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Blood Cancer Journal Jun 2021In 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... (Review)
Review
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.
Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Tretinoin
PubMed: 34193815
DOI: 10.1038/s41408-021-00514-3 -
Blood Apr 2019Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights,... (Review)
Review
Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion-based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all- retinoic acid- and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.
Topics: Aged; Arsenic Trioxide; Disease Management; Female; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Practice Guidelines as Topic; Pregnancy; Recurrence; Tretinoin
PubMed: 30803991
DOI: 10.1182/blood-2019-01-894980 -
British Journal of Haematology Oct 2019Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide... (Review)
Review
Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion. Immediate treatment with steroids at the first clinical suspicion is recommended and ATRA/ATO should be stopped in severe cases or if there is no response to treatment. The utility of steroid prophylaxis in order to prevent APL DS is less certain. Here we provide a detailed review of the pathogenesis, clinical signs and symptoms as well as management and prophylaxis strategies of APL DS.
Topics: Acute Kidney Injury; Arsenic Trioxide; Cell Differentiation; Humans; Hypotension; Leukemia, Promyelocytic, Acute; Pulmonary Edema; Steroids; Syndrome; Tretinoin
PubMed: 31410848
DOI: 10.1111/bjh.16151 -
Hematology/oncology and Stem Cell... Dec 2020Acute promyelocytic leukemia (APL) is a special disease entity of acute myeloid leukemia (AML). The clinical use of all-trans retinoic acid (ATRA) has transformed APL... (Review)
Review
Acute promyelocytic leukemia (APL) is a special disease entity of acute myeloid leukemia (AML). The clinical use of all-trans retinoic acid (ATRA) has transformed APL into the most curable form of AML. The majority of APL cases are characterized by the fusion gene PML-RARA. Although the PML-RARA fusion gene can be detected in almost all APL cases, translocation variants of APL have been reported. To date, this is the most comprehensive review of these translocations, discussing 15 different variants. Reviewed genes involved in APL variants include: ZBTB16, NPM, NuMA, STAT5b, PRKAR1A, FIP1L1, BCOR, NABP1, TBLR1, GTF2I, IRF2BP2, FNDC3B, ADAMDTS17, STAT3, and TFG. The genotypic and phenotypic features of APL translocations are summarized. All reported studies were either case reports or case series indicating the rarity of these entities and limiting the ability to drive conclusions regarding their characteristics. However, reported variants have shown variable clinical and morphological features, with diverse responsiveness to ATRA.
Topics: Genotype; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Translocation, Genetic
PubMed: 32473106
DOI: 10.1016/j.hemonc.2020.05.007 -
Cells Dec 2020The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological... (Review)
Review
The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.
Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; Skin; Skin Neoplasms; Tretinoin
PubMed: 33322246
DOI: 10.3390/cells9122660 -
Cytometry. Part B, Clinical Cytometry Jul 2022Prompt diagnosis of acute promyelocytic leukemia (APL) is critical for patient care. In this study, we aimed to characterize the immunophenotype of APL and explore...
BACKGROUND
Prompt diagnosis of acute promyelocytic leukemia (APL) is critical for patient care. In this study, we aimed to characterize the immunophenotype of APL and explore immunophenotypic difference between APL and its mimics using flow cytometric analysis.
METHODS
Eighty-five cases were collected, including 47 APL, 26 NPM1-mutated acute myeloid leukemia (AML) and 12 KMT2A-rearranged AML with an APL-like immunophenotype. Immunophenotypes were analyzed using flow cytometric analysis.
RESULTS
APL showed four distinct patterns (designated a-d) based on CD45/SSC plots. Blasts in patterns a-c showed high side scatter, whereas blasts in pattern d had low side scatter and were located in the traditional blast gate. Compared with patterns a-c, pattern d of APL (APL-D) was more often positive for CD2 (p = 0.0005) and CD34 (p = 0.0002) in blasts. All NPM1-mutated AML and KMT2A-rearranged AML cases with an APL-like immunophenotype had blasts in the traditional blast gate on CD45/SSC, mimicking APL-D. In comparison, uniform CD13 and positive CD64 were seen in 100% (n = 13) APL-D cases and in only 2 of 26 (8%) NPM1-mutated AML cases (p < 0.0001). In addition, APL-D cases were more likely to be positive for CD2 and/or CD34 than NPM1-mutated AML (p < 0.0001 and p = 0.0007, respectively). In comparison with APL-D, KMT2A-rearranged AML cases were less often positive for myeloperoxidase (MPO) (p = 0.001), with none being strongly positive. Similar to NPM1-mutated AML and different from APL-D, KMT2A-rearranged AML cases were rarely positive for CD34 and all negative for CD2.
