Isha Talwar* and Ajay
Department of Medical Science, Glocal University,Uttar Pradesh, India
Received date: February 25, 2020; Manuscript No. IPAPP-20-3473; Editor assigned date: February 28, 2020; PreQC No. IPAPP-20-3473 (PQ); Reviewed date: March 13, 2020; QC No. IPAPP-20-3473; Revised date: June 28, 2022; QI No. IPAPP-20-3473 (QI); Manuscript No. IPAPP-20-3473 (R); Published date: July 26, 2022, DOI: 10.36648/2393-88126.96.36.199
Citation: Talwar I, Ajay (2022) Acute Promyelocytic Leukemia:Current Treatment Protocols. Am J Pharmacol Pharmacother Vol.9 No.4: 20
Acute promyelocytic leukemia is a distinct subtype of acute myelocytic leukemia. It has distinct genetic and molecular profile than other acute leukemia subtypes. Due to its distinct molecular signature, the chemotherapeutic regimens utilized bear distinct treatment protocols. Various chemotherapeutic agents used include all-trans-retinoic acid, arsenic trioxide and taxanes. Recently, immunotherapy has been implored as a possible treatment protocol but with limited success.
Acute promyelocytic leukemia; All-trans-retinoid acid; Arsenic trioxide; Taxanes
Acute Promyelocytic Leukemia (APL) was first described as a distinct subtype of acute myeloid leukemia by Leif Hillestad in 1957. According to French-American-British classification, it is designated as ‘M3’ subtype. This disease is characterized by accumulation of abnormal Promyelocytes, fibrinogenopenia, disseminated intravascular coagulation and chromosomal translocation t (15; 17) (q22; q21). It accounts for 10%-15% of all cases of acute myeloid leukemia .
Arsenic is a naturally occurring substance existing in both organic and inorganic forms. Multiple studies have reported 85%-90% complete remission in Arsenic Trioxide-treated in both first time diagnosed as well as relapsed acute promyelocytic leukemia. After achieving complete remission, a molecular remission which is demonstrated by negative detection of promyelocytic leukemia RA receptor α (PML-RAR α) transcript .
Over 95% APL patients demonstrate t (15; 17) (q22; q21) translocation which results in fusion of RARα gene on 17q21 and Promyelocytic Leukemia (PML) gene on 15q22, which produces a PML-RARα fusion transcript. The PML-RARα chimeric protein prevents the activation of primary target genes required for normal myeloid differentiation. PML-RARα confers proliferation or survival advantage to hematopoietic progenitor cells.
Acute promyelocytic leukemia has very unique molecular and biological characteristics than other types of acute leukemias which have led to significantly different therapeutic approaches. Though the hematological, cytogenetic and molecular features in elder patients are similar to younger adults, the prognosis is poorer in older subjects due to cardiomyopathy .
Mechanisms of action o f all-trans-retinoic ac id and arsenic trioxide
ATRA as a single chemotherapeutic agent acts by inducing terminal differentiation of APL blasts into mature granulocytes thereby contributing to 80% Clinical Remission (CR). However, long-term relapses have been observed with single drug therapy. Combinations of both ATRA and ATO have demonstrated a higher CR rate of 92% in a median follow-up of 99 weeks .
There appear to be multiple mechanism of action for ATO therapy against APL. These include partial cellular differentiation and induction of apoptosis by downregulation of bcl-2 protein along with PML-RARα protein degradation .
Both Arsenic Trioxide (ATO) and All-Trans-Retinoic Acid (ATRA) act by degradation and cleaving of the PML-RARα oncoprotein. The PML-RARα catabolism differs for ATRA and ATO. ATRA targets the RARα moiety of the fusion protein while ATO targets the PML moiety. Thus, the synergistic effect of both the drugs can be used to treat APL. Studies have demonstrated that combined therapy of ATRA and ATO produce better results than either drug used alone .
