Induction,consolidation, and maintenance therapies with arsenic as a single agent for acute promyelocytic leukaemia in a 11‐year follow‐up

The aim of this study was to evaluate the effect of arsenic trioxide as a single agent in acute promyelocytic leukaemia cases for induction, consolidation, and maintenance therapy in a long‐term, 11‐year follow‐up. We studied 60 patients with acute promyelocytic leukaemia. Sixty percent of the patients were aged between 12 and 24 years. Arsenic trioxide was infused at a 0.15 mg/kg daily dose until complete remission was achieved. After 2 weeks of rest, arsenic trioxide was infused daily for 28 days as a consolidation therapy. Then, arsenic infusions were given every 3–4 months for 14 days for 2 years, and the patients were followed until relapse or death. The rates of complete remission, disease‐free survival, overall survival, and drug toxicity were evaluated. The morphologic complete remission was observed in 55 out of the 60 patients. The most common causes of a remission failure were early mortality because of the APL differentiation syndrome and the lack of response to arsenic treatment. The mean follow‐up was 90 months. The primary outcomes for males and females were a mean disease‐free survival of 101 and 97 months, respectively, and a mean overall survival of 103 and 101 months, respectively. From the 55 cases with remission, three patients died (late mortality). Of the 60 patients, 85% are still alive. Arsenic trioxide was generally well tolerated. The long‐term follow‐up of patients with APL, treated with arsenic alone as induction, consolidation, and maintenance therapy, shows high cure rates and excellent outcomes. Copyright © 2015 John Wiley & Sons, Ltd.     

Successful treatment of all-trans retinoic acid resistant and chemotherapy naïve acute promyelocytic patients with arsenic trioxide--two case reports

Arsenic trioxide(As2O3) has proved highly effective in treating both refractory or primary cases of acute promyelocytic leukemia (APL). The role of arsenic trioxide in APL treatment has been confirmed by study groups in China and in the USA. However, what is the role of As2O3 in treating APL? Should it be used as first line therapy, or should it be used as a second line drug. This still remains to be defined. Here, we report two cases of APL, who were treated successfully with As2O3 when they relapsed. Initially, both received all-trans retinoic acid (ATRA) for primary remission induction therapy, and obtained a complete remission. For ethical or personal reasons, they did not receive chemotherapy as consolidation therapy and when they relapsed at 23 months and 12 months later respectively, they both received As2O3 therapy after being resistant to ATRA treatment. Two courses of As2O3 were given and both reached complete remission. There were very few adverse reactions to the drug, only mild abdominal cramps, mild fluid retention, and transient elevation of transaminases. They both had rather good quality of life throughout the treatment and both remain in remission for 32 months and 10 months since therapy, respectively.     

Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies.

Arsenic trioxide has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). In clinical trials, arsenic trioxide induces complete remission in 87% of patients and molecular remission in 83% of patients. Two-year overall and relapse-free survival estimates are 63% and 49%, respectively. Treatment with arsenic trioxide may be associated with the APL differentiation syndrome, leukocytosis, and electrocardiographic abnormalities. The expanded use of arsenic trioxide in APL for postremission therapy, in conjunction with transplantation, and in patients with newly diagnosed APL is under investigation. The multiple mechanisms of action of arsenic trioxide suggest that it may have antitumor activity in malignancies other than APL and that it may be used in combination with other agents to expand its potential use. This article reviews the clinical use of arsenic trioxide to date and discusses new therapeutic strategies evolving from its diverse biologic activities.     

Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide.

PURPOSE: Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. PATIENTS AND METHODS: Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. RESULTS: Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37). CONCLUSION: Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.     

Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation

The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%-30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease.     

The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis

Arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) could induce apoptosis and differentiation in acute promyelocytic leukemia (APL) cells, respectively, thus the possibility of synergism between them was raised. This meta-analysis assessed the effectiveness and safety of ATO combined with ATRA in the treatment of APL. Compared with ATO alone, induction therapy with ATO/ATRA significantly increased the complete remission (CR) rate (RR: 1.08, 95% CI: 1.00-1.17, P = 0.04), shortened the time to achieve CR (WMD: −6.51, 95% CI: −11.32 to −1.70, P = 0.008), and improved the molecular remission rate after consolidation therapy (RR: 1.74, 95% CI: 1.14-2.66, P = 0.01) and the 1-year disease-free survival rate (RR: 1.22, 95% CI: 1.00-1.50, P = 0.05). There were no statistically significant differences between two treatments in terms of early death and main adverse events. These results suggested that ATO/ATRA could synergistically improve the overall outcome of newly diagnosed and relapsed APL patients, supporting the use of ATO/ATRA as an effective treatment for all APL patients previously untreated with ATO.     

Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.     

