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Acute Promyelocytic Leukemia (APML)

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (5 November 2024) | Viewed by 30710

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Dr. Gabriel Ghiaur

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Guest Editor

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
Interests: hematopoiesis; stem cell biology; bone marrow microenvironment; acute leukemia; drug resistance; clonal hematopoiesis; retinoids

Dr. Andrei Coliță

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Hematology Department, Colțea Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
Interests: acute leukemia; hematopoietic stem cell transplantation; tumor microenvironment

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Dear Colleagues,

Acute promyelocytic leukemia (APL) has become the poster child of success in hematological malignancies. Contemplating survival data from clinical trials, one may be left thinking that there are no mysteries or challenges left when it comes to the molecular and cellular biology of APL or to the management of this disease. Nevertheless, now more than ever, we should reflect on lessons learned from APL and imagine a future in which similar progress can be seen in all types of acute leukemia and cancer in general. More so, a close look at real life outcomes in this disease shows a sobering reality in which patients with APL suffer higher morbidity and mortality compared to data reported from clinical trials. Thus, a critical examination of how we diagnose and manage patients with APL on a day-to-day basis is necessary to improve the quality of life and overall outcomes for all patients with this disease, not only those treated in large academic centers from developed countries.

This Special Issue of Cancers aims to encompass the current clinical, epidemiological, and biological knowledge of APL and serve as a reference resource for academicians, clinicians, and molecular biologist alike.

Dr. Gabriel Ghiaur
Dr. Andrei Coliță
Guest Editors

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Keywords

use of retinoids in APL
use of arsenic trioxide in APL
early death in APL
minimal residual disease
differentiation syndromes
bone marrow microenvironment

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Published Papers (11 papers)

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11 pages, 644 KiB

Open AccessArticle

Risk Factors for Venous Thromboembolism in Acute Promyelocytic Leukemia

by Nikica Sabljic, Nikola Pantic, Marijana Virijevic, Jovan Rajic, Mirjana Cvetkovic, Lazar Trajkovic, Zlatko Pravdic, Zoran Bukumiric, Nada Suvajdzic Vukovic, Andrija Bogdanovic, Ana Vidovic, Milena Todorovic Balint, Jelena Bila, Danijela Lekovic, Irena Djunic, Darko Antic and Mirjana Mitrovic

Cancers 2024, 16(24), 4209; https://doi.org/10.3390/cancers16244209 - 17 Dec 2024

Viewed by 865

Abstract

Background: Acute promyelocytic leukemia (APL) is frequently associated with disseminated intravascular coagulation (DIC), leading to potentially life-threatening bleeding. Compared to bleeding, thromboses are a less commonly encountered problem. Objective: The objective of our study was to identify the incidence and predictive value of demographic data, clinical–laboratory parameters, and thrombosis risk assessment models (RAMs) for venous thromboembolism (VTE) in patients with APL. Methods: This study was a retrospective study conducted on adult patients with APL who were treated between 2006 and 2024 at the Clinic of Hematology UCCS with all-trans retinoic acid (ATRA) and anthracycline. The demographic and clinical–laboratory data related to VTE were collected and analyzed alongside the predictive value of two RAMs proposed by Al-Ani and Paterno and colleagues. Results: Among the one-hundred-fifty-five adult patients with APL, VTE was diagnosed in twenty-eight cases (18.1%). The most common location for thrombosis was in the central venous catheter (CVC), which affected twelve (42.8%) patients. A total of six (21.4%) patients had deep vein thrombosis (DVT), one patient (3.6%) showed a pulmonary embolism (PE), and thrombosis at unusual sites was present in nine (32.1%) patients. Our analyses showed that neither Al-Ani’s RAM nor the RAM proposed by Paterno and colleagues were predictive for VTE in patients with APL. The C statistics value for the Al-Ani model was ROC = 0.514, and, for Paterno’s RAM, it was ROC = 0.521. The independent risk factors for VTE, identified via multivariate analysis, were CD114 expression (p = 0.005, OR = 6.4 IC 95%: [1.8–23.2]) and the absence of bleeding at presentation (p = 0.013, OR = 0.086 IC 95%: [0.01–0.59]). Conclusions: To the best of our knowledge, this is the first study showing that a higher expression of CD114 increases the risk of VTE. The absence of bleeding at presentation in patients with APL correlates with thrombosis. Further analyses are needed to confirm these findings and help to develop therapeutic strategies to prevent VTE complications. So far, no risk assessment model has been sufficient to stratify patients with APL according to their risk of VTE. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