Complications of ATRA and/or ATO chemotherapy
Common treatment-related complications associated with ATRA and/or ATO use in APL include:
• Differentiation syndrome (retinoic acid syndrome). It is a potentially fatal complication occurring within first few days or weeks after onset of ATRA and/or ATO therapy. Complex signs and symptoms include-unexplained fever, dyspnea, hypotension, acute renal failure and peripheral edema. Due to this reason, most ATRA/ATO regimens include steroid prophylaxis.
• Pseudotumor cerebri is a complication of ATRA therapy most commonly observed in children and adolescents. It is characterized by headache and alteration in cerebrospinal fluid.
• QTs prolongation leading to ventricular arrhythmia may be potentially fatal complication of ATO therapy.
• Hepatotoxicity has also been reported in subject with ATO with or without ATRA in 60% of subjects undergoing treatment.
• It is a well-known side-effect of subjects on ATO and/or ATRA chemotherapy.
Diagnostic criteria of acute promyelocytic leukemia
At the time of diagnosis of APL, a WBC count of >10,000/μl and a platelet count of <40,000/μl indicates an adverse prognosis. For APL subjects in CR, minimal residual disease can be detected by analyzing the PML-RARα mRNA transcript of RTPCR. Thus, a molecular monitoring should be conducted at regular intervals. Those subjects exhibiting a second positive test within two or four weeks should be treated for disease relapse [11,12].
Classification of APL relapse is as below:
• WBC count- <10 × 109/L; Platelet count- >40 × 109/L.
• WBC count- <10 × 109/L; Platelet count- <40 × 109/L.
• WBC count- >10 × 109/L.
Advantage of arsenic trioxide over all-trans-retinoic acid
Arsenic trioxide is an excellent chemotherapeutic agent for relapsed or refractory subjects previously treated with all-transretinoic acid. Additionally, ATO reduces the risks of transplantation-associated complications. Allogenic bone marrow transplant patients undergoing ATO maintenance therapy exhibit effectiveness against minimal residual disease.
Though it is effective, precautions should be taken on prescribing the drug before or after bone marrow transplantation as it can prolong the QT/QTc interval. Therefore, ATO therapy should be restricted 30 days immediately prior to as well as after transplantation .
Intracranial hemorrhage caused as a result of disseminated intravascular coagulation, fibrinolysis, hypercoagulability, thrombocytopenia and proteolysis is a major cause of mortality in acute promyelocytic leukemia. However, it has been observed that ATRA therapy has a distinct advantage due to reduction of hemorrhagic episodes seen in acute promyelocytic leukemia .
As per modern guidelines, when acute promyelocytic leukemia diagnosis is suspected, All-Trans-Retinoic Acid (ATRA) therapy along with plasma and platelet transfusions and genetic confirmation is started. It has also been recommended that ATRA therapy should be immediately initiated on the This article is avbasis of clinical as well as morphological diagnosis. ATO with ATRA can be incorporated in induction as well as consolidation therapies for APL. ATO though an effective alternative drug has its disadvantage in being an embryotoxic agent due to which it cannot be prescribed during pregnancy. However, long-term safety of this drug is questionable as development of solid tumors has been reported sporadically in subjects undergoing ATO therapy [15-18].
Current therapy protocols in acute promyelocytic leukemia patients use specific drugs such as- ATRA and ATO in combination with chemotherapeutic drugs such as anthracyclins. But the use of these drugs is not cost-effective for patients belonging to developing countries .
Arsenic trioxide has been demonstrated to bear similar effect as conventional dosage with reduced side-effects. The low-dose regime also acts by inducing differentiation of acute promyelocytic leukemic blast cells. Besides this, arsenic trioxide has proven efficient in relapsed acute promyelocytic leukemia cases with high clinical remission rate along with alteration of abnormal coagulopathy [20-23].
It can be drawn from various studies and evidence available that Arsenic trioxide is the drug of choice in acute promyelocytic leukemia as it benefits afflicted subjects with minimal side effects even so when compared with conventional drug therapy.