Extramedullary relapse in a patient with acute promyelocytic leukemia: successful treatment with arsenic trioxide, all-trans retinoic acid and gemtuzumab ozogamicin therapies

Acute promyelocytic leukemia (APL) is characterized by the presence of the t(15;17) translocation, resulting in the PML-RAR fusion protein. Standard treatment consists of the combination of all-trans retinoic acid (ATRA) with an anthracycline that results in complete remission (CR) rates in excess of 90%. Recently, several new agents have been shown to have clinical activity in APL. These include a liposomal formulation of ATRA (lipo-ATRA), and gemtuzumab ozogamicin (GO). Herein, we report a patient with APL who relapsed with extramedullary disease 2.5 years after lipo-ATRA therapy and was successfully treated with the sequence of A2O3, ATRA, and GO and we summarize our experience with patients with isolated extramedullary relapse in APL.     

Differentiating agents in pediatric malignancies: All-trans-retinoic acid and arsenic in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is the most potentially curable type of acute myeloid leukemia. It is characterized by the chromosomal translocation t(15;17), which results in the fusion gene PML-RAR-α. The introduction of all-trans- retinoic acid (ATRA) was a major advance in treatment of this disease. This agent induces terminal differentiation of malignant myeloid cells to mature neutrophils, and its side effects are usually well tolerated in children. ATRA does not eradicate the malignant myeloid clone in APL and, eventually, resistance develops. Arsenic trioxide induces nonterminal differentiation of malignant promyelocytes and promotes apoptosis. APL patients treated with ATRA or arsenic trioxide have rapid resolution of their coagulopathy. Because both of these drugs are well tolerated in children and their synergy has been shown in animal models, the possibility of combining ATRA and arsenic trioxide in frontline therapy for children with APL is being considered.     

Contemporary Treatment of APL

Acute promyelocytic leukemia (APL) is characterized by coagulopathy, leukopenic presentation and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). For the last 25 years, APL has been treated with a combination of ATRA and chemotherapy for induction followed by consolidation and maintenance therapy. This general treatment approach has resulted in cure rates of 80–90 %. ATO, originally approved in relapsed APL, has been incorporated into contemporary upfront treatment regimens with excellent response rates. Recent studies show that most patients with APL can be cured with ATRA and ATO alone, eliminating cytotoxic chemotherapy and resulting in superior outcomes compared to standard treatment. We will herein review historical treatment of APL, treatment considerations in specific patient populations, and therapeutic updates.     

全反式维甲酸联合化疗治疗小儿急性早幼粒细胞白血病

目的观察全反式维甲酸（ATRA）联合化疗治疗小儿急性早幼粒细胞白血病（APL）的疗效。方法22例初治患儿用ATRA诱导治疗;当患儿获完全缓解（CR）后,给予DA方案或IDA方案或HA方案或AA方案巩固治疗3个疗程;以后再用ATRA、化疗交替巩固治疗36个月。结果2例在诱导治疗前死于弥散性血管内凝血（DIC）、颅内出血;22例获CR,CR率100％（20／20）。1、3、5年无病生存（DFS）率分别为100％（20／20）、93．3％（14／15）、84．7％（11／13）。ATRA常见毒副作用依次为皮肤和口唇干燥、头痛、恶心、呕吐、肝功能损害及维甲酸综合征。结论ATRA联合化疗治疗小儿APLCR率高、远期疗效好;在诱导治疗前,DIC、颅内出血仍是APL患儿死亡的主要原因;ATRA毒副作用可耐受。     

Is cytarabine required in the treatment of acute promyelocytic leukemia?

