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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 45021

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Dr. Xavier Thomas

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Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France
Interests: Acute leukemia; hematopoietic stem cell transplantation; myelodysplastic syndromes; targeted therapy.
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Dr. Maël Heiblig

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Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France
Interests: acute leukemia; hematopoietic stem cell transplantation; myelodysplastic syndromes; targeted therapy
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Dear Colleagues,

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) ,cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between promyelocytic leukemia (PML) gene and retinoic acid receptor-α (RARα). Because of a severe bleeding tendency often resulting in an early fatal course, APL has historically been considered as one of the most fatal forms of acute leukemia. Advances in therapy, including anthracycline- and cytarabine-based chemotherapy, have significantly improved the outcome. Additionally, the introduction of all-trans retinoic acid (ATRA) and, more recently, the development of arsenic trioxide (ATO)-containing regimens has transformed APL to the most curable form of AML in adults. Treatment with these new agents introduced the concept of cure through targeted therapy. With the revolutionary ATRA–ATO combination therapies, chemotherapy may now safely be omitted, at least in low-risk APL patients. Concomitantly, expert panels have recommended that molecular remission should be considered a therapeutic objective in APL, and molecular response has been adopted as a study endpoint in modern clinical trials.

APL is the best example of how targeted therapies can trigger definitive cures. ATRA–ATO combination therapy is the first model of molecular target-based therapy and represents, with the introduction of tyrosine kinase inhibitor therapy in chronic myeloid leukemia, one of the major advances in therapy for hematological disease over the last three decades, having paved the way in which cancer should be treated. However, open issues remain, notably regarding the type of ATO schedule and the refinements in strategies in high-risk APL. Other areas of ongoing needs include efforts to decrease the early death rate, to define APL treatments in children and in case of post-ATO relapses, and to introduce a new drug formula with the attempt to give only oral ambulatory therapy.

This Special Issue will highlight the current state of the art in APL with future prospects for improving therapies and recall the constant progresses made over the last decades that have yielded APL status to evolve from highly fatal to highly curable.

Dr. Xavier Thomas
Dr Maël Heiblig
Guest Editors

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Keywords

acute promyelocytic leukemia
prognosis
treatment
all-trans retinoic acid
arsenic trioxide
chemotherapy
PML-RARA

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 180 KiB

Open AccessEditorial

Acute Promyelocytic Leukemia

by Xavier Thomas and Maël Heiblig

Cancers 2020, 12(12), 3718; https://doi.org/10.3390/cancers12123718 - 11 Dec 2020

Cited by 3 | Viewed by 1987

Abstract

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor-α (RARα) [...] Full article

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

Research

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16 pages, 2754 KiB

Open AccessArticle

Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia

by Isabel Weinhäuser, Diego A. Pereira-Martins, Cesar Ortiz, Douglas R. Silveira, Luíse A. A. Simões, Thiago M. Bianco, Cleide L. Araujo, Luisa C. Koury, Raul A. M. Melo, Rosane I. Bittencourt, Katia Pagnano, Ricardo Pasquini, Elenaide C. Nunes, Evandro M. Fagundes, Ana B. Gloria, Fábio Kerbauy, Maria de Lourdes Chauffaille, Armand Keating, Martin S. Tallman, Raul C. Ribeiro, Richard Dillon, Arnold Ganser, Bob Löwenberg, Peter Valk, Francesco Lo-Coco, Miguel A. Sanz, Nancy Berliner, Emanuele Ammatuna, Antonio R. Lucena-Araujo, Jan Jacob Schuringa and Eduardo M. Rego Show full author list Hide full author list

Cancers 2020, 12(11), 3134; https://doi.org/10.3390/cancers12113134 - 27 Oct 2020

Cited by 7 | Viewed by 3696

Abstract

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2^high transcript levels were associated with cell cycle arrest, while SLIT2^low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated. Full article

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

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16 pages, 1221 KiB

Open AccessArticle

Impact of CD56 Continuously Recognizable as Prognostic Value of Acute Promyelocytic Leukemia: Results of Multivariate Analyses in the Japan Adult Leukemia Study Group (JALSG)-APL204 Study and a Review of the Literature

by Akihiro Takeshita, Norio Asou, Yoshiko Atsuta, Hiroaki Furumaki, Toru Sakura, Yasunori Ueda, Masashi Sawa, Nobuaki Dobashi, Yasuhiro Taniguchi, Rikio Suzuki, Masaru Nakagawa, Shigehisa Tamaki, Maki Hagihara, Katsumichi Fujimaki, Hitoshi Minamiguchi, Hiroyuki Fujita, Masamitsu Yanada, Yoshinobu Maeda, Noriko Usui, Yukio Kobayashi, Hitoshi Kiyoi, Shigeki Ohtake, Itaru Matsumura, Tomoki Naoe, Yasushi Miyazaki and the Japan Adult Leukemia Study Group Show full author list Hide full author list