CONCLUSIONS
APL and its immunophenotypic mimics share some immunophenotypic similarities but can be distinguished by CD2, CD13, CD34, CD64, and MPO.
Topics: Antigens, CD34; Diagnosis, Differential; Flow Cytometry; Humans; Immunophenotyping; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Nuclear Proteins
PubMed: 35716019
DOI: 10.1002/cyto.b.22085 -
Acta Haematologica 2019Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending,... (Review)
Review
Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending, morphology supplemented by immunophenotyping can provide clues to the diagnosis of specific cytogenetic/genetic categories of AML. Most importantly, acute promyelocytic leukaemia can be diagnosed with a high degree of certainty. However, provisional identification of cases associated with t(8; 21), inv(16), t(1; 22), and NPM1 mutation may also be possible. In addition, transient abnormal myelopoiesis of Down's syndrome can generally be diagnosed morphologically.
Topics: Chromosome Inversion; Chromosomes, Human; Down Syndrome; Humans; Leukemia, Promyelocytic, Acute; Myelopoiesis; Neoplasm Proteins; Nuclear Proteins; Nucleophosmin; Translocation, Genetic; World Health Organization
PubMed: 30965338
DOI: 10.1159/000496097 -
Cells Aug 2019Promyelocytic leukemia (PML) bodies are dynamic intracellular structures that recruit and release a variety of different proteins in response to stress, virus infection,... (Review)
Review
Promyelocytic leukemia (PML) bodies are dynamic intracellular structures that recruit and release a variety of different proteins in response to stress, virus infection, DNA damage and cell cycle progression. While PML bodies primarily are regarded as nuclear compartments, they are forced to travel to the cytoplasm each time a cell divides, due to breakdown of the nuclear membrane at entry into mitosis and subsequent nuclear exclusion of nuclear material at exit from mitosis. Here we review the biochemical and biophysical transitions that occur in PML bodies during mitosis and discuss this in light of post-mitotic nuclear import, cell fate decision and acute promyelocytic leukemia therapy.
Topics: Active Transport, Cell Nucleus; Animals; Cell Nucleus; Cells, Cultured; Cytoplasm; Humans; Intranuclear Inclusion Bodies; Leukemia, Promyelocytic, Acute; Mice; Mitosis; Nuclear Envelope; Promyelocytic Leukemia Protein
PubMed: 31416160
DOI: 10.3390/cells8080893 -
Ugeskrift For Laeger Jan 2018Acute promyelocytic leukaemia has changed from being a highly fatal to a highly curable disease. Over time, key discoveries have identified the genetic and molecular... (Review)
Review
Acute promyelocytic leukaemia has changed from being a highly fatal to a highly curable disease. Over time, key discoveries have identified the genetic and molecular abnormalities, which cause the disease. First choice of treatment has now changed from all-trans retinoic acid (ATRA) and chemotherapy to a chemo-free combination of arsenic trixoide and ATRA. This new regimen has shown equal responses and overall cure rates compared with the previous standard of care containing conventional chemotherapy, but with much lower toxicity. This will pave the way for better and easier treatment for elderly and frail patients.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disseminated Intravascular Coagulation; History, 20th Century; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Tretinoin
PubMed: 29336301
DOI: No ID Found -
Blood May 2021The retinoic acid receptors (RARA, RARB, and RARG) are ligand-regulated nuclear receptors that act as transcriptional switches. These master genes drew significant... (Review)
Review
The retinoic acid receptors (RARA, RARB, and RARG) are ligand-regulated nuclear receptors that act as transcriptional switches. These master genes drew significant interest in the 1990s because of their key roles in embryogenesis and involvement in a rare malignancy, acute promyelocytic leukemia (APL), in which the RARA (and very rarely, RARG or RARB) genes are rearranged, underscoring the central role of deregulated retinoid signaling in leukemogenesis. Several recent provocative observations have revived interest in the roles of retinoids in non-APL acute myeloid leukemia (AML), as well as in normal hematopoietic differentiation. We review the role of retinoids in hematopoiesis, as well as in the treatment of non-APL AMLs. From this perspective, broader uses of retinoids in the management of hematopoietic tumors are discussed.
Topics: Animals; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Receptors, Cytoplasmic and Nuclear; Retinoids
PubMed: 33651885
DOI: 10.1182/blood.2020010100