Acute promyelocytic leukemia

Opinion statement The treatment of acute promyelocytic leukemia (APL) is different from other subtypes of acute myelocytic leukemia (AML). All trans-retinoic acid (ATRA) is an essential component of the standard remission induction for all newly diagnosed APL patients. Remission induction with ATRA and chemotherapy given concurrently appears to be associated with fewer relapses. With further consolidation chemotherapy without high-dose cytosine arabinoside, the disease-free survival rate can reach 70% to 80%, and many of these patients are cured, more so than in any other AML subtype. APL is especially sensitive to anthracyclines, which should be included in the chemotherapy cycles at a higher dose than in other AML subtypes. Maintenance with low-dose chemotherapy (oral daily 6-mercaptopurine with weekly methotrexate) or ATRA further improves the long-term outcome. New approaches are also available for relapsing patients, although the optimal treatment is unknown. Patients who did not receive oral ATRA in first relapse can be treated with this agent, as can first relapsing patients who have been off the drug for more than 1 year. Because of poor remission rates, ATRA should not be used in patients with second or subsequent relapses (whether ATRA was given in the past), in patients with relapses early after ATRA discontinuation, or in patients relapsing while on ATRA therapy. Arsenic trioxide can also be used, especially in patients resistant to ATRA. Because arsenic trioxide is still experimental and not yet widely available, patients who are unlikely to respond to ATRA or who unsuccessfully undergo ATRA reinduction should be treated with chemotherapy. Patients in second or subsequent remission induced with ATRA or chemotherapy should receive consolidation chemotherapy. When arsenic trioxide is used for reinduction, the drug should be continued for several cycles; however, adding consolidation chemotherapy might improve the results. Because it is unknown whether APL in second or subsequent remission is curable with salvage therapy, allogeneic hematopoietic stem cell transplantation is often considered for patients with a human leukocyte antigen (HL-A)-identical sibling and autologous transplantation when a donor does not exist. However, compared with the new treatments, the role of transplantation for relapse is unclear. In first remission, there is no role for transplantation. A new liposomal formulation of intravenous ATRA is being investigated and seems effective in late first relapses, and it may be able to induce and maintain first remissions in selected patients without chemotherapy.     

PML-RARα inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by generation of the PML-RARα fusion gene. PML-RARα can homodimerize with another PML-RARα, and the hybrid binds the histone-deacetylase recruiting co-repressor complex with higher affinity than the wild-type RARα. However, the co-repressor complex is releasable by pharmacological doses of all-trans retinoic acid (ATRA). More than 90% of patients with APL achieve a complete remission (CR) with differentiation therapy consisting of ATRA combined with chemotherapy. A new synthetic retinoid, tamibaroten, showed therapeutic effectiveness in patients with ATRA-resistant APL with increased expression of cellular retinoic acid binding protein (CRABP), and about 60% of patients with relapsed APL achieved a CR. Arsenic trioxide triggers the rapid degradation of PML-RARα through the targeting of the PML moieties of the fusion protein and showed a high CR rate in relapsed APL. The combination of ATRA, chemotherapy, and/or new agents improved the long-term survival in patients with APL.     

Acute progranulocytic leukemia

Acute progranulocytic leukemia (APL) is characterized by unique biologic and clinical features. Understanding of these unique features has resulted in dramatic improvements in therapy for patients with APL. Current therapy with all-trans-retinoic acid (ATRA) plus an anthracycline with or without cytosine-arabinoside has yielded complete response rates of 85% or greater and long-term disease-free survival rates of 70% or greater. Arsenic trioxide has also surfaced as an effective induction therapy for relapsed APL. Further progress in the care of patients with APL awaits better definition of optimal schedules for ATRA plus chemotherapy, the role of arsenic trioxide, the use of current molecular monitoring for minimal residual disease, optimal therapy for minimal residual disease, and improved methods to address complications of APL including early hemorrhagic deaths and ATRA toxicities.     

全反式维甲酸联合亚砷酸治疗儿童急性早幼粒细胞白血病疗效分析

目的:评价全反式维甲酸（all-trans retinoic acid,ATRA）联合亚砷酸(ATO)治疗儿童急性早幼粒细胞性白血病(acute promyelocytic leukemia,APL) 的疗效。方法:2009年8月至2013年4月于我院儿科就诊的APL患儿18例,将亚砷酸注射液（0.1% ATO）按6mg/m2稀释于50g/L的葡萄糖溶液200-400ml中,静脉滴注持续3-5h,1次/d,ATRA 20-35mg/(m·d),口服,3次/d。结果:18例患儿获得完全缓解（CR）率为94.4%;12例初治患儿均获得CR,6例复发患儿中5例获得CR。获得缓解时间（26.2±1.2）天,无明显不良反应发生。结论:ATRA联合亚砷酸治疗儿童APL疗效显著,有效缩短达到CR的时间,毒副作用基本可以耐受,本方案可以有效缩短治疗时间,降低患儿家庭经济负担,对患儿长期治疗具有重要作用,是一种经济有效的治疗方案。     

