The Acute promyelocytic leukemia and the current treatment protocols

Received: 01-Oct-2021 Accepted Date: Oct 15, 2021 ; Published: 26-Oct-2021

Introduction

Gastric 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 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 and/or survival advantage to hematopoietic progenitor cells. Acute promyelocytic leukemia has very unique molecular and biological characteristics than other types of acute leukemia which has 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. 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 down regulation 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. Arsenic Trioxide is an excellent chemotherapeutic agent for relapsed or refractory subjects previously treated with Acid. Additionally, ATO reduces the risks of transplantation-associated complications. Allogeneic 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 basis 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 embryo toxic 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. 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.