Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia

Abstract

The aim of this study was to determine the efficacy and safety of treatment of pediatric acute promyelocytic leukemia (APL) with single-agent arsenic trioxide (ATO). A total of 19 children (< 15 years of age) with newly diagnosed APL were treated with single-agent ATO for remission induction and postremission therapy. Seventeen of the children (89.5%) achieved complete hematologic remission, and 2 early deaths occurred from intracranial hemorrhage. ATO-induced leukocytosis was observed in 13 (68.4%) patients. Other ATO-related toxicities were minimal and transient. Postremission ATO therapy continued for 3 years; the most common side effect was ATO-induced neutropenia. With a median follow-up of 53 months (range, 23-76 months), the calculated 5-year overall survival and eventfree survival were 83.9% and 72.7%, respectively, which are comparable with results achieved by the use of ATRA plus chemotherapy, which is the standard therapy for APL. No chronic arsenic toxicity or second malignancies were found during the follow-up period, and arsenic retention was not significant in patients off treatment more than 24 months. IntroductionAcute promyelocytic leukemia (APL) accounts for approximately 10% of childhood acute myeloid leukemia. [1][2][3][4] APL is characterized by the French-American-British M3 subtype morphology, a distinctive immunophenotype, and, in the majority of cases, there is a t(15;17) chromosomal translocation that generates the promyelocytic leukemia-retinoic acid receptor-␣ (PML-RARa) fusion gene. This specific genetic lesion determines the unique response to treatment with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO). 5 Since the introduction of ATRA in the 1980s and ATO in the 1990s, the strategy for treating APL has shifted from conventional chemotherapy to cancer cell differentiation and cancer-targeted therapy. The combination of ATRA and anthracycline-based chemotherapy is currently the standard approach to treat newly diagnosed APL. With this regimen, the hematologic complete remission (HCR) rate has improved significantly, to more than 90%; 5-year disease-free survival is more than 70%. 5-10 However, some problems still remain; notably, ATRA-related side effects appear to be more pronounced in children than in adult patients, 4,11-13 the optimal postremission therapy still remains to be defined, and approximately 20% to 30% of patients eventually relapse and develop drug resistance.ATO has proven to be another highly effective agent in APL therapy. 14-21 ATO differs from ATRA because of its dual effects of inducing partial differentiation and apoptosis of APL cells. Although highly efficacious, ATO is most commonly used in refractory or relapsed APL for inducing remission. It has previously been shown that single-agent ATO is equally effective in inducing remission in newly diagnosed cases of adult APL. However, little is known about the use of single-agent ATO in the treatment of children with APL. The optimal dosage and route of administration during remission induction and ...

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“…48 Arsenic trioxide is highly efficacious in treatment of both newly diagnosed and relapsed acute promyelocytic leukemia; however, a number of studies describe the occurrence of cardiotoxicity when this drug is used in children. [49][50][51][52] Tyrosine Kinase Inhibitors. Tyrosine kinase inhibitors such as dasatinib, lapatinib, imatinib, and nilotinib have been implicated in prolonging the QT interval in adults, with an incidence of 1% to 10%.…”

Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL

“…The experience with ATO as a single agent reported in India, China, and Iran demonstrates that this agent is highly effective and treatment has acceptable toxicity. [37][38][39][40] Moreover, in the North American Leukemia Intergroup Study C9710, the addition of ATO to standard therapy with ATRA plus daunorubicin as consolidation resulted in significant improvement in the DSF and EFS of adult patients in all risk groups.…”

Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment

“…12 However, almost 5% of patients with APL treated with As 2 O 3 show As 2 O 3 refractory disease. 49 Because it is possible that a PML B2 mutation may be partly related to the As 2 O 3 refractory phenotype, repeated genetic analyses at several time points of the clinical course may be useful for predicting patients at high risk for a poor Figure 1A) and were used in this assay. PML nuclear bodies can be observed in the cells at diagnosis (i and iii), but at the terminal stage, PML and its fusion proteins were observed in the cytoplasm showing a diffuse pattern (iv and vi).…”