全反式维甲酸联合三氧化二砷治疗儿童急性早幼粒细胞白血病疗效观察

 目的　观察全反式维甲酸（ ATRA ）联合三氧化二砷（ As2O3）治疗儿童初发急性早幼粒细胞白血病（ APL）的疗效和不良反应。方法　ATRA 联合As2O3治疗初发 APL患儿16例。治疗方案：ATRA 25 mg·m-2·d-1，分2～3次口服，As2O3 0.16 mg·kg-1·d-1，加入生理盐水或50 g／L葡萄糖溶液静脉滴注，持续 4～6 h，1次／d。结果　14 例患者获得完全缓解（CR），CR率87.5 ％，CR时间短，没有明显不良反应。结论　ATRA联合As2O3治疗儿童APL能获得很好疗效。     

Successful treatment after acute promyelocytic leukemia (APL) syndrome of relapsed API with arsenic trioxide

A 52-year-old female was diagnosed with relapsed APL in 2000. After obtaining informed consent, we administered 10 mg/day of arsenic trioxide intravenously. The complications were vomiting, increased transaminase and ATRA syndrome which included high fever, retention of body fluid, pleural effusion, pericardial effusion and respiratory failure from day 16. Administration of steroid and low dose chemotherapy (DNR 60 mg x day 1-2, BH-AC 250 mg x day 1-2) with arsenic was effective for APL syndrome, and complete remission (CR) was obtained at day 35 and PML-RAR mRNA became negative. After obtaining CR, consolidation chemotherapy was conducted and the patient was maintained the CR for more than 18 months. Although arsenic trioxide may be effective for relapsed APL, sufficient caution is needed because of the possibility of various complications.     

All-transretinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia

BACKGROUND: All-transretinoic acid (ATRA) and chemotherapy has improved complete remission rates and disease free survival in acute promyelocytic leukemia (APL). There is scanty data from Middle East. AIM: To determine the efficacy of ATRA and multi-agent combination chemotherapy in treatment of APL in a single Centre in Kuwait. SET-UPS AND DESIGN: Tertiary cancer centre, retrospective study. METHODS AND MATERIAL: All newly diagnosed APL patients were treated with oral ATRA 45 mg/m2 daily until complete remission (CR), intravenous daunorubicin 50 mg/m2 on days 1,3 and 5, cytosine arabinoside 100 mg/m2 12 hrly on days 1 through 10 and etoposide 100 mg/m2 on days 1 through 5. Post remission three courses of intensive consolidation chemotherapy were administered. Since October 1999, maintenance chemotherapy consisting of oral 6 mercaptopurine 9 mg/m2 daily, methotrexate 15 mg/m2 weekly and ATRA 45 mg/m2 for 2 weeks every three months was added. Complete remission rates and duration, relapse rate and toxicity were studied. RESULTS: 22 of 24 evaluable patients (91.6%) achieved CR. The median duration of remission was 13 months (range 2-55 months). Three patients (12.5%) relapsed. Two patients (8.3%) developed retinoic acid syndrome and responded to dexamethasone. Five patients (20.8%) died one each of refractory disease, during remission induction and of relapse. Two patients died while in remission. CONCLUSION: ATRA and combination chemotherapy results in high complete remission rates and low relapse rate in newly diagnosed APL. Maintenance therapy may be useful in preventing relapses.     

Treatment of relapsed acute promyelocytic leukemia

By all-trans retinoic acid (ATRA) and chemotherapy over 70% of patients with newly diagnosed acute promyelocytic leukemia (APL) may be cured; 20-30% of patients still relapse and require salvage therapy. For relapsed or refractory APL, a standard treatment has not yet been defined. However, several effective drugs and approaches have been described. Treatment options for relapsed APL include chemotherapy regimens used in the treatment of relapsed acute myeloid leukemia usually combined with ATRA or of other differentiating agents such as liposomal ATRA or synthetic retinoids. Presently, allogeneic peripheral stem cell or bone marrow transplantation is the treatment of choice for younger patients who have a histocompatible donor, as it gives the chance of cure in second or further relapse. For patients without a donor or for those who are not suitable for allogeneic transplantation, autologous stem cell or bone marrow transplantation may offer at least the possibility of a prolongation of remission, if the harvested cells are negative in the RT-PCR of PML/RAR alpha. Arsenic compounds have a high antileukemic effectiveness on APL cells. Arsenic trioxide has recently been approved for relapsed or refractory APL. With this drug, complete hematologic remission rates of 80-92% and long-lasting molecular remissions were achieved in relapsed patients. For patients who do not qualify for these treatment options, monoclonal anti-CD33 antibodies may represent further treatment options.     

