Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet

Abstract

Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

“…However, other studies have described cases with a good prognosis, or at least similar to that of APL patients with typical transcripts, even in the presence of atypical isoforms [67,72,78,80]. Therefore, according to the most recent recommendations, standard therapy should not be changed based on the PML-RARA isoforms [85].…”

“…To date, 12 molecular fusion variants of APL have been described, all involving the RARA gene [86] ( Table 2). The ZBTB16 (formerly PLZF)-RARA fusion, derived from the t(11;17)(q23;q21) rearrangement [87], has been reported in more than 30 patients, making it the most frequent APL molecular variant [85,86]. Other reported translocations led to the rearrangement of RARA gene with NPM1 [88], NUMA1 [89], STAT5B [90], PRKAR1A [91], FIP1L1 [92], BCOR [93], NABP1 (formerly OBFC2A) [94], TBL1XR1 (formerly TBLR1) [95], GTF2I [96], IRF2BP2 [97], and FNDC3B [98].…”

“…Other reported translocations led to the rearrangement of RARA gene with NPM1 [88], NUMA1 [89], STAT5B [90], PRKAR1A [91], FIP1L1 [92], BCOR [93], NABP1 (formerly OBFC2A) [94], TBL1XR1 (formerly TBLR1) [95], GTF2I [96], IRF2BP2 [97], and FNDC3B [98]. Although the detection of these APL molecular variants can escape standard molecular diagnosis, their characterization is essential for the appropriate management and treatment of patients, since a variable sensitivity to treatment has been reported [85] (Table 2).…”

Dual Inhibition of Pyruvate Dehydrogenase Complex and Respiratory Chain Complex Induces Apoptosis by a Mitochondria‐Targeted Fluorescent Organic Arsenical in vitro and in vivo

“…Arsenical had been used to treat with psoriasis, syphilis or rheumatism in China and Greece since two thousand years ago . To date the most dramatic finding in the history of arsenical drugs is that arsenic trioxide (ATO) was successfully used to treat acute promyelocytic leukemia (APL) in 1970 s . Nowadays, ATO and all‐trans retinoic acid (ATRA) have been the first‐line treatment regimens to trigger the cell redifferentiation or apoptosis‐inducing therapy for APL .…”

“…Arsenical had been used to treat with psoriasis, syphilis or rheumatism in China and Greece since two thousand years ago. [1] To date the most dramatic finding in the history of arsenical drugs is that arsenic trioxide (ATO) was successfully used to treat acute promyelocytic leukemia (APL) [2] in 1970 s. [3] Nowadays, ATO and all-trans retinoic acid (ATRA) have been the first-line treatment regimens to trigger the cell redifferentiation or apoptosis-inducing therapy for APL. [1c,4] Besides that ATO was approved to treat APL by the Food and Drug Administration (FDA) in 2000, [5] organic arsenicals darinaparsin (DAR) and 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) also have been approved by FDA to carry out the pre-clinical trials for the treatment of cancer, such as leukemia, lymphoma and solid tumor.…”