Acute promyelocytic leukemia current treatment algorithms

In 1957, Hillestad et al. defined acute promyelocytic leukemia (APL) for the first time in the literature as a distinct type of acute myeloid leukemia (AML) with a “rapid downhill course” characterized with a severe bleeding tendency. APL, accounting for 10–15% of the newly diagnosed AML cases, results from a balanced translocation, t(15;17) (q22;q12-21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene. The PML–RARA fusion oncoprotein induces leukemia by blocking normal myeloid differentiation. Before using anthracyclines in APL therapy in 1973, no effective treatment was available. In the mid-1980s, all-trans retinoic acid (ATRA) monotherapy was used with high response rates, but response durations were short. Later, the development of ATRA, chemotherapy, and arsenic trioxide combinations turned APL into a highly curable malignancy. In this review, we summarize the evolution of APL therapy, focusing on key milestones that led to the standard-of-care APL therapy available today and discuss treatment algorithms and management tips to minimize induction mortality.Subject terms: Chemotherapy, Acute myeloid leukaemia     

Acute promyelocytic leukemia in childhood

Acute promyelocytic leukemia (APL) is a relatively rare form of acute myelogenous leukemia (AML). In the United States, APL in children constitutes only 5% to 10% of AML. Molecularly, the disease is characterized by a fusion protein, promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-α that results from a balanced reciprocal translocation between the PML gene on chromosome 15 and the RAR-α (RARA) gene on chromosome 17. A major advance in the field of APL treatment has been the use of all-trans-retinoic acid (ATRA). Advances in the treatment of APL have taken this form of AML from a disease with significant morbidity and mortality to one with an excellent outcome. This has resulted largely from the incorporation of ATRA into frontline regimens with chemotherapy. Anthracyclines remain a cornerstone of treatment at this point. Recent trials have shown a role for arsenic trioxide in both newly diagnosed and relapsed APL.     

Effect of arsenic trioxide or ATRA on primary APL cell or HL-60 cells and their value analysis in hyperleukocytosis

We have done a lots of works to detect the mechanism of hyperleukocytosis in patients with acute promyelocytic leukemia (APL) after treatment with all trans retinoic acid (ATRA). The early results of study showed that some important factors are related to the hyperleukocytosis, for example, the relationship between serum G-CSF and variation of promyelocytes or more matured granulocytes[1,2]. The further study also indicated that effect of G-CSF on leukemia cells was related to the variat…     

The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral,outpatient therapy

The therapeutic potential of arsenic derivatives has long been recognized and was recently rediscovered in modern literature. Early studies demonstrated impressive activity of this compound in patients with relapsed acute promyelocytic leukemia (APL). Over the last 2 decades, intravenous arsenic trioxide has been used successfully, both alone and in combination with other agents, for the treatment of APL and, with some success, of other myeloid neoplasms. Arsenic trioxide is currently part the standard of care for patients with APL. More recently, oral formulations of this compound have been developed and are entering clinical practice. In this review, the authors discuss the evolution of arsenic in the treatment of APL and other myeloid neoplasms. Cancer 2016;122:1160–8. © 2015 American Cancer Society.     

Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical results and open questions

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia. The specific translocation t(15;17), which results in the fusion gene PML–RARA is the diagnostic and pathomechanistic hallmark of APL. By combination, treatment consisting of the differentiating agent all-trans retinoic acid (ATRA), which targets this molecular lesion, and cytotoxic chemotherapy, cure can be achieved in over 70% of patients. Recently, arsenic trioxide (ATO) has emerged to be the most active single agent in the treatment of APL. Previous studies employing ATO in relapse settings reported average complete remission rates of 85% and a mean overall survival of over 60%. In recent approaches installing ATO in first-line treatment, ATO-induced response rates comparable to previous combination regimen. The results of these newer studies indicate that the backbone of chemotherapy can be dramatically reduced or completely replaced by ATO and ATRA with similar or even better outcome.     

Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide

An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene.     

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。     

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.     

Granulocyte colony-stimulating factor potentiates differentiation induction by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in the acute promyelocytic leukemia cell line HT93A

The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125?μM) and apoptosis at high concentrations (1-2?μM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1?μM ATRA and/or 50?ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1?μM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50?ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL.     

Diagnosis and treatment of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL), characterized by a translocation between the promyelocytic leukemia gene (PML) on chromosome 15 and the retinoic acid receptor-α (RARα) gene on chromosome 17, has become a model for targeted treatment of cancer. Advances in our understanding of the fundamental biology of this disease have led to the development of tools for diagnosis, monitoring of minimal residual disease, and detection of early relapse. Differentiation therapy with all-trans retinoic acid in combination with chemotherapy has significantly improved survival in patients with APL. Moreover, arsenic trioxide, which induces differentiation and apoptosis of APL cells, has become standard treatment for relapsed disease, and its role in the treatment of newly diagnosed APL is under active investigation. The lessons learned from APL have broad applications to other forms of leukemia and to cancer in general, whereby molecularly targeted therapy is directed to specifically defined subgroups.     

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。     

Acute promyelocytic leukemia: where did we start,where are we now,and the future

Historically, acute promyelocytic leukemia (APL) was considered to be one of the most fatal forms of acute leukemia with poor outcomes before the introduction of the vitamin A derivative all-trans retinoic acid (ATRA). With considerable advances in therapy, including the introduction of ATRA initially as a single agent and then in combination with anthracyclines, and more recently by development of arsenic trioxide (ATO)-containing regimens, APL is now characterized by complete remission rates of 90% and cure rates of ∼80%, even higher among low-risk patients. Furthermore, with ATRA–ATO combinations, chemotherapy may safely be omitted in low-risk patients. The disease is now considered to be the most curable subtype of acute myeloid leukemia (AML) in adults. Nevertheless, APL remains associated with a significant incidence of early death related to the characteristic bleeding diathesis. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure.     

Management of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) has become the most potentially curable subtype of acute myeloid leukemia (AML) in adults. With current treatment strategies that incorporate all-trans retinoic acid (ATRA), long-term disease-free survival and potential cure rates of 70% to 80% can be expected. Such progress reflects what can be accomplished with insights into the molecular pathogenesis of leukemia, identification of a molecular target, and rapid accrual to a series of clinical trials. The leukemic promyelocytes from patients with APL are uniquely susceptible to a variety of novel agents in addition to ATRA, including arsenic trioxide, and in preliminary studies, gemtuzumab ozogamicin, the immunoconjugate comprised of an anti-CD33 monoclonal antibody linked to the potent cytotoxic agent calicheamicin. Incorporation of such agents into the treatment of patients with high-risk disease may be an important future direction to pursue.     

All-trans retinoic acid in the treatment of pediatric acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among ‘Nordic’ origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-α gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90–95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children 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.     

Unlocking the potential of retinoic acid in anticancer therapy

All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A. Its antitumour activities have been extensively studied in a variety of model systems and clinical trials; however, to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide. After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor. Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity. Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes. This review discusses the current progresses in the understanding how ATRA can be utilised in the therapy of non-APL AML and other cancers.