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19 pages, 1144 KiB

Open AccessReview

Acute Promyelocytic Leukemia-like AML: Genetic Perspective and Clinical Implications

by Luca Guarnera, Emiliano Fabiani, Giulia Falconi, Giorgia Silvestrini, Maria Luigia Catanoso, Mariadomenica Divona and Maria Teresa Voso

Cancers 2024, 16(24), 4192; https://doi.org/10.3390/cancers16244192 - 16 Dec 2024

Viewed by 1051

Abstract

Acute promyelocytic leukemia (APL) is a rare type of AML, characterized by the t(15;17) translocation and accounting for 8–15% of cases. The introduction of target therapies, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), radically changed the management of APL, making it the most curable AML subtype. However, a small percentage (estimated to be 2%) of AML presenting with APL-like morphology and/or immunophenotype lacks t(15;17). This rare APL-like AML group, whose first case was described in the early 1990s, now includes over 40 entities. These diseases present great heterogeneity in terms of genetic lesions, clinical presentation, sensitivity to targeted agents and chemotherapy, and prognosis. Furthermore, the diagnosis is very challenging. Thus, in this paper, we aim to comprehensively review the literature reports and studies addressing APL-like entities, investigate the biological mechanisms of leukemogenesis, evaluate the clinical characteristics, and discuss future lines of research and possible clinical approaches. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

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16 pages, 725 KiB

Open AccessReview

Acute Promyelocytic Leukemia in the Real World: Understanding Outcome Differences and How We Can Improve Them

by Aram Bidikian, Jan Philipp Bewersdorf, Tariq Kewan, Maximilian Stahl and Amer M. Zeidan

Cancers 2024, 16(23), 4092; https://doi.org/10.3390/cancers16234092 - 6 Dec 2024

Viewed by 2173

Abstract

The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL), resulting in excellent rates of remission and long-term survival. However, real-world outcomes often fall short of those observed in clinical trials due to various factors related to patient demographics and clinical practices. This review examines APL treatment outcomes in real-world settings and highlights the phenomenon of APL clusters. Clinical trials frequently exclude older patients and individuals with significant comorbidities, yet these groups represent a substantial portion of patients in clinical practice. Early mortality remains high in real-world settings, compounded by delayed diagnosis and treatment initiation, as well as the inexperience of some community providers and limited resources of their centers in managing APL and its associated complications. High rates of disease and induction-related complications further exacerbate early mortality. Continuous education and collaboration between community healthcare centers and expert institutions are essential, and international partnerships between resource-limited settings and expert centers can improve global APL outcomes. Ongoing monitoring for measurable residual disease (MRD) recurrence and long-term treatment toxicity, coupled with comprehensive patient evaluations, and experienced management, can enhance long-term outcomes. The clustered incidence of APL, while frequently reported, remains poorly understood. Regular reporting of these clusters could provide valuable insights into disease pathology and aid in developing predictive models for APL incidence, which would guide future resource allocation. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

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18 pages, 1326 KiB

Open AccessReview

MRD in Acute Leukemias: Lessons Learned from Acute Promyelocytic Leukemia

by David Kegyes, Praveena S. Thiagarajan and Gabriel Ghiaur

Cancers 2024, 16(18), 3208; https://doi.org/10.3390/cancers16183208 - 20 Sep 2024

Viewed by 1276

Abstract

Introduction: Advances in molecular biology, polymerase chain reaction (PCR), and next-generation sequencing (NGS) have transformed the concept of minimal residual disease (MRD) from a philosophical idea into a measurable reality. Current Treatment Paradigms and Lessons Learned from APL: Acute promyelocytic leukemia (APL) leads the way in this transformation, initially using PCR to detect MRD in patients in remission, and more recently, aiming to eliminate it entirely with modern treatment strategies. Along the way, we have gained valuable insights that, when applied to other forms of acute leukemia, hold the potential to significantly improve the outcomes of these challenging diseases. Does the BM Microenvironment Play a Role in MRD?: In this review, we explore the current use of MRD in the management of acute leukemia and delve into the biological processes that contribute to MRD persistence, including its overlap with leukemia stem cells and the role of the bone marrow microenvironment. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

