Acute promyelocytic leukemia
Acute promyelocytic leukemia is the M3 subtype of acute myelogenous leukemia, a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene and is distinguished from other forms of AML by its responsiveness to all-trans retinoic acid therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness. Currently it is one of the most treatable forms of leukemia with a 12-year progression-free survival rate that is estimated to be approximately 70%. Signs and symptoms The symptoms tend to be similar to AML in general with the following being possible symptoms: Easy bleeding from low platelets may include: Bruising Gingival bleeding Nose bleeds Increased menstrual bleeding Pathogenesis Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor-alpha gene on chromosome 17. In 95% of cases of APL, retinoic acid receptor-alpha gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene on chromosome 15, a translocation denoted as t(15;17)(q22;q12). 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, nucleophosmin(NPM1), nuclear matrix associated, signal transducer and activator of transcription 5b, protein kinase A regulatory subunit 1α, factor interacting with PAPOLA and CPSF1, BCL6 corepressor or oligonucleotide/oligosaccharide-binding fold containing 2A 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 cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor molecule and histone deacetylase. Although the chromosomal translocation involvingRARA is believed to be the initiating event, additional mutations are required for the development of leukemia. RAR-α/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 morphologic examination of a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. Definitive diagnosis requires testing for the PML/RARA fusion gene. This may be done by polymerase chain reaction, fluorescent in situ hybridization, or conventional cytogenetics of peripheral blood or bone marrow. This mutation involves a translocation of the long arm chromosomes of 15 and 17. On rare occasions, a cryptic translocation may occur which cannot be detected by cytogenetic testing; on these occasions PCR testing is essential to confirm the diagnosis. Presence of multiple Auer rods on peripheral blood smear is highly suggestive of acute promyelocytic leukemia.
Treatment = Initial treatment = APL is unique among leukemias due to its sensitivity to all-trans retinoic acid, the acid form of vitamin A. Treatment with ATRA dissociates the NCOR-HDACL complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells. ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own.
ATRA alone is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy. As of 2013 the standard of treatment for concurrent chemotherapy has become Arsenic trioxide, before 2013 the standard of treatment was anthracycline-based chemotherapy. Both chemotharapies result in a clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile. ATRA therapy is associated with the unique side effect of retinoic acid syndrome.
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.
It given in conjunction with ATRA 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 is induced, the standard of care is to undergo 2 years of Maintenance chemotherapy with methotrexate, mercaptopurine and ATRA. A significant portion of patients will relapse without consolidation therapy. In the 2000 European APL study, the 2-year relapse rate for those that did not receive consolidation chemotherapy therapy was 27% compared to 11% in those that did receive consolidation therapy (p.
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