Until the late 1980s, chemotherapy with anthracyclines and cytarabine (AraC) was the only treatment approach for acute promyelocytic leukemia (APL), as for other types of acute myeloid leukemia. Many studies have shown that treatment with all-trans retinoic acid (ATRA), followed by anthracycline-AraC chemotherapy, significantly decreases the incidence of relapse and improves survival in newly diagnosed APL, compared with this chemotherapy alone. This approach was associated with consistent morbidity and mortality during consolidation and maintenance treatment, however, mainly resulting from myelosuppression induced by anthracycline-AraC courses. Several groups have reported high rates of complete remission and low rates of relapse with ATRA and chemotherapy using anthracyclines alone, suggesting that AraC could be avoided in the chemotherapy of APL, reducing toxicity. These results were not confirmed in other studies, however, raising the issue of the role of AraC in treatment of patients with newly diagnosed APL.     

The present status in all-trans retinoic acid (ATRA) treatment for acute promyelocytic leukemia patients: further understanding and comprehensive strategy are required in the future.

All-trans retinoic acid (ATRA) has recently been recognized as the first line therapeutic agent in the treatment of patients with acute promyelocytic leukemia (APL). The extraordinary high remission rate achieved by ATRA in comparison with other chemotherapeutic agents suggested that ATRA differentiation induction therapy seemed superior to conventional chemotherapy for APL patients. However, after the great excitement aroused after the initial successes, we have to take stock and examine in detail several problems which have emerged preventing us from improving the clinical outcome in APL. Maintenance in order to prolong remission and prevention of or retreatment for the relapse are the major subjects of concern at present. Efforts should be made either to keep ATRA effective for APL patients or to resensitize the relapsing patients for repeated ATRA therapy. The administration of ATRA should be carefully adapted in accordance with the individual patient's condition. From both conceptual and practical points of view, ATRA differentiation therapy should be combined with chemotherapy, bone marrow transplantation and biomodifier treatment. Thus, a more comprehensive strategy must be planned and developed in the near future. Using molecular biological techniques, the diagnosis of APL can be more precisely made and the course of the disease more closely monitored. The central dogma, still to be revealed, is the relationship between APL pathogenesis, the chromosome translocation present with the relevant molecular alterations and the response to ATRA treatment. Current studies in all these above fields have provided us with a deeper understanding of the pathogenesis of APL and the physiological function and curative action of ATRA.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

The Present Status in All-trans Retinoic Acid (ATRA) Treatment for Acute Promyelocytic Leukemia Patients: Further Understanding and Comprehensive Strategy are Required in the Future

All-trans retinoic acid (ATRA) has recently been recognized as the first line therapeutic agent in the treatment of patients with acute promyelocytic leukemia (APL). The extraordinary high remission rate achieved by ATRA in comparison with other chemotherapeutic agents suggested that ATRA differentiation induction therapy seemed superior to conventional chemotherapy for APL patients. However, after the great excitement aroused after the initial successes, we have to take stock and examine in detail several problems which have emerged preventing us from improving the clinical outcome in APL.

Maintenance in order to prolong remission and prevention of or retreatment for the relapse are the major subjects of concern at present. Efforts should be made either to keep ATRA effective for APL patients or to resensitize the relapsing patients for repeated ATRA therapy. The administration of ATRA should be carefully adapted in accordance with the individual patient's condition. From both conceptual and practical points of view, ATRA differentiation therapy should be combined with chemotherapy, bone marrow transplantation and biomodifier treatment. Thus, a more comprehensive strategy must be planned and developed in the near future. Using molecular biological techniques, the diagnosis of APL can be more precisely made and the course of the disease more closely monitored. The central dogma, still to be revealed, is the relationship between APL pathogenesis, the chromosome translocation present with the relevant molecular alterations and the response to ATRA treatment. Current studies in all these above fields have provided us with a deeper understanding of the pathogenesis of APL and the physiological function and curative action of ATRA. This will no doubt enhance the development of the ATRA treatment regimen thereby widening the spectrum of leukemias and other neoplasias to be treated with differentiation therapy.     