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22 pages, 1205 KiB

Open AccessReview

History of Developing Acute Promyelocytic Leukemia Treatment and Role of Promyelocytic Leukemia Bodies

by Pierre Bercier and Hugues de Thé

Cancers 2024, 16(7), 1351; https://doi.org/10.3390/cancers16071351 - 29 Mar 2024

Cited by 3 | Viewed by 2501

Abstract

The story of acute promyelocytic leukemia (APL) discovery, physiopathology, and treatment is a unique journey, transforming the most aggressive form of leukemia to the most curable. It followed an empirical route fueled by clinical breakthroughs driving major advances in biochemistry and cell biology, including the discovery of PML nuclear bodies (PML NBs) and their central role in APL physiopathology. Beyond APL, PML NBs have emerged as key players in a wide variety of biological functions, including tumor-suppression and SUMO-initiated protein degradation, underscoring their broad importance. The APL story is an example of how clinical observations led to the incremental development of the first targeted leukemia therapy. The understanding of APL pathogenesis and the basis for cure now opens new insights in the treatment of other diseases, especially other acute myeloid leukemias. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

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28 pages, 345 KiB

Open AccessReview

Acute Promyelocytic Leukemia: Review of Complications Related to All-Trans Retinoic Acid and Arsenic Trioxide Therapy

by Alexandra Ghiaur, Cristina Doran, Mihnea-Alexandru Gaman, Bogdan Ionescu, Aurelia Tatic, Mihaela Cirstea, Maria Camelia Stancioaica, Roxana Hirjan and Daniel Coriu

Cancers 2024, 16(6), 1160; https://doi.org/10.3390/cancers16061160 - 15 Mar 2024

Cited by 8 | Viewed by 3581

Abstract

The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid receptor α gene (PML::RARA). The PML::RARA fusion is a molecular target for all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Therapies based on ATRA plus ATO have excellent outcomes in terms of complete remission rates, overall survival, and achievement of deep and durable molecular responses with a very low incidence of relapse. However, although the combination of ATRA and ATO has lower hematologic toxicity than standard chemotherapy, its use is associated with a spectrum of distinctive toxicities, such as differentiation syndrome, liver toxicity, QT interval prolongation, and neurotoxicity. Rigorous monitoring of patients’ clinical evolution is indispensable for identifying and addressing each complication. The objective is to maintain an equilibrium between treatment-induced adverse events and therapeutic efficacy. This paper focused on non-hematologic complications associated with the combination of ATRA and ATO. Additionally, we discuss late-onset complications of this therapy. In summary, the majority of treatment-related adverse events are manageable, self-limiting, and reversible. More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

14 pages, 344 KiB

Open AccessReview

Differentiation Syndrome in Acute Leukemia: APL and Beyond

by Ashley C. Woods and Kelly J. Norsworthy

Cancers 2023, 15(19), 4767; https://doi.org/10.3390/cancers15194767 - 28 Sep 2023

Cited by 8 | Viewed by 4438

Abstract

Differentiation syndrome (DS) is a frequent and potentially life-threatening clinical syndrome first recognized with the advent of targeted therapeutics for acute promyelocytic leukemia (APL). DS was subsequently observed more broadly with targeted therapeutics for acute myeloid leukemia (AML). DS is typically characterized by fever, dyspnea, hypotension, weight gain, pleural or pericardial effusions, and acute renal failure. The incidence in patients with APL ranges from 2 to 37%, with the wide variation likely attributed to different diagnostic criteria, use of prophylactic treatment, and different treatment regimens. Treatment with corticosteroids +/- cytoreductive therapy should commence as soon as DS is suspected to reduce DS-related morbidity and mortality. The targeted anti-leukemic therapy should be discontinued in patients with severe DS. Here, we discuss the pathogenesis of DS, clinical presentations, diagnostic criteria, management strategies, and implementation of prospective tracking on clinical trials. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

16 pages, 361 KiB

Open AccessReview

Hematopoietic Stem Cell Transplantation in Acute Promyelocytic Leukemia in the Era of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO)

by Andrei Colita, Alina Daniela Tanase, Ciprian Tomuleasa and Anca Colita

Cancers 2023, 15(16), 4111; https://doi.org/10.3390/cancers15164111 - 15 Aug 2023