Cancers 2020, 12(6), 1444; https://doi.org/10.3390/cancers12061444 - 1 Jun 2020

Cited by 5 | Viewed by 3597

Abstract

Background: After long-term analysis of the JALSG-APL204 study we recently reported that maintenance therapy with tamibarotene was more effective than all-trans retinoic acid (ATRA) by reducing relapse in APL patients. Here, the clinical significance of other important prognostic factors was evaluated with multivariate analyses. Patients and Methods: Newly diagnosed acute promyelocytic leukemia (APL) patients were registered with the study. Induction was composed of ATRA and chemotherapy. Patients who achieved molecular remission after consolidation were randomly assigned to maintenance with tamibarotene or ATRA. Results: Of the 344 eligible patients, 319 (93%) achieved complete remission (CR). After completing consolidation, 269 patients underwent maintenance random assignment—135 to ATRA, and 134 to tamibarotene. By multivariate analysis, overexpression of CD56 in blast was an independent unfavorable prognostic factor for relapse-free survival (RFS) (p = 0.006) together with more than 10.0 × 10⁹/L WBC counts (p = 0.001) and the ATRA arm in maintenance (p = 0.028). Of all phenotypes, CD56 was related most clearly to an unfavorable prognosis. The CR rate, mortality rate during induction and overall survival of CD56⁺ APL were not significantly different compared with CD56⁻ APL. CD56 is continuously an independent unfavorable prognostic factor for RFS in APL patients treated with ATRA and chemotherapy followed by ATRA or tamibarotene maintenance therapy. Full article

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

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12 pages, 467 KiB

Open AccessArticle

Acute Promyelocytic Leukemia during Pregnancy: A Systematic Review of the Literature

by Andrea Santolaria, Alfredo Perales, Pau Montesinos and Miguel A. Sanz

Cancers 2020, 12(4), 968; https://doi.org/10.3390/cancers12040968 - 14 Apr 2020

Cited by 14 | Viewed by 3685

Abstract

The management of pregnant women with acute promyelocytic leukemia (APL) is a challenging situation where limited evidence-based information is available. We performed a systematic literature review to analyze the outcomes reported for both mother and fetus when APL is diagnosed during pregnancy. PubMed, Scopus and Web of Science databases were systematically searched to identify studies reporting cases of APL during pregnancy. Sixty-six articles met the eligibility criteria (53 single case reports). Ninety-two patients were eligible for induction therapy, with most them being treated with all-trans retinoic acid alone (32%) or combined with chemotherapy (43%), while the remaining patients received chemotherapy alone. Three patients were treated with arsenic-based regimens after delivery. Overall complete remission rate was 89%, with no statistically significant differences according to the type of induction and gestational age. During the first trimester, women were more likely to experience spontaneous and induced abortion compared to those during the second trimester (88% vs. 30%) (p < 0.0001), while only one patient diagnosed during the third trimester terminated in stillbirth. Twelve of 16 infants with neonatal complications had respiratory distress syndrome. Except two early deaths (Potter’s syndrome and pulmonary hemorrhage), all neonates evolved favorably. This study confirms that gestational age does not affect the results in the mother, but is closely related to fetal viability. Our results may be useful for the process of decision making that requires the involvement of the patient, hematologist, obstetrician and neonatologist. Full article

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

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14 pages, 2038 KiB

Open AccessArticle

Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2

by Károly Jambrovics, Iván P. Uray, Jeffrey W. Keillor, László Fésüs and Zoltán Balajthy

Cancers 2020, 12(3), 648; https://doi.org/10.3390/cancers12030648 - 11 Mar 2020

Cited by 9 | Viewed by 3214

Abstract

Randomized trials in acute promyelocytic leukemia patients have shown that treatment with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior in efficacy to monotherapy, with significantly decreased mortality. So far, there are little data available to explain the success of the ATRA and ATO combination treatment in molecular terms. We showed that ATRA- and ATO-treated cells had the same capacity for superoxide production, which was reduced by two-thirds in the combined treatment. Secreted inflammatory biomarkers (monocyte chemoattractant protein-1 [MCP-1], interleukin-1 beta [IL-1β] and tumor necrosis factor-α [TNF-α]) were significantly decreased and were further reduced in a transglutaminase 2 (TG2) expression-dependent manner. The amount of secreted TNF-α in the supernatant of NB4 TG2 knockout cells was close to 50 times lower than in ATRA-treated differentiated wild-type NB4 cells. The irreversible inhibitor of TG2 NC9 not only decreased reactive oxygen species production 28-fold, but decreased the concentration of MCP-1, IL-1β and TNF-α 8-, 15- and 61-fold, respectively in the combined ATRA + ATO-treated wild-type NB4 cell culture. We propose that atypical expression of TG2 leads to the generation of inflammation, which thereby serves as a potential target for the prevention of differentiation syndrome. Full article

