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Cancers
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Acute Promyelocytic Leukemia (APML)
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Acute Promyelocytic Leukemia (APML)

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

Deadline for manuscript submissions: 5 November 2024 | Viewed by 11170

Special Issue Editors

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

Special Issue Information

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (7 papers)

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Review

22 pages, 1205 KiB  
Review
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
Viewed by 560
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, [...] Read more.
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  
Review
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
Viewed by 671
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 [...] Read more.
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  
Review
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 1 | Viewed by 1963
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 [...] Read more.
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  
Review
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 2 | Viewed by 1544
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 [...] Read more.
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  
Review
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
Viewed by 1443
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 [...] Read more.
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  
Review
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 - 08 Jul 2023
Cited by 2 | Viewed by 1437
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, [...] Read more.
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  
Review
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 - 03 Jul 2023
Cited by 2 | Viewed by 2967
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 [...] Read more.
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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