Advances in therapies for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), results from the arrest of the maturation of hematopoietic progenitors at the promyelocyte stage. It has been shown that APL is associated with a reciprocal chromosomal translocation, involving chromosomes 15 and 17, which fuses the gene encoding the retinoic acid receptor α (RARα) and the promyelocytic leukemia (PML) gene. The resultant PML-RARα fusion protein plays a critical role in the pathogenesis of APL. Although there are many subtypes of AML, all are typically managed using a standard chemotherapy regimen of an anthracycline plus cytarabine arabinoside (CA). Despite high rates of complete remission following standard chemotherapy, most patients relapse and long-term disease-free survival is only 30-40%. The introduction of drugs such as all-trans retinoic acid (ATRA) that promote progenitor differentiation by directly inhibiting the PML-RARα fusion protein has changed the treatment paradigm for APL and markedly improved patient survival. The purposes of the present review are to provide the latest results and future directions of clinical research into APL and to illustrate how new therapies, such as ATRA plus anthracycline-based induction and consolidation therapy, risk-adapted therapy, salvage therapy containing arsenic trioxide-based regimens, and hematopoietic stem cell transplantation, have improved the treatment outcomes for APL patients.     

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.     

Extensive splenic infarction,deep vein thrombosis and pulmonary emboli complicating induction therapy with all-trans-retinoic acid (ATRA) for acute promyelocytic leukemia

Bleeding is a common complication during initial induction treatment for acute promyelocytic leukemia (APL). Administration of all-trans-retinoic acid (ATRA), which is in routine use for APL in the past decade improves the bleeding tendency dramatically. Nevertheless, thrombotic events have still been reported in a small proportion of APL patients treated with ATRA. Here we describe a case of splenic infarction and life threatening thrombosis in a young patient with APL treated with ATRA. We review the relevant literature and discuss the pathophysiology, risk factors and treatment of this complication occurring during therapy, for APL.     

Alterations in Fas (CD 95/Apo-1) and Fas ligand (CD178) expression in acute promyelocytic leukemia during treatment with ATRA

Over the recent years, treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) has become a widely accepted therapeutic regimen and is considered a model of differentiation therapy in malignant diseases. However, the role of ATRA treatment beyond that of the induction of differentiation of leukemic blasts is still far from being fully understood. Data from in vivo and in vitro studies have demonstrated that during ATRA treatment of APL there are significant changes not only in the expression of the apoptotic molecules Fas and Fas ligand, but also in the expression of other molecules involved both in the regulation of apoptosis and in interactions between host immune and leukemia cells. These effects may thus contribute, at least in part, to the beneficial effects of ATRA therapy in APL. In this report we review the current status of studies that contribute to our understanding of treatment with ATRA. We focus on ATRA-induced changes in apoptotic pathways, particularly as it relates to the Fas/Fas ligand system.     

Prolonged third remission in a patient with acute promyelocytic leukemia after consolidation chemotherapy with intermittent intermediate dose ara-C and maintenance with intermittent all-trans retinoic acid (ATRA)

The benefit of all-trans-retinoic acid (ATRA) in the front line therapy of acute promyelocytic leukemia (APL) is well established, but its role in postremission therapy and in the treatment of relapse is currently under investigation. Moreover, the impact of cytosine arabinoside (Ara-C) in the therapy of APL has been questioned in recent studies. We report a prolonged third molecular remission (MR) in a patient with hyperleukocytotic APL after induction with ATRA, consolidation chemotherapy (CT) with intermittent intermediate dose Ara-C and maintenance therapy with intermittent ATRA. While the first two remissions were relatively short (8 months and 11 months, resp.), the duration of the third continuous CR (49+ months) is more than twice as long as the length of the two previous remissions combined. In this case Ara-C followed by intermittent ATRA maintenance was a safe and effective therapy for relapsed disease. A third molecular remission of such duration and quality is unusual.     

Retinoic acid resistance in acute promyelocytic leukemia.

