Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy

Au, Wing‐Yan; Tam, Sidney; Fong, Bonnie Mei-Wah; Kwong, Yok–Lam

doi:10.1182/blood-2008-06-161000

Cited by 85 publications

(62 citation statements)

References 14 publications

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“…Additionally, although the combination regimen significantly decreased the incidence of bone marrow relapse, the incidence of CNS relapse remains a challenge, probably because of the relatively poor entry of the drugs through the blood-brain barrier (42)(43)(44). Because CNS leukemia may be accompanied or preceded by resurgence of the PML-RAR␣ transcript level, intrathecal prophylactics should be considered in the future, with closer monitoring of this specific disease marker.…”

Section: Discussionmentioning

confidence: 99%

Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

378

332

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All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combinationbased therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% ؎ 3.4% and 91.7% ؎ 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n ‫؍‬ 80) were 94.8% ؎ 2.5% and 97.4% ؎ 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RAR␣ types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.combination therapy ͉ 5-year EFS ͉ 5-year OS ͉ residual disease ͉ arsenic retention A cute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemia (AML) and is characterized by an accumulation of abnormal promyelocytes in the bone marrow and a severe bleeding tendency. Additionally, in the great majority of cases, APL is associated with the t(15,17) chromosomal translocation and resultant PML-RAR␣ transcripts that encode the leukemogenic PML-RAR␣ fusion protein (1). Five decades ago, APL was the most fatal type of acute leukemia and was considered essentially untreatable (2). The first breakthrough came with the use of anthracyclines, which improved the complete remission (CR) rate but provided a low 5-year overall survival (OS) (3). The introduction of all-trans retinoic acid (ATRA) therapy resulted in terminal differentiation of APL cells and a 90-95% CR rate in patients (1, 4), and subsequent combination of ATRA with chemotherapy raised the 5-year disease-free survival (DFS) rate up to 74% (5). In the 1990s, significant benefits of arsenic trioxide (ATO) were reported, which further improved the outcome of patients with APL (6, 7). ATO exerts dose-dependent dual effects on APL cells, with low concentrations inducing partial differentiation and relatively high concentrations triggering apoptosis. Of note, both ATRA and ATO induce catabolism of the PML-RAR␣ fusion protein, demonstrating a paradigm for rationally targeted therapy in leukemia. However, between 20% and 30% of newly diagnosed APL patients treated with regimens based on the use of ATRA or ATO as single agents will develop disease recurrence or drug resistance.To improve further the clinical outcome of APL, therapeutic strategies should be designed to include combinatorial use of drugs with distinct but convergent mechanisms that may amplify treatment effic...

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Section: Discussionmentioning

confidence: 99%

Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

378

332

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“…ATO is known to cross into the CNS and achieves levels of approximately 30% to 50% of the serum levels. 86,87 In general, unless a patient has a significant space-occupying chloroma in the brain parenchyma, radiation therapy is not given. Intrathecal chemotherapy is given twice weekly until clear and then weekly for 4 weeks, and then monthly for 4 to 6 months, although such a schedule is necessarily arbitrary.…”

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confidence: 99%

How I treat acute promyelocytic leukemia

Tallman

Altman

2009

Blood

240

229

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Acute promyelocytic leukemia is the first malignant disease highly curable with targeted therapy directed at a unique molecular abnormality. The characteristic bleeding diathesis is the most notorious manifestation of the disease, which historically has accounted for a high mortality rate during induction. Acute promyelocytic leukemia is one of the few hematologic diseases that must be recognized under the microscope by the practicing hematologist because early institution of all-trans retinoic acid (ATRA) at the first suspicion of the disease before confirmation of the diagnosis and aggressive blood product support are critical to reduce early mortality. ATRA plus anthracycline-based chemotherapy for induction and consolidation followed by maintenance ATRA with low-dose chemotherapy is currently the standard of care. However, the combination of ATRA and arsenic trioxide, with minimal chemotherapy to control leukocytosis, is very effective therapy for newly diagnosed patients. This combination may replace conventional approaches for most, if not all, patients in the very near future. Acute promyelocytic leukemia should be considered in any patient with newly diagnosed acute myeloid leukemia because the treatment is urgent and different from all other subtypes. (Blood. 2009; 114:5126-5135) IntroductionAcute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with distinctive biologic and clinical features that is now highly curable. Most patients are young, present with leukopenia, and exhibit a life-threatening coagulopathy, which is the most notorious manifestation of the disease. The cells from almost all patients have a balanced reciprocal translocation between chromosomes 15 and 17, 1 which generates a fusion transcript joining the PML (promyelocyte) and RAR-␣ (retinoic acid receptor-␣) genes. 2 Leukemic promyelocytes have the unique ability to undergo differentiation with exposure to retinoic acid and both differentiation and apoptosis with exposure to arsenic trioxide (ATO). The disease is relatively rare in adults, accounting for only 10% to 15% of the approximately 13 400 adults diagnosed with AML in the United States each year. Although the incidence of APL among children with AML is similar in some series, a higher overall percentage of APL in children with AML compared with adults has been reported in others. 3 In children, the disease is often associated with a high white blood cell count (WBC Ͼ 10 000/ L), the microgranular variant (M3V), and more all-trans retinoic acid (ATRA)-related toxicities, particularly pseudotumor cerebri. 4 Intensive studies of the biology and treatment of the disease have resulted in a remarkably thorough understanding of its pathogenesis. 5 Furthermore, a cure rate of approximately 80% to 90% of patients who survive induction and achieve complete remission (CR) can be expected. 6 Yet there are nuances in the approach to patients with APL that are often overlooked, and complicated issues in treatment that remain to be studied. Here, the initial approa...

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“…The concentration of arsenic in the cerebrospinal fluid correlates well with the plasma level, reaching up to 14 to 20-30% of plasma levels in patients treated with ATO intravenously and 18% in patients receiving oral formulation of ATO. [29][30][31][32] Interactions with other substances Synergistic actions between ATO and other substances have been described. Combined with ATRA, a remarkable intensification of anti-leukemic effects was observed in vitro and in vivo.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia

2011

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Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). This review provides insights into the mode of action and the pharmacological properties of ATO, and summarizes the most relevant results of more than 20 treatment studies in relapsed or newly diagnosed APL published between 1997 and 2011. ATO acts by targeting multiple pathways in APL leading to apoptosis and myeloid differentiation. It induces complete remission without myelosuppression and causes only few adverse effects. In relapsed APL, ATO-based salvage therapy has been able to induce long-lasting remissions and possible cure in 50-81% of patients. In newly diagnosed APL, two main strategies are currently pursued. ATO is either included into induction therapy with the aim to minimize or eliminate chemotherapy, or it is incorporated as an additive into established first-line concepts with all-trans-retinoic acid and chemotherapy to reinforce their anti-leukemic efficacy. Recent results suggest a high efficacy of ATO in both concepts. In conclusion, experimental research and clinical studies have made contributions toward a better understanding of the molecular mechanisms induced by ATO in APL cells and have established this historic substance as an important candidate for the further improvement of APL therapy.

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Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy

Cited by 85 publications

References 14 publications

Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia

Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia

How I treat acute promyelocytic leukemia

Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia

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