急性早幼粒细胞白血病对全反式维甲酸耐药的机制及其逆转

目的　揭示急性早幼粒细胞白血病 (APL)产生维甲酸耐药的机制 ,探讨耐药性逆转的方法。方法　MTT法测定细胞增殖 ,极限稀释法诱导APL细胞耐药性。RT PCR及流式细胞仪测定MDR1、消炎痛及PGE1增殖影响实验分别间接测定GST酶活性或cAMP作用。干扰素、高三尖杉酯碱(HHT)及三氧化二砷 (As2 O3 )进行体外耐药细胞逆转实验。结果　对全反式维甲酸 (ATRA)耐药的HL6 0细胞MDR1阴性 ,初发时MDR1为阴性的APL患者复发后仍为阴性。消炎痛对耐药的HL6 0增殖分化无影响 ,前列腺素E(PGE)可部分恢复ATRA对耐药HL6 0的作用。干扰素可明显逆转HL6 0的耐药性。As2 O3 与HHT对ATRA耐药的HL6 0细胞有明显作用。结论　APL细胞耐药并非多药耐药 ,消炎痛或干扰素明显逆转其耐药性 ,ATRA与As2 O3 化疗药无交叉耐药性。     

三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病50例疗效观察

 目的　观察三氧化二砷（ATO）联合全反式维甲酸（ATRA）治疗初发急性早幼粒细胞白血病（APL）的疗效。方法　98例初发APL患者分为对照组和治疗组,对照组48例,治疗组50例。对照组采用常规ATRA+DA双诱导方案治疗;治疗组采用ATRA每天25 mg／m2,ATO每天0.15 mg／kg（ATRA后第10天开始）联合治疗,直至完全缓解（CR）,CR后接受ATO和ATRA联合巩固治疗。比较两组CR率、PML-RARα融合基因转阴时间及5年无病生存率。结果　对照组和治疗组CR率分别为89.5 %（43／48）和90.0 %（45／50）,获得CR时间分别为（30.0±5.1）d和（28.1±4.4）d,两组CR率（χ2＝-0.068,P＝0.946）及获得CR时间（t＝1.757,P＝0.083）相比差异均无统计学意义。在所有获得CR的患者中,3例分别在CR后第276、385和394天复发。所有患者发病时PML-RARα融合基因均阳性,对照组和治疗组CR时分别有25.0 %（5／20）和29.4 %（5／17）转阴,巩固后分别有92.5 %（37／40）和97.6 %（41／42）转阴。对照组和治疗组5年无病生存率分别为（85.3±5.9）%和（87.6±5.6）%,差异无统计学意义（χ2＝0.232,P＝0.630）。结论　ATO联合ATRA能有效治疗初发APL患者,可以作为常规化疗方案外的另一选择。     

Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks

To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate ± 6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early-death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p = 0.393) and the low-risk and high-risk group (p = 0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors.     

Anti-leukemic and anti-angiogenesis efficacy of arsenic trioxide in new cases of acute promyelocytic leukemia

Arsenic trioxide is now considered the standard agent in treatment of refractory cases of acute promyelocytic leukemia (APL). This drug is also shown to have anti-angiogenesis effect against APL cells in vitro. This study evaluated clinical efficacy and anti-angiogenesis effect of arsenic trioxide in 17 new cases of APL. Arsenic trioxide was given in a dosage of 0.15 mg kg(-1) and remission rate, survival rate, toxicities and effect on vascular density of bone marrow was studied. The bone marrow vascular density was examined using immunohistochemistry for von Willebrand Factor (vWF) and CD31 markers. Bone marrow vascular density was determined by calculating mean vessel number in 3 hot spot, high power microscopic fields. Bone marrow vascular density was reduced as identified by anti-vWF immunohistochemical staining (Mean before treatment = 201.6 mm(-2) +/- 20.4 (SEM), mean after treatment = 109.4 +/- 17.2 (SEM), p < 0.001) and anti-CD31 immunostaining (mean before treatment = 199.17 mm(-2) +/- 21.5 (SEM), mean after treatment = 99.5 mm(-2) +/- 22.1 (SEM), p < 0.05). Treatment efficacy results showed 100% complete remission rate after median of 30 days and 72% survival rate after median 860 days of follow-up. Main toxicities included hyper-leukocytosis, hepatic toxicity and APL differentiation syndrome. The results imply that arsenic trioxide is an effective anti-leukemia and anti-angiogenesis agent in new cases of APL.