Primary resistance of PML-RARalpha-positive acute promyelocytic leukemia (APL) to the induction of clinical remission (CR) by all-trans retinoic acid (ATRA) is rare but markedly increases in frequency after > or =2 relapses from chemotherapy-induced CRs. Nevertheless, even in de novo cases, the primary response of ATRA-naive cases is variable by several measures, suggesting involvement of heterogeneous molecular elements. Secondary, acquired ATRA resistance occurs in most patients treated with ATRA alone and in many patients who relapse from combination ATRA chemotherapy regimens despite limited ATRA exposure. Although early studies suggested that an adaptive hypercatabolic response to pharmacological ATRA levels is the principal mechanism of ATRA resistance, recent studies suggest that molecular disturbances in APL cells have a predominant role, particularly if disease relapse occurs a few months after discontinuing ATRA therapy. This review summarizes the systemic and APL cellular elements that have been linked to clinical ATRA resistance with emphasis on identifying areas of deficient information and important topics for further investigation. Overall, the subject review strongly supports the hypothesis that, although APL is an infrequent and nearly cured disease, much can be gained by understanding the complex relationship of ATRA resistance to the progression and relapse of APL, which has important implications for other leukemias and malignancies.     

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 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     

Relapse of acute promyelocytic leukemia with PML-RARalpha mutant subclones independent of proximate all-trans retinoic acid selection pressure.

Relapse of acute promyelocytic leukemia (APL) following all-trans retinoic acid (ATRA) therapy has been associated with the acquisition of mutations in the high-affinity ATRA binding site in PML-RARalpha, but little information is available about the selection dynamics of the mutation-harboring subclones. In this study, 6/18 patients treated with sequential ATRA and chemotherapy on protocol INT0129 relapsed with complete replacement of the nonmutant pretreatment APL cell population by a PML-RARalpha mutant subclone. Two patients relapsed in proximity of ATRA treatment; however, in four patients there was a 6-48 month hiatus between the last ATRA treatment and relapse. The mutant subclones were not detectable in samples tested > or = 3 months before relapse at > or = 1 in 10(2) (10(-2)) sensitivity. In one patient, a functionally weak mutation was detected at 10(-4) sensitivity before therapy but only limited pre-relapse enrichment of the mutant subclone was observed on subsequent ATRA therapy. These results indicate that proximate ATRA selection pressure is frequently not the main determinant for the emergence of strongly dominant PML-RARalpha mutant subclones and suggest that APL subclones harboring PML-RARalpha mutations are predisposed to the acquisition of secondary genetic/epigenetic alterations that result in a growth/survival advantage.     

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.     

All-trans retinoic acid and hematopoietic growth factors regulating the growth and differentiation of blast progenitors in acute promyelocytic leukemia

Although acute leukemia is generally thought to be characterized by maturation arrest, it has been shown that differentiation occurs in blast cells of acute myelogenous leukemia (AML) in vitro as well as in vivo, and that morphologically abnormal mature polymorphonuclear neutrophils (PMNs) often seen in patients with AML are possibly derived from spontaneously differentiating leukemic cells. Acute promyelocytic leukemia (APL) is an unique example in which these features of AML are evident in an almost complete form; administration of all-trans retinoic acid (ATRA) induces differentiation of neoplastic cells into mature neutrophils and successfully induce complete remission in most patients. However, PMNs appearing during ATRA treatment are morphologically abnormal, as indicated not only by the presence of Auer rods but also by neutrophil secondary-granule deficiency that is commonly seen in AML. Moreover, ATRA has heterogeneous effects on the growth of blast progenitors in APL in different patients, being inhibitory, stimulatory or ineffective, which might account in part for the leukemia relapse in patients treated with ATRA alone. Hematopoietic growth factors regulate the growth of blast progenitors in APL. Among them, granulocyte colony-stimulating factor (G-CSF) is unique in that it preferentially stimulates clonal growth, but not self-renewal, in many APL cases, and synergistically enhances the differentiation-inducing effect of ATRA when used in combination. Many other compounds also exert such synergistic effects with ATRA, for which a variety of mechanisms have been suggested. It is crucial to precisely elucidate the functions of these molecules governing the growth/differentiation balance of AML blast progenitors and the mechanisms underlying their deregulated differentiation program in order to achieve effective differentiation therapy for patients with AML, not restricted to APL.