Arsenic trioxide and all-trans retinoic acid (ATRA) treatment for acute promyelocytic leukemia in all risk groups: study protocol for a randomized controlled trial

Zhang, Xinxin; Zhang, Huiyun; Chen, Limei; Wang, Mengchang; Xi, Jieying; Liu, Xin; Xie, Ming; Li, Dengzhe; Gulati, Ekamjyot Singh; Gong, Sha; Wang, Huaiyu

doi:10.1186/s13063-018-2812-3

Cited by 20 publications

(36 citation statements)

References 17 publications

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“…We started a trial about the simultaneous application of ATRA and ATO in post-remission therapy. It was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-15006821) (24). To date, none of the participants relapsed.…”

Section: Discussionmentioning

confidence: 99%

Real‑world data on the dose‑related effect of arsenic trioxide in the relapse of acute promyelocytic leukemia

et al. 2020

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Acute promyelocytic leukemia (APL) has become a highly curable disease with all-trans retinoic acid-based regimens. However, following the administration of arsenic trioxide (ATO), the relapse rate remains at 1-10%. It is not known whether the dosage of ATO is associated with the relapse rate in real-world settings. According to 2019 National Comprehensive Cancer Network guidelines, the recommended cumulative ATO dosage in post-remission therapy is 7.95-12 mg/kg in APL. In the current study, 112 patients with newly diagnosed APL receiving a combination of all-trans retinoic acid, anthracycline-based chemotherapy and different dosages of ATO for variable courses, were divided into the high-dose (ATO dosage, ≥12 mg/kg) and low-dose groups (ATO dosage, <12 mg/kg). Relapse risk factors were analyzed by multiple factor analysis. The relationship between relapse rate and ATO dosage in post-remission was elucidated by determining the 4-year cumulative incidence of relapse (CIR). Based on the ATO dosage in post-remission therapy, 72 (64.3%) patients were in the low-dose group and 40 (35.7%) were in the high-dose group. An increased ATO dosage was demonstrated to be an independent protective factor in terms of probability of relapse (P=0.004). With a median follow-up time of 53 months, the 4-year CIR was 16.7% in the low-dose group and 0% in the high-dose group, respectively (P=0.008). No patient relapsed when administered an ATO dosage >6 mg/kg. In conclusion, the relapse rate of APL was significantly associated with ATO dosage in post-remission therapy. An increased ATO dosage may serve as a protective factor of relapse. ATO dosage should therefore reach up to 12 mg/kg, with consideration to reduce the dosage in the future.

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Section: Discussionmentioning

confidence: 99%

Real‑world data on the dose‑related effect of arsenic trioxide in the relapse of acute promyelocytic leukemia

et al. 2020

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“…Compared to chemotherapy alone, ATRA resulted in significantly higher remission rates in APL patients [28] but even projected more promising outlooks when combined with a standard dose of induction chemotherapy. [29,30] Likewise, combined treatment of APL cells with ATRA and arsenic trioxide (ATO), a small molecule with known anti-leukemic properties, resulted in longlasting terminal differentiation and sustained demethylation of target genes suggesting a relapse-free treatment strategy. [30,31] The promising results observed in patients with advanced APL were a major driving force for testing ATRA on solid tumors.…”

Section: Retinoic Acid-mediated Signaling Pathwaysmentioning

confidence: 99%

“…[29,30] Likewise, combined treatment of APL cells with ATRA and arsenic trioxide (ATO), a small molecule with known anti-leukemic properties, resulted in longlasting terminal differentiation and sustained demethylation of target genes suggesting a relapse-free treatment strategy. [30,31] The promising results observed in patients with advanced APL were a major driving force for testing ATRA on solid tumors. Biological models have previously demonstrated that ATRA is equally capable of enforcing apoptosis and/or differentiation via the RA receptor pathway in other organs.…”

Section: Retinoic Acid-mediated Signaling Pathwaysmentioning

confidence: 99%

Critical regulatory levels in tumor differentiation: Signaling pathways, epigenetics and non‐coding transcripts

et al. 2021

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Approaches to induce tumor differentiation often result in manageable and therapynaïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non-coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build-up.

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“…This study showed that ATO can replace chemotherapy in high-risk patients, without increasing the risk of relapse and with a milder toxicity profile in terms of myelosuppression and infectious episodes. The randomized, multicenter, pan-European APOLLO trial (NCT02688140) and a Chinese study [45] are ongoing to specifically assess the role of ATO/ ATRA frontline in high-risk APL.…”

Section: Clinical Use Of Arsenic In Apl: the Long Journey To A Chemotmentioning

confidence: 99%

When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

Gurnari¹,

Bellis²,

Divona³

et al. 2019

Chemotherapy

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Arsenic has been known for centuries for its double-edged potential: a poison and at the same time a therapeutic agent. The name "arsenikon," meaning "potent," speaks itself for the pharmaceutical properties of this compound, questioned and analyzed for at least 2000 years. In the last decades, acute promyelocytic leukemia (APL) has evolved from a highly fatal to a curable disease, due to the use of all-transretinoic acid and, more recently, arsenic trioxide combinations. The success of these entirely chemo-free regimens increased the awareness of APL and reduced the prevalence of early deaths, which was an impending issue in this disease. Further improvements are expected with the next use of oral arsenic formulations, which will allow a complete outpatient approach, at least in the post-induction settings, further improving patients' quality of life. The wide use of standardized approaches in APL will also help unravel long-standing open questions, including the pathogenesis, prevention, and treatment of the differentiation syndrome and of short-term organ toxicities. In the long term, the study of survivorship issues, such as fertility and organ-related and psychological damages, in the increasing number of survivors will help further improve their life after APL.

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Arsenic trioxide and all-trans retinoic acid (ATRA) treatment for acute promyelocytic leukemia in all risk groups: study protocol for a randomized controlled trial

Cited by 20 publications

References 17 publications

Real‑world data on the dose‑related effect of arsenic trioxide in the relapse of acute promyelocytic leukemia

Real‑world data on the dose‑related effect of arsenic trioxide in the relapse of acute promyelocytic leukemia

Critical regulatory levels in tumor differentiation: Signaling pathways, epigenetics and non‐coding transcripts

When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

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