Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial

Iland, Harry; Collins, Marnie; Bradstock, Ken; Supple, Shane G.; Catalano, Alberto; Hertzberg, Mark; Browett, Peter; Grigg, Andrew; Firkin, Frank; Campbell, Lynda J.; Hugman, Amanda; Reynolds, John; Iulio, Juliana Di; Tiley, Campbell; Taylor, Kerry; Filshie, Robin; Seldon, Michael; Taper, John; Szer, Jeff; Moore, John J.; Bashford, John; Seymour, John F.

doi:10.1016/s2352-3026(15)00115-5

Cited by 141 publications

(137 citation statements)

References 30 publications

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“…4 Pivotal studies have demonstrated the superiority of arsenic trioxide (ATO) in combination with ATRA for all APL patients in all risk groups. [5][6][7][8][9] ATO in combination with ATRA is now approved by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for use as first line therapy in adult patients with low-and intermediate-risk APL and as second-line therapy in relapsed APL patients. 10,11 Although the ATO and ATRA regimen in some studies appear to be efficient and well-tolerated in pediatric APL patients, it is still not recommended in children.…”

Section: Introductionmentioning

confidence: 99%

Addressing the room for improvement in management of acute promyelocytic leukemia

Nørgaard

Friis

Kristensen

et al. 2019

European J of Haematology

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Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population. Objectives and methods: We used the comprehensive Danish National AcuteLeukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and longterm clinical outcome in APL between 2000 and 2014.Results: Twenty-two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04-0.86, P = 0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz-score were independent prognostic variables. Conclusions:The very low EDR for on-trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL. K E Y W O R D Sacute promyelocytic leukemia, diagnostic awareness, early death, prognosis

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Section: Introductionmentioning

confidence: 99%

Addressing the room for improvement in management of acute promyelocytic leukemia

Nørgaard

Friis

Kristensen

et al. 2019

European J of Haematology

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“…The early death rate was lower than in the APML3 trial, but not significantly so (3.2% vs 7.1%, P =0.29), while achieving a CR rate of 95% and a 2-year DFS of 97.5% 38. After a median follow-up of 4.2 years, there was a significant improvement in 5-year OS (94%, P =0.02; Figure 1), DFS (95%, P =0.001; Figure 2) and EFS (90%, P =0.02) when compared to APML3 41. In addition, high-risk patients in the APML4 trial appeared to benefit as the freedom from relapse was not significantly different between risk groups (Figure 3).…”

Section: The Arsenic Eramentioning

confidence: 91%

“…In addition, non-high-risk patients treated with ATRA-ATO in the UK AML17 trial achieved a 4-year OS of 95% with an overall 4-year cumulative incidence of morphological relapse of 1% in the ATRA-ATO arm despite no maintenance therapy 40. In the APML4 trial,38,41 the lack of significant difference in the freedom from relapse between high- and non-high-risk patients appears to be the result of the ATRA-ATO-Ida induction and prolonged ATRA-ATO consolidation, not a historical maintenance regimen. In the era of oral ATRA-arsenic therapy, it may be that prolonged oral consolidation or maintenance therapy will prove useful in high-risk patients in combination with less chemotherapy intensive regimens.…”

Section: The Role Of Maintenancementioning

confidence: 99%

Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives

McCulloch

Brown

Iland

2017

OTT

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Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique morphological appearance, associated coagulopathy and canonical balanced translocation of genetic material between chromosomes 15 and 17. APL was first described as a distinct subtype of AML in 1957 by Dr Leif Hillestad who recognized the pattern of an acute leukemia associated with fibrinolysis, hypofibrinogenemia and catastrophic hemorrhage. In the intervening years, the characteristic morphology of APL has been described fully with both classical hypergranular and variant microgranular forms. Both are characterized by a balanced translocation between the long arms of chromosomes 15 and 17, [t(15;17)(q24;q21)], giving rise to a unique fusion gene PML-RARA and an abnormal chimeric transcription factor (PML-RARA), which disrupts normal myeloid differentiation programs. The success of current treatments for APL is in marked contrast to the vast majority of patients with non-promyelocytic AML. The overall prognosis in non-promyelocytic AML is poor, and although there has been an improvement in overall survival in patients aged <60 years, only 30%–40% of younger patients are still alive 5 years after diagnosis. APL therapy has diverged from standard AML therapy through the empirical discovery of two agents that directly target the molecular basis of the disease. The evolution of treatment over the last 4 decades to include all-trans retinoic acid and arsenic trioxide, with chemotherapy limited to patients with high-risk disease, has led to complete remission in 90%–100% of patients in trials and rates of overall survival between 86% and 97%.

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“…Two pilot studies have proven the high efficacy of chemotherapy-free regimens based on As 2 O 3 in newly diagnosed APL 35,36. Subsequently, several recent reports provide evidence of the efficacy and safety of ATRA plus As 2 O 3 , with or without a chemotherapy protocol, for first-line therapy in patients with newly diagnosed APL 37–39. Furthermore, a recent meta-analysis by Ma et al showed significant benefits of the ATRA plus As 2 O 3 protocol, compared with the standard ATRA plus chemotherapy protocol, particularly in low- to intermediate-risk APL patients 30.…”

Section: Discussionmentioning

confidence: 99%

Maintenance therapy with all-trans retinoic acid and arsenic trioxide improves relapse-free survival in adults with low- to intermediate-risk acute promyelocytic leukemia who have achieved complete remission after consolidation therapy

Liang

Zheng

Shi

et al. 2017

OTT

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BackgroundCurrently, the optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who have achieved complete remission (CR) after completing consolidation chemotherapy remains controversial. The comparative effectiveness of the all-trans retinoic acid (ATRA) plus arsenic trioxide (As2O3) maintenance strategy with classic ATRA plus chemotherapy has not been evaluated. In this study, we compared the efficacy and toxicity of maintenance therapy with ATRA plus As2O3 and classic ATRA plus chemotherapy in low- to intermediate-risk APL patients reaching the first CR after induction and consolidation therapy.MethodsA retrospective review of 58 adult patients diagnosed with APL was conducted. After receiving consolidation therapy and achieving CR, 30 patients were administered maintenance therapy with an ATRA plus As2O3 regimen (ATRA+As2O3 group), whereas 28 patients were administered 3-monthly cycles of an ATRA plus chemotherapy regimen (ATRA+chemotherapy group).ResultsGrade 3–4 neutropenia was significantly more frequent in the ATRA+chemotherapy group (N=9, 32.1%) than in the ATRA+As2O3 group (N=0) (P=0.001). At a median follow-up of 49.1 months (range: 9.7–97.4 months) from the completion of consolidation, no relapses were observed in the ATRA+As2O3 group, whereas seven relapses occurred in the ATRA+chemotherapy group. The risk of relapse in the patients administered ATRA+As2O3 maintenance was significantly lower than that in those administered ATRA+chemotherapy maintenance (P=0.004). Based on log-rank analysis, only maintenance therapy with ATRA and As2O3 was associated with a significantly higher relapse-free survival (P=0.0159).ConclusionMaintenance therapy with ATRA and As2O3 was beneficial in low- to intermediate-risk APL patients who were effectively treated to achieve CR. Further clinical trials with reliable designs are needed to confirm these observations.

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Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial

Cited by 141 publications

References 30 publications

Addressing the room for improvement in management of acute promyelocytic leukemia

Addressing the room for improvement in management of acute promyelocytic leukemia

Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives

Maintenance therapy with all-trans retinoic acid and arsenic trioxide improves relapse-free survival in adults with low- to intermediate-risk acute promyelocytic leukemia who have achieved complete remission after consolidation therapy

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