The Clinical Observation on Arsenic Trioxide with ATRA in Treating Acute Promyelocytic Leukemia for Six Years.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2868-2868 ◽  
Author(s):  
Zhou Zhong ◽  
Zhen-cai Liu ◽  
Jian-wei Li
Keyword(s):  
Side Effects ◽  
Complete Remission ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Relapse Rate ◽  
Severe Infection ◽  
Myocardial Damage ◽  
Promyelocytic Leukemia ◽  
Control Group ◽  
Treatment Side Effects

Abstract Objective: To observe the efficacy of arsenic trioxide(AS2O3) with ATRT for the treatment of patients with acute promyelocytic leukemia(APL). Methods: Seventy-four patients with APL, from 2000 to 2006, were randomly divided into two groups. Thirty-eight patients as treating group received AS2O3+ATRA, another thirty-six patients as control group were treated only AS2O3+ARTA+chemotherapy(DA or HA). Results: The first induced complete remission (CR) was 100%, the three-year relapse rate was 2.6%, the six-year continuous complete remission(CCR) rate was 94.6% for treating group. The rate of CR, the three-year relapse and CCR were 81.3%, 30.7% and 61.5% respectively for control group. The side effects such as myelosuppression, severe infection or septicemia, hepatic, renal and myocardial damage, and the digestive tract side effect were mild compared with that in control group(p<0.01). In treating group, the hyperleukocytosis was not observed, Incidence of the three-year treatment-related mortality (TRM) was 0%, the control group was 16.7%. Conclusion: The combination of AS2O3 and ATRA can obtain a higher CCR, low relapse rate and mild treatment side effects.

Single Agent Tamibarotene Has Activity in Acute Promyelocytic Leukemia Patients Previously Treated with ATRA and Arsenic Trioxide, but Does Not Produce Durable Responses

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3751-3751 ◽  
Author(s):  
David Sanford ◽  
Francesco LoCoco ◽  
Miguel A. Sanz ◽  
Eros Di Bona ◽  
Steven Coutre ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Partial Response ◽  
Adverse Events ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Promyelocytic Leukemia ◽  
Cell Transplant

Abstract Background: Treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is highly effective as first-line therapy, although approximately 10% of patients relapse after treatment. Several mechanisms of ATRA resistance have been proposed including accelerated clearance of ATRA and increased levels of cellular retinoic acid-binding protein (CRABP), which induces retinoic acid metabolism. Tamibarotene is a synthetic retinoid that does not significantly bind CRABP, suggesting that it might be effective in APL patients with ATRA resistance. Tamibarotene has shown efficacy in APL patients with relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA Methods: We conducted a multicenter phase II clinical trial of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (concomitant or sequential). Participants were treated with single agent tamibarotene at a daily dose of 6 mg/m2 for up to 56 days during induction. Patients achieving a complete response were eligible to continue on consolidation treatment with tamibarotene at the same dose for a maximum of six 28 day cycles. The primary outcome for this trial was to determine the rate of durable complete response (CR) using tamibarotene as a single agent. Secondary outcomes included the rate of morphologic complete remission, partial response, cytogenetic complete response, molecular complete response as well as the safety profile and tolerability of this medication. Results: We enrolled 14 patients from March 2008 to October 2011 at 8 centers. The median age of the participants was 56 years (range 20-76). Twelve patients had relapsed APL and 2 had primary refractory disease. Patients had a median of 2 remissions (range 1-5) prior to enrollment with a median time from the most recent remission to study screening of 23 months (range 2-102). Twelve patients (86%) had received other treatments including stem cell transplant (n=4) in addition to ATO and ATRA prior to enrollment. Eight patients achieved a morphologic remission during treatment with tamibarotene and 2 had a partial response (>50% reduction in BM blasts). Three (21%) patients with complete morphologic remission had a CR, whereas 5 (36%) had a complete remission with incomplete hematologic recovery (CRi), without meeting pre-specified recovery of neutrophil (>1,000/μL) and platelet counts (>100,000/μL). Seven out of 8 patients who achieved CR or CRi relapsed after treatment. The median duration of response for patients achieving CR was 203 days (range 183-212). The median overall survival for the entire group was 233 days (95% CI 196-526 days). Thirteen patients reported treatment-emergent adverse events, although the majority were mild (Grade 1-2). The most frequently reported adverse events included rash (n=6, grade 1-3), headache (n=4, grade 1) and neutropenia (n=3, grade 3-4). Two patients experienced APL differentiation syndrome (grade 2). Two patients discontinued the study due to adverse events: one patient developed progressive multifocal leukoencephalopathy and the other developed pneumonia, although neither of these events was thought to be related to tamibarotene. Discussion: These results suggest that tamibarotene has activity in patients with relapsed APL after treatment with ATO and ATRA. Although the CR rate of 21% is lower than that reported in a previous trial using tamibarotene (58%; Tobita, 1997), the 24 patients in that study had received ATRA alone or in combination with chemotherapy, but not ATO. Thus, tamibarotene has significant clinical activity in this heavily pre-treated population with acceptable toxicity. Further studies using tamibarotene as initial therapy and in combination with ATO are warranted. Disclosures LoCoco: Lundbeck: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau. Cortes:CytRx: Research Funding.

