The RAR receptor is dependent on retinoic acid for regulation of transcription.Eight other rare gene rearrangements have been described in APL fusing RARA to promyelocytic leukemia zinc finger (PLZF), nucleophosmin, nuclear matrix associated, signal transducer and activator of transcription 5b (STAT5B), protein kinase A regulatory subunit 1α (PRKAR1A), factor interacting with PAPOLA and CPSF1 (FIP1L1), BCL-6 corepressor or oligonucleotide/oligosaccharide-binding fold containing 2A (NABP1) genes. Some of these rearrangements are ATRA-sensitive or have unknown sensitivity to ATRA because they are so rare; STAT5B/RARA and PLZF/RARA are known to be resistant to ATRA.The fusion of PML and RARA results in expression of a hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cells DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC). Although the chromosomal translocation involving RARA is believed to be the initiating event, additional mutations are required for the development of leukemia.RARA/PLZF gene fusion produces a subtype of APL that is unresponsive to tretinoin therapy and less responsive to standard anthracycline chemotherapy hence leading to poorer long-term outcomes in this subset of patients. Diagnosis
Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of the blood film or a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. The presence of promyelocytes containing multiple Auer rods (termed faggot cells) on the peripheral blood smear is highly suggestive of acute promyelocytic leukemia.
This is associated with the development of dyspnea, fever, weight gain, peripheral edema and is treated with dexamethasone. The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes.The monoclonal antibody, gemtuzumab ozogamicin, has been used successfully as a treatment for APL, although it has been withdrawn from the US market due to concerns regarding potential toxicity of the drug and it is not currently marketed in Australia, Canada or the UK. Given in conjunction with ATRA, it produces a response in around 84% of patients with APL, which is comparable to the rate seen in patients treated with ATRA and anthracycline-based therapy. It produces less cardiotoxicity than anthracycline-based treatments and hence may be preferable in these patients. Maintenance therapy
After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy with methotrexate, mercaptopurine and ATRA. A significant portion of patients relapsed without consolidation therapy. In the 2000 European APL study, the 2-year relapse rate for those that did not receive consolidation chemotherapy (ATRA not included) therapy was 27% compared to 11% in those that did receive consolidation therapy (p<0.01). Likewise in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance.However, recent research on consolidation therapy following ATRA-ATO, which became the standard treatment in 2013, has found that maintenance therapy in low-risk patients following this therapy may be unnecessary, although this is controversial.