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| Acute promyelocytic leukemia | |
|---|---|
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| Bone marrow smear from a patient with acute promyelocytic leukemia, showing characteristic abnormalpromyelocytes.[1] | |
| Specialty | Hematology andoncology |
| Usual onset | ~40 years old[2] |
| Causes | Uncontrolled proliferation ofpromyelocytes[2] |
| Prognosis | 80-90% five-year survival rate |
| Frequency | Develops in about 600 to 800 people per year (United States)[2] |
Acute promyelocytic leukemia (APML,APL) is a subtype ofacute myeloid leukemia (AML), acancer of thewhite blood cells.[3] In APL, there is an abnormal accumulation of immaturegranulocytes calledpromyelocytes. The disease is characterized by a t(15;17)chromosomal translocation[4] involving theretinoic acid receptor alpha (RARA) gene and is distinguished from other forms of AML by its responsiveness toall-trans retinoic acid (ATRA; also known as tretinoin) therapy. Acute promyelocytic leukemia was first characterized in 1957[5][6] by French and Norwegian physicians as a hyperacute fatal illness,[3] with a median survival time of less than a week.[7] Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study.[8][7][9]
The symptoms tend to be similar to AML in general with the following being possible symptoms:[10]
Easy bleeding from low platelets may include:
Acute promyelocytic leukemia is characterized by a chromosomal translocation involving theretinoic acid receptor alpha (RARA) gene onchromosome 17.[3] In 95% of cases of APL, theRARA gene on chromosome 17 is involved in a reciprocal translocation with thepromyelocytic leukemia gene (PML) onchromosome 15, a translocation denoted as t(15;17)(q22;q21).[3] The RAR receptor is dependent onretinoic acid for regulation of transcription.[3]
Eight other rare gene rearrangements have been described in APL fusingRARA topromyelocytic leukemia zinc finger (PLZF),[11]nucleophosmin, nuclear matrix associated,signal transducer and activator of transcription 5b (STAT5B), protein kinase A regulatory subunit 1α (PRKAR1A), factor interacting withPAPOLA andCPSF1 (FIP1L1),BCL-6 corepressor oroligonucleotide/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.[3]
The fusion ofPML andRARA results in expression of a hybrid protein with altered functions. Thisfusion 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 (NCOR) molecule andhistone deacetylase (HDAC). Although the chromosomal translocation involvingRARA is believed to be the initiating event, additional mutations are required for the development ofleukemia.[3]
RARA/PLZFgene fusion produces a subtype of APL that is unresponsive to tretinoin therapy and less responsive to standard anthracyclinechemotherapy hence leading to poorer long-term outcomes in this subset of patients.[3]
Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of theblood film or abone marrow aspirate or biopsy as well as finding the characteristic rearrangement. The presence of promyelocytes containing multipleAuer rods (termedfaggot cells) on the peripheral blood smear is highly suggestive of acute promyelocytic leukemia. Definitive diagnosis requires testing for the PML/RARA fusion gene. This may be done bypolymerase chain reaction (PCR),fluorescencein situ hybridization, or conventionalcytogenetics of peripheral blood or bone marrow. This mutation involves a translocation of the long arms ofchromosomes 15 and 17. On rare occasions, a cryptic translocation may occur which cannot be detected bycytogenetic testing; on these occasions PCR testing is essential to confirm the diagnosis.[3]
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APL is unique among leukemias due to its sensitivity toall-trans retinoic acid (ATRA; tretinoin), the acid form ofvitamin A.[3] In the early 1980s, sporadic reports of the use of 13-cis RA in APL appeared. The group from the Shanghai Institute of Hematology was the first to use a different, all-trans form of RA for treating APL which resulted in complete remission without developing marrow aplasia(Huang ME, Ye YC, Chen SR...Wang ZY. Use of all trans retinoid acid in the treatment of acute promyelocytic leukemia. Blood 1988, 72:567). Treatment with ATRA dissociates the NCOR-HDAC 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.[3] Unlike other chemotherapies, ATRA does not directly kill themalignant cells.[3] 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 inducingremission but it is short-lived in the absence of concurrent "traditional" chemotherapy.[3] As of 2013 the standard of treatment for concurrent chemotherapy has becomearsenic trioxide, which combined with ATRA is referred to ATRA-ATO;[13][14] before 2013 the standard of treatment wasanthracycline (e.g.daunorubicin,doxorubicin,idarubicin ormitoxantrone)-based chemotherapy. Both chemotherapies result in a clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile.[8]
ATRA therapy is associated with the unique side effect ofdifferentiation syndrome.[15] This is associated with the development ofdyspnea, fever, weight gain,peripheral edema and is treated withdexamethasone.[16] The etiology of retinoic acid syndrome has been attributed tocapillary leak syndrome fromcytokine release from the differentiating promyelocytes.[16]
Themonoclonal antibodygemtuzumab ozogamicin has been used successfully as a treatment for APL,[17] although it was withdrawn from the US market in 2010 due to concerns regarding potential toxicity of the drug and was not marketed in Australia, Canada or the UK.[17][18] In 2017, it was reapproved for use in the US[19][20] and EU.[21] 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.[17] It produces lesscardiotoxicity than anthracycline-based treatments and hence may be preferable in these patients.[17]