scholarly journals Pharmacokinetic Characteristics, Tissue Bioaccumulation and Toxicity Profiles of Oral Arsenic Trioxide in Rats: Implications for the Treatment and Risk Assessment of Acute Promyelocytic Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Wensheng Liu ◽  
Bin Wang ◽  
Yilei Zhao ◽  
Zhiqiang Wu ◽  
Andi Dong ◽  
...  
Keyword(s):  
Oral Administration ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Whole Blood ◽  
Promyelocytic Leukemia ◽  
Absolute Bioavailability ◽  
Control Group ◽  
Atomic Fluorescence Spectrometry ◽  
Maximum Plasma ◽  
Arsenic Metabolites

Oral arsenic trioxide (ATO) has demonstrated a favorable clinical efficiency in the treatment of acute promyelocytic leukemia (APL). However, the pharmacokinetic characteristics, tissue bioaccumulation, and toxicity profiles of arsenic metabolites in vivo following oral administration of ATO have not yet been characterized. The present study uses high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) to assess the pharmacokinetics of arsenic metabolites in rat plasma after oral and intravenous administration of 1 mg kg−1 ATO. In addition, the bioaccumulation of arsenic metabolites in blood and selected tissues were evaluated after 28 days oral administration of ATO in rats at a dose of 0, 2, 8, and 20 mg kg−1 d−1. The HPLC-HG-AFS analysis was complemented by a biochemical, hematological, and histopathological evaluation conducted upon completion of ATO treatment. Pharmacokinetic results showed that arsenite (AsIII) reached a maximum plasma concentration rapidly after initial dosing, and the absolute bioavailability of AsIII was 81.03%. Toxicological results showed that the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and white blood cells (WBC) in the 20 mg kg−1 d−1 ATO group were significantly increased compared to the control group (p &lt; 0.05). The distribution trend of total arsenic in the rat was as follows: whole blood &gt; kidney &gt; liver &gt; heart. Dimethylated arsenic (DMA) was the predominant bioaccumulative metabolite in the whole blood, liver, and heart, while monomethylated arsenic (MMA) was the predominant one in the kidney. Collectively, these results revealed that oral ATO was rapidly absorbed, well-tolerated, and showed organ-specific and dose-specific bioaccumulation of arsenic metabolites. The present study provides preliminary evidence for clinical applications and the long-term safety evaluation of oral ATO in the treatment of APL.

The First Case Report of APL (ACUTE PROMYELOCYTIC LEUKEMIA) in An HIV Positive Patient On (Highly Active Antiretroviral Therapy) Treated with ARSENIC TRIOXIDE.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4166-4166 ◽  
Author(s):  
Afshan Malik ◽  
Randy L. Levine
Keyword(s):  
Bone Marrow ◽  
Antiretroviral Therapy ◽  
Complete Remission ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Bone Marrow Biopsy ◽  
Highly Active Antiretroviral Therapy ◽  
Promyelocytic Leukemia ◽  
Normal Bone ◽  
Highly Active