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

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Review

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21 pages, 359 KiB

Open AccessReview

PLZF-RAR_α, NPM1-RAR_α, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review

by Marta Sobas, Maria Carme Talarn-Forcadell, David Martínez-Cuadrón, Lourdes Escoda, María J. García-Pérez, Jose Mariz, María J. Mela-Osorio, Isolda Fernández, Juan M. Alonso-Domínguez, Javier Cornago-Navascués, Gabriela Rodríguez-Macias, María E. Amutio, Carlos Rodríguez-Medina, Jordi Esteve, Agnieszka Sokół, Thais Murciano-Carrillo, María J. Calasanz, Manuel Barrios, Eva Barragán, Miguel A. Sanz and Pau Montesinos Show full author list Hide full author list

Cancers 2020, 12(5), 1313; https://doi.org/10.3390/cancers12051313 - 21 May 2020

Cited by 22 | Viewed by 4130

Abstract

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RAR_α being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RAR_α and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RAR_α and 2 NPM1-RAR_α), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 10⁹/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far. Full article

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

22 pages, 1229 KiB

Open AccessReview

Classic and Variants APLs, as Viewed from a Therapy Response

by Marie-Claude Geoffroy and Hugues de Thé

Cancers 2020, 12(4), 967; https://doi.org/10.3390/cancers12040967 - 14 Apr 2020

Cited by 39 | Viewed by 5546

Abstract

Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of “classic” APL pathogenesis and therapy response. Full article

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

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22 pages, 1315 KiB

Open AccessReview

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

by Alessandro Liquori, Mariam Ibañez, Claudia Sargas, Miguel Ángel Sanz, Eva Barragán and José Cervera

Cancers 2020, 12(3), 624; https://doi.org/10.3390/cancers12030624 - 8 Mar 2020

Cited by 86 | Viewed by 13713 | Correction

Abstract

Although acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this disease are still a matter of study. APL is defined by the PML-RARA rearrangement as a consequence of the translocation t(15;17)(q24;q21). However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. Additional somatic mutations are known to occur recurrently in several genes, such as FLT3, WT1, NRAS and KRAS, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. How this mutational spectrum, including point mutations in the PML-RARA fusion gene, could contribute to the 10%–15% of relapsed or resistant APL patients is still unknown. Moreover, due to the uncertain impact of additional mutations on prognosis, the identification of the APL-specific genetic lesion is still the only method recommended in the routine evaluation/screening at diagnosis and for minimal residual disease (MRD) assessment. However, the gene expression profile of genes, such as ID1, BAALC, ERG, and KMT2E, once combined with the molecular events, might improve future prognostic models, allowing us to predict clinical outcomes and to categorize APL patients in different risk subsets, as recently reported. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. We will also describe different standardized molecular approaches to study MRD, including those recently developed. Finally, we will discuss how novel molecular findings can improve the management of this disease. Full article

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

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14 pages, 4232 KiB

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The Impact of Flt3 Gene Mutations in Acute Promyelocytic Leukemia: A Meta-Analysis

by Gledson L. Picharski, Diancarlos P. Andrade, Ana Luiza M. R. Fabro, Luana Lenzi, Fernanda S. Tonin, Raul C. Ribeiro and Bonald C. Figueiredo

Cancers 2019, 11(9), 1311; https://doi.org/10.3390/cancers11091311 - 5 Sep 2019

Cited by 33 | Viewed by 4479

Abstract

The association of FLT3 mutations with white blood cell (WBC) counts at diagnosis and early death was studied in patients with acute promyelocytic leukemia (APL). Publications indexed in databases of biomedical literature were analyzed. Potential publication bias was evaluated by analyzing the standard error in funnel plots using the estimated relative risk (RR). Mixed-effect models were used to obtain the consolidated RR. All analyses were conducted using the R statistical software package. We used 24 publications in the final meta-analysis. Of 1005 males and 1376 females included in these 24 publications, 645 had FLT3-ITD (internal tandem duplication) mutations. Information on FLT3-D835 mutations was available in 10 publications for 175 patients. Concurrent occurrence of the two mutations was rare. WBC count at diagnosis was ≥10 × 10⁹/L in 351 patients. For patients with the FLT3-ITD mutation, RR was 0.59 for overall survival (OS) and 1.62 for death during induction. For those with FLT3-D835 mutations, the RR was 0.50 for OS and 1.77 for death during induction. RR for WBC count ≥10 × 10⁹/L was 3.29 and 1.48 for patients with FLT3-ITD and FLT3-D835, respectively. APL patients with FLT3-ITD or FLT3-D835 are more likely to present with elevated WBC counts and poorer prognosis than those without these mutations. Full article

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

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