Cited by 3 | Viewed by 2580

Abstract

Acute promyelocytic leukemia (APL) currently represents one of the malignant hemopathies with the best therapeutic responses, following the introduction of all-trans retinoic acid (ATRA) and subsequently of arsenic trioxide (ATO) treatment. As a result, a large proportion of patients with APL achieve long-term responses after first-line therapy, so performing a hematopoietic stem cell transplant as consolidation of first complete remission (CR) is no longer necessary. Even in the case of relapses, most patients obtain a new remission as a result of therapy with ATO and ATRA, but an effective consolidation treatment is necessary to maintain it. The experience accumulated from studies published in the last two decades shows the effectiveness of hematopoietic stem cell transplantation (HSCT) in improving the outcome of patients who achieve a new CR. Thus, the expert groups recommend transplantation as consolidation therapy in patients with a second CR, with the indication for autologous HSCT in cases with molecular CR and for allogeneic HSCT in patients with the persistence of minimal residual disease (MRD) or with early relapse. However, there is a variety of controversial aspects related to the role of HSCT in APL, ranging from the fact that outcome data are obtained almost exclusively from retrospective studies and historical analyses to questions related to the type of transplantation, the impact of minimal residual disease, conditioning regimens, or the role of other therapeutic options. All these questions justify the need for controlled prospective studies in the following years. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

11 pages, 270 KiB

Open AccessReview

Management of Acute Promyelocytic Leukemia at Extremes of Age

by Sabine Kayser and Shannon E. Conneely

Cancers 2023, 15(14), 3637; https://doi.org/10.3390/cancers15143637 - 15 Jul 2023

Cited by 4 | Viewed by 2500

Abstract

Tailored treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal disease to one of the most curable malignant diseases in humans. Due to its high efficacy, ATO/ATRA is the standard first-line therapy in younger adult, non-high-risk APL patients. However, early death is still a major issue in APL, particularly in older patients. Thus, rapid diagnostics, immediate access to ATRA-based therapy, and supportive care are of utmost importance. Nevertheless, challenging situations occur, particularly in patients excluded from controlled studies with clinical knowledge mainly based on case reports and registries. Besides the treatment of newly diagnosed patients, managing toxicities and complications remains challenging. This review discusses the approach to the treatment of APL in elderly and pediatric patients. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

17 pages, 663 KiB

Open AccessReview

The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away

by Yuya Nagai and Alexander J. Ambinder

Cancers 2023, 15(14), 3535; https://doi.org/10.3390/cancers15143535 - 8 Jul 2023

Cited by 9 | Viewed by 2726

Abstract

Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA’s success has deepened our understanding of the role of the RARα pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RARα pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

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21 pages, 1301 KiB

Open AccessReview

The Coagulopathy of Acute Promyelocytic Leukemia: An Updated Review of Pathophysiology, Risk Stratification, and Clinical Management

by Jack Hermsen and Bryan Hambley

Cancers 2023, 15(13), 3477; https://doi.org/10.3390/cancers15133477 - 3 Jul 2023

Cited by 11 | Viewed by 5651

Abstract

Acute promyelocytic leukemia (APL) has a well-established mechanism and a long-term prognosis that exceeds that of any other acute leukemia. These improving outcomes are due, in part, to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two targeted and highly active agents in this disease. However, there remains a considerable morbidity and mortality risk in APL secondary to clinically significant hemorrhagic and/or thrombotic events. Prevention and treatment of these coagulopathic complications remain significant impediments to further progress in optimizing outcomes for patients with APL. Moreover, the relative rarity of APL hinders adequately powered randomized controlled trials for evaluating APL coagulopathy management strategies. This review draws from peer-reviewed works falling between initial descriptions of APL in 1957 and work published prior to January 2023 and provides an updated overview of the pathophysiology of hemorrhagic and thrombotic complications in APL, outlines risk stratification parameters, and compiles current clinical best practices. An improved understanding of the pathophysiologic mechanisms driving hemorrhage and thrombosis along with the completion of well-designed trials of management strategies will assist clinicians in developing interventions that mitigate these devastating complications in an otherwise largely curable disease. Full article

(This article belongs to the Special Issue Acute Promyelocytic Leukemia (APML))

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