Abstract Abstract 4166 We report here for the first time the use of arsenic trioxide in the treatment of Acute Promyelocytic Leukemia in a patient with HIV on HAART (Highly Active Antiretroviral Therapy). A 37 year old man with a 7 year history of asymptomatic HIV infection, an undetectable viral load and a CD4 count of > 800 cells/mm3 presented with a furuncle and a new onset leukopenia. He denied constitutional symptoms or bleeding problems, but he did complain of fatigue and apthous ulcers. His medications included Epivir, Viramune, Videx EC, Viagra and Avelox. He denied smoking, ETOH abuse or intravenous drug abuse. On Physical Exam, he was afebrile and he did not have organomegaly or lymphadenopathy. Laboratory results revealed a white blood cell count of 1.6 K/uL with 7.9% neutrophils, 90.7% lymphocytes, 0.2% eosinophils, 0.3% basophils and 0.9% monocytes, hemoglobin of 12.4 g/dL, MCV of 96.3fL and platelet count of 112K/mL. Coagulation studies were normal. Bone marrow biopsy revealed a hypercellular marrow with immature myeloid cells (CD34 Positive and HLA-DR Negative). Peripheral blood PCR studies were positive for t (15:17) PML-RARA Translocation. The diagnosis of (APL) Acute Promyelocytic Leukemia (AML-M3 Subtype) was made and he was admitted to the hospital for induction chemotherapy with ATRA (All-Trans -Retinoic-Acid) 40 mg orally twice daily with Idarubicin 12mg/m2 followed by consolidation and maintenance treatment. He continued to take his HAART throughout his chemotherapy. Pt tolerated therapy well. On Day 68 Peripheral blood FISH for t 15:17 was done which was negative. On Day 77 a repeat Bone marrow biopsy revealed a complete remission with no evidence of leukemia and a normocellular marrow maturing trilineage hematopoiesis, and normal cytogenetics. He was non-compliant with maintenance ATRA because of nausea. He remained in remission for 1 year after which repeat labs on a routine visit showed leukopenia and thrombocytopenia. A bone Marrow biopsy done at that time showed recurrent APL with 80% infiltration with promyelocytes. Arsenic Trioxide 0.15 mg/kg/day therapy was begun. After 3 months of therapy the patient achieved complete remission with a normal bone marrow biopsy and a negative PCR for t (15:17) with no evidence of leukemia. Subsequently he underwent standard consolidation treatment 0.15 mg/kg/day 5 days a week for 4 weeks. Seventeen months later he is in Complete Remission and is doing well while still on Highly Active Antiretroviral Therapy. The occurrence of AML has been reported in HIV with a predominance of M2, M4 and M5 subtypes. Six cases of APL in HIV patients have been reported to date. In all of these cases ATRA and an anthracycline have been used to induce remission. Here we report the seventh case of APL/HIV and first successful use of arsenic trioxide with concomitant HAART. On the day of submitting the subtract, he presented with pancytopenia and is currently being worked up for possible relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Preparation and characterization of erythrocyte membrane cloaked PLGA/arsenic trioxide nanoparticles and evaluation of their in vitro anti-tumor effect

RSC Advances ◽  
2018 ◽  
Vol 8 (36) ◽  
pp. 20068-20076 ◽  
Author(s):  
Jing Su ◽  
Geyi Liu ◽  
Yumei Lian ◽  
Zul Kamal ◽  
Xiao Que ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Side Effects ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Erythrocyte Membrane ◽  
Intravenous Injection ◽  
Promyelocytic Leukemia

Arsenic trioxide (ATO) is used for acute promyelocytic leukemia (APL) that is resistant to all-trans-retinoic acid, but its direct intravenous injection sometimes induces severe toxic side effects.

