Long-term outcome of relapsed acute promyelocytic leukemia treated with oral arsenic trioxide-based reinduction and maintenance regimens: A 15-year prospective study

AbstractArsenic trioxide, as a single agent, has proven efficacy in inducing molecular remission in patients with acute promyelocytic leukemia (APL). There is limited long-term outcome data with single-agent As2O3 in the management of newly diagnosed cases of APL. Between January 1998 to December 2004, 72 newly diagnosed cases of APL were treated with a regimen of single-agent As2O3 at our center. Complete hematologic remission was achieved in 86.1%. At a median follow-up of 25 months (range: 8-92 months), the 3-year Kaplan-Meier estimate of EFS, DFS, and OS was 74.87% ± 5.6%, 87.21% ± 4.93%, and 86.11% ± 4.08%, respectively. Patients presenting with a white blood cell (WBC) count lower than 5 × 109/L and a platelet count higher than 20 × 109/L at diagnosis (n = 22 [30.6%]) have an excellent prognosis with this regimen (EFS, OS, and DFS of 100%). The toxicity profile, in the majority, was mild and reversible. After remission induction, this regimen was administered on an outpatient basis. Single-agent As2O3, as used in this series, in the management of newly diagnosed cases of APL, is associated with responses comparable with conventional chemotherapy regimens. Additionally, this regimen has minimal toxicity and can be administered on an outpatient basis after remission induction.

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Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy

Leukemia ◽

10.1038/leu.2017.178 ◽

2017 ◽

Vol 32 (1) ◽

pp. 21-29 ◽

Cited By ~ 11

Author(s):

D Martínez-Cuadrón ◽

◽

P Montesinos ◽

E Vellenga ◽

T Bernal ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Older Patients ◽

De Novo ◽

Promyelocytic Leukemia ◽

Newly Diagnosed ◽

Term Outcome ◽

Long Term Outcome

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Oral Arsenic Trioxide, ATRA and Ascorbic Acid (AAA) Maintenance Following First Complete Remission in Acute Promyelocytic Leukemia - Long-Term Data and Unique Prognostic Indicators

Blood ◽

10.1182/blood-2019-125185 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3853-3853

Author(s):

Harinder Gill ◽

Rita Yim ◽

Cyrus R Kumana ◽

Yok-Lam Kwong

Keyword(s):

Ascorbic Acid ◽

Complete Remission ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Univariate Analysis ◽

Promyelocytic Leukemia ◽

Cns Involvement ◽

Long Term Outcome ◽

First Complete Remission

Background Oral arsenic trioxide (oral-As2O3)-based regimens are highly effective in the treatment of newly-diagnosed or relapsed acute promyelocytic leukemia (APL)1,2. Data on the long-term outcome of patients who received prolonged maintenance with oral-As2O3-based regimens in first complete remission (CR1) following non-arsenic-based induction is lacking. Methods Patients aged ≥ 18 years with APL in first complete remission (CR1) were recruited for maintenance treatment with oral-As2O3 (10mg/day), all-trans-retinoic acid (ATRA) (45mg/m2/day in 2 divided doses), ascorbic acid (1g/day) (AAA). AAA was administered for 2 weeks every 2 months for a total of 2 years. Prior induction treatment comprised ATRA (45mg/m2/day in 2 divided doses for 42 days) and daunorubicin (50mg/m2/day for 3 days). Consolidation comprised 2 monthly cycles of daunorubicin (50 mg/m2/day for 2 days) and cytarabine (100 mg/m2/day for 5 days). Daunorubicin induction and consolidation chemotherapy were omitted in patients aged ≥ 70 years or those with cardiac co-morbidities. Results Between 1 August 2002 and 31 July 2019, 129 patients (63 men and 66 women) with a median age of 46 (18-82) years underwent maintenance with AAA. After a median follow-up of 100 (8-215) months, 117 (90.1%) patients completed 2 years of AAA maintenance. Seventeen (13.2%) patients relapsed after a median of 19 (17-96) months from CR1 (morphologic relapse, N=14; molecular relapse; N=3). Two patients had central nervous system (CNS) involvement at first relapse (R1). There were 13 (10.1%) deaths. Five patients died from refractory APL. Eight patients died in remission (pneumonia, N=4; acute myocardial infarction, N=2; second malignancy, N=2). The 5-year and 10-year relapse-free survival (RFS) were 88.8% and 85.1% respectively. The 5-year and 10-year overall survival (OS) were 94.2% and 87.4%. On univariate analysis, PML-RARA bcr3 (short) isoform (P=0.02), FLT3-ITD (P=0.005) and CNS involvement at diagnosis (P=0.002) were associated with worse RFS. On multivariate analysis, FLT3-ITD (P=0.005) and central nervous system (CNS) involvement at diagnosis (P=0.004) were associated with worse RFS. On univariate analysis, PML-RARA bcr3 isoform (P=0.03), FLT3-ITD (P=0.01) and relapsed APL (P=0.002) were associated with worse OS. On multivariate analysis, therapy-related APL (P=0.03), FLT3-ITD (P=0.03) and relapsed APL (P=0.03) were associated with worse OS. Grade 1 leucopenia occurred in 7 (5.4%). The commonest non-hematological toxicity was headache and occurred in 38 (29.5%) (Grade 1/2, N=38; Grade 3/4, N=0). Grade 1 hepatoxicity occurred in 7 (5.4%) patients during AAA maintenance. Cutaneous herpes zoster infection occurred in 6 (4.7%) patients. Conclusion Maintenance therapy with oral-As2O3, ATRA and ascorbic acid in CR1 was safe and resulted in excellent long-term survivals in APL. References: 1. Gill H, Yim R, Lee HKK, Mak V, Lin SY, Kho B et al. Long-term outcome of relapsed acute promyelocytic leukemia treated with oral arsenic trioxide-based reinduction and maintenance regimens: A 15-year prospective study. Cancer 2018; 124(11): 2316-2326. 2. Gill H, Kumana CR, Yim R, Hwang YY, Chan TSY, Yip SF et al. Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5-year prospective study. Cancer 2019 [Epub]. Figure Disclosures No relevant conflicts of interest to declare.

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Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00205-6 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Yu Zheng ◽

Yuan-Fei Mao ◽

Hui-Jin Zhao ◽

Li Chen ◽

Li-Ning Wang ◽

...

Keyword(s):

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Arsenic Speciation ◽

Promyelocytic Leukemia ◽

Chronic Liver ◽

Dimethylarsinic Acid ◽

Metabolic Pattern ◽

Methylation Index ◽

Arsenic Methylation

Abstract Background Arsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO. Methods A total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAsIII, inorganic arsenate (iAsV), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients’ plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+ 3 oxidative state) methylation transferase (AS3MT) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method. Results The study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAsIII in patient’s urine (40.08% vs. 1.94%, P < 0.001), hair (29.25% vs. 13.29%, P = 0.002) and nails (30.21% vs. 13.64%, P = 0.003) than the healthy controls’, indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28, P = 0.047) and hepatic steatosis (0.19 vs. 0.3, P = 0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of the AS3MT gene were associated with impaired urine secondary methylation index (SMI). Conclusions The long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs of AS3MT gene should be considered when determining the dosage of ATO.

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