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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 -
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 -
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 -
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 -
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 -
Blood Feb 2009The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized... (Review)
Review
The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Databases, Factual; Europe; Female; Health Planning Guidelines; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Hematologic; Recurrence; Societies, Medical; Tretinoin
PubMed: 18812465
DOI: 10.1182/blood-2008-04-150250 -
Hematology. American Society of... Dec 2016Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML), which presents with a distinct coagulopathy. Therapeutic advances have made APL... (Review)
Review
Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML), which presents with a distinct coagulopathy. Therapeutic advances have made APL one of the true success stories in oncology, transforming this once lethal disease into the most curable form of AML. For many patients, cure will now be achieved without the use of chemotherapy. It is hoped that limiting chemotherapy will reduce mortality even further, particularly among more vulnerable older adults whose survival lagged behind that of younger patients. It should be noted that early death persists in patients with APL and continues to negatively affect survival. Further, among survivors treated with chemotherapy or even arsenic trioxide (ATO), there remains the potential for long-term toxicities that must be monitored. Understanding the management of these issues is an important complement to ensure maximal survival for patients with APL.
Topics: Adult; Age Factors; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Humans; Leukemia, Promyelocytic, Acute; Oxides; Survival Rate
PubMed: 27913456
DOI: 10.1182/asheducation-2016.1.10 -
International Journal of Molecular... Jan 2021Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and... (Review)
Review
Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided excellent survival rates, has been initially validated in adults and, recently, translated in the pediatric setting. This review summarizes currently available data on the use of ATRA and ATO combination in pediatric APL, providing a particular focus on peculiar issues and challenges, such as the occurrence of and death during induction (early death), as well as the advantage offered by the ATO/ATRA combination in sparing long-term .
Topics: Age Factors; Clinical Studies as Topic; Combined Modality Therapy; Disease Management; Disease Susceptibility; Humans; Leukemia, Promyelocytic, Acute; Molecular Diagnostic Techniques; Phenotype; Precision Medicine; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 33440683
DOI: 10.3390/ijms22020642 -
Archives of Pathology & Laboratory... Oct 2015The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of... (Review)
Review
The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of patients with APL harbor complex, cryptic, or variant translocations, which typically involve RARA. With the exception of ZBTB16/RARA, these variants have similar morphologic and immunophenotypic features as classic APL. Study of the variant forms of APL not only gives insight into the pathogenesis of APL but also allows us to understand the mechanism of retinoid therapy. It is important to identify these cryptic and variant translocations because certain variants, including ZBTB16/RARA and STAT5B/RARA, are resistant to treatment with all-trans retinoic acid, arsenic trioxide, and anthracyclines.
Topics: Antineoplastic Agents; Diagnosis, Differential; Drug Resistance, Neoplasm; Humans; Kruppel-Like Transcription Factors; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Zinc Finger Protein; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; STAT5 Transcription Factor; Translocation, Genetic
PubMed: 26414475
DOI: 10.5858/arpa.2013-0345-RS