Proteome Analysis of Apoptotic MR2 Cells, Acute Promyelocytic Leukemia Cell Line with All-Trans Retinoic Acid Resistance, Induced by Arsenic Trioxide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4726-4726
Author(s):  
Pengcheng He ◽  
Mei Zhang ◽  
Xiaoning Wang ◽  
Huaiyu Wang ◽  
Jieying Xi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Cell Line ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Beta Tubulin ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Although all-trans retinoic acid(ATRA) provides complete remission in 90% patients with untreated acute promyelocytic leukemia(APL), it becomes ineffective to quite a few APL patients who have received ATRA before when their disease relapsed and used ATRA again. Arsenic trioxide(ATO) can make APL patients with ATRA-resistance obtain complete remission again by inducing APL cells apoptosis. However, the molecular mechanisms of apoptosis in ATRA-resistance APL cells induced by ATO remain unclear. For this reason, we take the apoptotic MR2 cells (APL cell line with ATRA-resistance) induced by ATO as a model, to screen and identify the proteins related with ATO-induced apoptosis by comparative proteomics. After MR2 cells were dyed with annexin V and PI staining, the percentage of the apoptotic MR2 cells induced by 1.0μmol/L ATO for 0h, 6h, 12h, 24h and 48h respectively was detected by Flow cytometry. The results showed that the majority of the apoptotic cells were in the earlier and later stage of apoptosis respectively, when MR2 cells were treated with ATO for 24 and 48 hours in sequence. The total proteins of MR2 cells of the control group, the earlier stages apoptosis group and the later stages apoptosis group were separated by two-dimensional electrophoresis(2-DE) respectively. Then, the differences in proteome profile among three groups were analyzed by ImageMaster™ 2D Platinum software. 14 protein pots were selected to be identified by Matrix-assisted laser desorption/ionization time of flight-mass spectrometry(MALDI-TOF-MS), in which the quantity of the protein differentially expressed was more than two times(≥2 or ≤0.5) among MR2-0h, MR2-24h and MR2-48h cells’ 2-DE map. However, only 11 proteins were successfully identified and their definite information was obtained. Among them, there were 8 proteins that were all probably involved in the mechanisms of apoptosis in MR2 cells and they were Calreticulin(CRT), Heat shock 70 kDa protein(HSP70), High mobility group protein B1(HMGB1), Ran-specific GTPase-activating protein(RanGAP1), Elongation factor 1-beta(EF-1β), Beta-tubulin, Cofilin-1, and Prolyl 4-hydroxylase(P4H) respectively. CRT was probably related with the early stage of apoptosis in MR2 cells, while RanGAP1 and HSP70 might related with the late stage of apoptosis in MR2 cells. Moreover, so far there was no related report on the roles of CRT, HMGB1, RanGAP1, cofilin-1 and beta-tubulin in the mechanisms of APL cells apoptosis. These differential proteins identified provide the new clues for further researching the molecular mechanisms of apoptosis in the ATRA-resistance APL cells induced by ATO.

Complete Remission after Treatment of Acute Promyelocytic Leukemia with Arsenic Trioxide

1998 ◽  
Vol 339 (19) ◽  
pp. 1341-1348 ◽  
Author(s):  
Steven L. Soignet ◽  
Peter Maslak ◽  
Zhu-Gang Wang ◽  
Suresh Jhanwar ◽  
Elizabeth Calleja ◽  
...  
Keyword(s):  
Complete Remission ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia

Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: a pilot report

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3136-3143 ◽  
Author(s):  
Dao-Pei Lu ◽  
Jing-Ying Qiu ◽  
Bin Jiang ◽  
Qin Wang ◽  
Kai-Yan Liu ◽  
...  
Keyword(s):  
Side Effects ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Disease Stage ◽  
Remission Induction ◽  
Pharmacokinetic Studies ◽  
Newly Diagnosed ◽  
Urinary Arsenic

