. It is distinguished from all other forms of acute leukemia by unique cytogenetics, clinical and biologic characteristics.
The APL blasts are characterized by typical morphology and by the presence of the recurrent balanced chromosomal translocation t(15;17)(q21;q22) generating the fusion genes PML/RARα _and RARα/PML.
- Current WHO system classification: t(15;17)(q24.1;q21.1); PML-RARA
- Older French-American-British (FAB) system classification: AML-M3.
Classical APL M3 morphology. Atypical promyeloctes with hypergranular cytoplasm (often with Auer rods) and often bilobed nuclei
When a diagnosis of APL is suspected based on clinical presentation and/or morphology, treat the disease as a medical emergency.
Many patients die before reaching a reference center or an experienced hematologist, therefore the rate of patients dying early is underestimated in prospective clinical trials. However, if patients do not experience early life-threatening events the reported cure rates in APL are the highest among acute leukemias of the adult.
Treatment of APL is staged, e.g. Induction therapy, Consolidation therapy and Maintenance therapy – and may span 1-3 years. Each therapeutic stage has a different objective:
Objectives of the Therapeutic Stages for Treatment of APL
- Objective of induction therapy: Achieve complete hematological remission (CR).
- Objective of consolidation therapy: Maintain the CR achieved during induction therapy and prevent the risk of relapse, and so induction therapy is followed by post-remission therapy.
- Objective of maintenance therapy: Achieve molecular remission to provide long-term disease-free survival (DFS).
Pathophysiology
The “normal” retinoic acid alpha receptor (RARA) gene, encoded by the long arm of chromosome 17, is mainly expressed in hematopoietic cells and is important in regulating gene expression. If retinoid acid is absent, nuclear co-repressor factor binds to RARA causing transcriptional repression. If retinoic acid is present, RARA is activated prompting terminal differentiation of the myeloid compartment.
The ubiquitously expressed promyelocytic (PML) gene, encoded by the long arm of chromosome 15, is an important tumor suppressor gene involved in several key cellular processes like senescence and apoptosis.
Over 95% of APL cases are characterized by a balanced translocation between chromosome 17q21 and chromosome 15q22, leading to production of the abnormal fusion gene PML‑RARA. PML‑RARA oncoprotein is able to recruit the nuclear co-repressor complex with higher affinity as compared to the physiological counterpart RARA. This binding causes transcriptional repression of multiple genes and overall the repression of retinoic acid signaling which ultimately leads to differentiation block of leukemic cell at the stage of promyelocytes. The fusion gene product, PML‑RARA, causes the retinoic acid receptor to bind more tightly to the nuclear co-repressor factor, hence the gene cannot be activated with physiologic doses of retinoic acid.
The PML-RARA translocation is detectable by conventional karyotyping (although cases harbouring cryptic translocations can be missed with this technique) or fluorescence in situ hybridization (FISH) studies; the fusion transcript PML‑RARA is detectable by polymerase chain reaction (PCR) techniques.
There are three possible PML-RARA isoforms generated by t(15;17) translocations. The breakpoint region in RARa gene is consistently located in intron 2, but can vary within PML locus. The three breakpoints on the PML gene can occur at intron 3 (L form), intron 6 (S form) or exon 6 (V form) and their identification is important for subsequent MRD monitoring
In less than 5% of cases, rearrangements of RARa gene occur with a gene partner different from PML:
- PZLF (promyelocytic zinc finger) t(11;17)(q23;q21)
- NPM (nucleophosmin) t(5;17)(q35;q12-21)
- NuMa (nuclear mitotic apparatus) t(11;17)(q13;q21)
- STAT5b (17;17)(q11;q21)
- IRF2BP2 (interferon regulatory factor 2 binding protein 2) t(7;16)(q31’q22), t(15;17)(q22;q21)
The list of gene partners should not be considered exhaustive. The fusion partner significantly impacts disease characteristics and response to therapy. For example, APL with PLZF-RARA is insensitive to retinoic acid and less sensitive than APL to conventional chemotherapy.
About 40% of APL patients express additional chromosomal abnormalities (trisomy 8 and isochromosome 17) that do not appear to impact their overall prognosis.
Epidemiology
Approximately 600 to 800 new cases of APL are diagnosed annually in the USA. APL is equally incident in both sexes, and is estimated at 6 cases per 10 million people, with some variability between ethnic groups. In the UK and Scandinavia, APL represents approximately 10% of all AML cases; in Italy estimated incidence is 11.5%; in Spain it ranges from 12% in the north to 21% in the south. Populations from Latin America have a higher incidence of APL of 20-30%.
Age-associated incidence for APL is markedly lower than for other AMLs, with incidence peaking at about 40 years.