According to recent updates, the combination of ATRA and arsenic trioxide (ATO) is now preferred for induction therapy in many cases, offering at least as effective results with fewer side effects compared to traditional chemotherapy.[22] In cases of relapse, options include re-treatment with ATO or the targeted drug gemtuzumab ozogamicin (Mylotarg).[23]
After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy withmethotrexate,mercaptopurine and ATRA.[24] A significant portion of patients relapsed withoutconsolidation therapy.[16] 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).[25] Likewise, in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance.[26]
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.[14]
In 1998,Arsenic trioxide (As2O3) had been evaluated for treatment of relapsed/refractory disease. Remission with arsenic trioxide has been reported.[27]Studies have shown arsenic reorganizesnuclear bodies and degrades the mutant PML-RAR fusion protein.[27] Arsenic also increases caspase activity which then inducesapoptosis.[27]
Arsenic trioxide (As2O3) can also reduce the relapse rate for high risk patients.[28] InJapan a synthetic retinoid,tamibarotene, is licensed for use as a treatment for ATRA-resistant APL.[29]
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Some evidence supports the potential therapeutic utility ofhistone deacetylase inhibitors such asvalproic acid orvorinostat in treating APL.[30][31][32] According to one study, a cinnamon extract has effect on the apoptotic process in acute myeloid leukemiaHL-60 cells.[33]
Prognosis is generally good relative to other leukemias. Because of the acuteness of onset compared to other leukemias, early death is comparatively more common. If untreated, it has median survival of less than a month. It has been transformed from a highly fatal disease to a highly curable one. The cause of early death is most commonly severe bleeding, oftenintracranial hemorrhage. Early death from hemorrhage occurs in 5–10% of patients in countries with adequate access to healthcare and 20–30% of patients in less developed countries. Risk factors for early death due to hemorrhage include delayed diagnosis, late treatment initiation, and highwhite blood cell count on admission.[34] Despite advances in treatment, early death rates have remained relatively constant, as described by several groups including Scott McClellan, Bruno Medeiros, andAsh Alizadeh atStanford University.[35]
Relapse rates are extremely low. Most deaths following remission are from other causes, such as second malignancies, which in one study occurred in 8% of patients. In this study, second malignancies accounted for 41% of deaths, and heart disease, 29%. Survival rates were 88% at 6.3 years and 82% at 7.9 years.[36]
In another study, 10-year survival rate was estimated to be approximately 77%.[8]
Acute promyelocytic leukemia represents 10–12% of AML cases.[17] The median age is approximately 30–40 years,[37] which is considerably younger than the other subtypes of AML (70 years), however in elderly population APL has peculiar characteristics.[38] Incidence is higher among individuals of Latin American or South European origin.[39] It can also occur as a secondary malignancy in those that receive treatment withtopoisomerase II inhibitors (such as theanthracyclines andetoposide) due to the carcinogenic effects of these agents, with patients withbreast cancer representing the majority of such patients.[40][41][42] Around 40% of patients with APL also have achromosomal abnormality such astrisomy 8 or isochromosome 17 which do not appear to impact on long-term outcomes.[3]
In 1998, researchers at theUniversity of Hong Kong revived oral arsenic or the “modern” liquor arsenicalis to treat APL patients. The research group from the University of Hong Kong andQueen Mary Hospital did a series of works to observe the clinical effect of oralarsenic trioxide. They proposed that oral arsenic trioxide had a short-term efficacy and safety profile similar to intravenous arsenic trioxide. They then found that oral arsenic trioxide, particularly in prolonged maintenance with andATRA may obviate the need ofstem cells transplantation in relapsed pediatric APL individuals. Their recent findings proposed a triple combination regimen withoral arsenic trioxide, ATRA, andascorbic acid maintenance, which was safe and resulted in favorable long-term survival. As of 2023[update] they are still testing this strategy prospectively to further rigorously assess its long-term effects. Gill et al. reported the results of a clinical study of newly-diagnosed APL from 1991 to 2021. They found that oral arsenic trioxide-based regimens significantly improved all survivals of APL individuals. In view of these findings, arsenic trioxide (intravenous or oral) may be incorporated into all phases of treatment. In addition, the use of an entirely nonchemotherapy in elderly patients can also be explored to reduce drug toxicity.[43]
As of 2023[update] another oral arsenic compound,Realgar-Indigo naturalis formula (RIF) with the chemical formula of As4S4, has been shown promising for APL treatment, including the adult, pediatric and elderly APL patients, by researchers in China.[43]
Hence, ATRA-ATO for induction and consolidation has emerged as the new standard of care for patients with low-(to-intermediate) risk acute promyelocytic leukemia. ATRA-ATO therapy is also a reasonable choice for patients with severe comorbidities, older adults, patients with cardiac dysfunction who cannot tolerate anthracycline-based regimens or overall poor functional status. Maintenance therapy after the initial consolidation is widely debated. Maintenance may not be necessary for patients receiving intensive induction/consolidation including ATO.
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