Abstract In the past 6 years, we treated 129 patients who had acute promyelocytic leukemia (APL) with a new arsenic agent, oral tetra-arsenic tetra-sulfide (As4S4). Nineteen of the patients had newly diagnosed APL, 7 had first relapse, and 103 had hematologic complete remission (HCR). HCR was achieved in all patients with newly diagnosed APL and in all those with hematologic relapse. Of 16 patients with newly diagnosed disease and available cytogenetic and molecular analyses, 14 had cytogenetic and molecular complete remission (CR). Cytogenetic and molecular CR was also obtained in 5 of the 7 patients with hematologic relapse. In the HCR group, 35 of 44 patients positive for PML-RARα at baseline became negative. In the newly diagnosed group, estimated disease-free survival (DFS) rates for 1 and 3 years were 86.1% and 76.6%, respectively, with a median follow-up time of 13.5 months (range, 2-40 months). In the HCR group, DFS rates for 1 and 6 years were 96.7% and 87.4%, respectively, with a median follow-up of 23 months (range, 2-71 months). Treatment with As4S4 was well tolerated, with only moderate side effects, including asymptomatic prolongation of corrected QT interval, transient elevation in liver enzyme levels, rash, and mild gastrointestinal discomfort; neither myelosuppression nor appreciable long-term side effects occurred. Degeneration or apoptosis of APL promyelocytes was observed during As4S4therapy. Pharmacokinetic studies showed that the agent was absorbed rapidly. Most urinary arsenic excretion occurred within the first 24 hours. Both blood and urinary arsenic levels declined after discontinuation of As4S4. Our results show, for the first time, that As4S4 treatment alone is highly effective and safe in both remission induction and maintenance therapy in patients with APL, regardless of disease stage.

scholarly journals Oral arsenic trioxide–based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6535-6543 ◽  
Author(s):  
Wing-Yan Au ◽  
Cyrus R. Kumana ◽  
Harold K. K. Lee ◽  
Shek-Ying Lin ◽  
Herman Liu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Chemotherapeutic Agents ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
Wbc Count ◽  
First Complete Remission

Abstract Seventy-six patients with acute promyelocytic leukemia (APL) in first complete remission after induction and consolidation by daunorubicin and cytosine arabinoside received oral arsenic trioxide (As2O3)-based maintenance. Three regimens were used: oral As2O3 (10 mg/day, regimen A, n = 20), oral As2O3 plus all-trans retinoic acid (ATRA, 45 mg/m2 per day, regimen AA, n = 19), and oral As2O3 plus ATRA plus ascorbic acid (1000 mg/day, regimen AAA, n = 37), each given for 2 weeks every 2 months for 2 years. Patients receiving A, AA, and AAA maintenance did not differ significantly in clinicopathologic features and risk factors. Headache, dyspepsia, reversible liver function derangement, and herpes zoster reactivation were adverse effects observed during maintenance. QTc prolongation and arrhythmias were not encountered. At a median follow-up of 24 months (range, 1-115 months), there were 8 relapses. The 3-year leukemia-free-survival, event-free-survival, and overall-survival were 87.7%, 83.7%, and 90.6%, respectively. Adverse prognostic factors included male gender for leukemia-free-survival, and unrelated cancers for overall survival. Age, presentation WBC count and platelet count, and the type of oral As2O3 maintenance regimens had no impact on survivals. Prolonged oral As2O3 maintenance was feasible and safe and resulted in favorable outcomes when used with a simple induction and consolidation regimen compared with other protocols composed of multiple chemotherapeutic agents.

Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide

Blood ◽  
2001 ◽  
Vol 98 (2) ◽  
pp. 266-271 ◽  
Author(s):  
Peter Westervelt ◽  
Randy A. Brown ◽  
Douglas R. Adkins ◽  
Hanna Khoury ◽  
Peter Curtin ◽  
...  
Keyword(s):  
Complete Remission ◽  
Sudden Death ◽  
Phase I ◽  
Effective Dose ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Pulmonary Hemorrhage ◽  
Promyelocytic Leukemia ◽  
Minimal Effective Dose ◽  
Efficacy Of Treatment

Arsenic trioxide has been shown to be effective in treating acute promyelocytic leukemia (APL), with minimal overall toxicity reported to date. A phase I/II study was initiated in June 1998 using arsenic trioxide for relapsed APL to determine the maximum tolerated or minimal effective dose and to determine the efficacy of treatment at that dose. Ten patients received 1 to 4 monthly cycles of treatment with 0.1 mg/kg per day intravenous arsenic trioxide. Six of 7 patients evaluable for response achieved cytogenetic or molecular complete remission. However, 3 patients died suddenly during the first cycle of treatment. Autopsies obtained on 2 of these failed to identify a cause of sudden death, despite evidence of pulmonary hemorrhage in one. A third patient, for whom an autopsy was not performed, became asystolic and died while on continuous cardiac telemetry. These observations suggest that arsenic trioxide may be significantly or even fatally toxic at doses currently used and that caution is warranted in its use.

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