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Aman, Adi K., and Tonny . "PENERIMA ASAM RETINOID a (a RETINOID ACID RECEPTOR) DI LEUKEMIA AKUT PROMYELOSITIK DENGAN BATANGAN (ROD) AUER." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 15, no. 3 (March 16, 2018): 117. http://dx.doi.org/10.24293/ijcpml.v15i3.966.
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Acute Promyelocytic Leukemia (APL) is a subtype of AML with a defined clinical course and biology that is distinct from otherforms of AML. The term M3-AML was assigned to the hyper granular promyelocytic leukaemia that is characterized by blast cells withazurophilic granules, bundles of auer rods and reniform or bilobed nucleus. Clinically, APL is related to disseminate intravascularcoagulation and abnormal fibrinolysis. Cytogenetically, APL may cause translocation on the promyelocytic leukaemia (PML) gene,and chromosome 15 and with the retinoic acid receptor α (RARA) gene, on chromosome 17. The diagnosis of APL is shown by bonemarrow morphologically The majority of cells in the bone marrow are abnormal, having some similarities with promyelocytes. Themalignant cells bear numerous large granules and several auer rods. Aspirates of bone marrow are also taken for cytogenesis evaluationand for detecting the translocation. A twelve years girl was admitted to the hospital with haemorrhage from the gums during 5 dayafter extraction of a tooth. On physical examination there is no organomegaly shown. The laboratory examination found normocyticnormochromic anaemia, leucopoenia and thrombocytopenia with 15% blast cell and 5% promyelocytes with multiple auer rods. Thebone marrow aspirates showed predominant of promyelocyte cells (70%) with multiple auer rods.
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Ismail, Imilia, Sarina Sulong, and Rosline Hassan. "MicroRNAs as Potential Biomarkers in Acute Promyelocytic Leukaemia." New Journal of Science 2014 (December 7, 2014): 1–6. http://dx.doi.org/10.1155/2014/932342.
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Acute promyelocytic leukaemia (APL) is an M3 subtype of acute myeloid leukaemia (AML). This classification is based on the morphology of promyelocytic cell. The clinical characteristics of APL can be recognized by haemorrhagic episodes, a differentiation block at the promyelocytic stage, and sensitivity to the differentiation response to all-trans-retinoic acid (ATRA). Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the production of PML/RARα fusion protein. Recent studies reported that microRNAs (miRNAs) have also been proposed to contribute to the pathogenesis of APL. miRNAs have been associated with the pathogenesis of cancer and their involvement as oncogenic and tumour suppressor activities have been identified. They are involved in various biological processes including the cell proliferation, differentiation, growth and development, metabolism, apoptosis, and haematopoiesis. The new discovery of miRNAs as possible therapeutic markers will provide new insight for the diagnosis and therapeutic entries for the treatment of APL. This review highlights the potential of miRNAs as biomarkers in APL.
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Sirulnik, Andres, Ari Melnick, Arthur Zelent, and Jonathan D. Licht. "Molecular pathogenesis of acute promyelocytic leukaemia and APL variants." Best Practice & Research Clinical Haematology 16, no. 3 (September 2003): 387–408. http://dx.doi.org/10.1016/s1521-6926(03)00062-8.
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Sørensen, Dag Reidar, Mouldy Sioud, and Per Ole Iversen. "A combined immunostimulatory and immunoinhibitory short interference RNA reduces hypercoagulability in a rat model of acute promyelocytic leukaemia." Thrombosis and Haemostasis 104, no. 08 (2010): 350–54. http://dx.doi.org/10.1160/th09-12-0816.
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SummaryAcute promyelocytic leukaemia (APL) confers an increased risk of thrombosis and bleeding. Current treatments are insufficient to inhibit these complications. We recently showed that a combined immunoinhibitory and immunostimulatory short interference (si) RNA effectively inhibited leukaemic growth and metastasis in rats with APL. We now asked if the reported anti-leukaemic effects of siRNA treatment could be explained by inhibition of hypercoagulability. We measured markers of coagulation and fibrinolysis in plasma collected from APL rats with overt leukaemia using conventional assays. Coagulopathy developed in untreated leukaemic rats evidenced by increase in several haemostatic markers. Treatment of leukaemic rats with the siRNA reduced (p < 0.05) the concentration of thrombin-anti-thrombin complex (a marker of coagulation) by 40% compared with rats treated with an inactive, control siRNA. Substantial reductions (p < 0.05) were also obtained for two markers of fibrinolysis: D-dimer (72%) and plasminogen activator inhibitor type 1 (51%). The activity of tissue factor, the main initiator of coagulation, was not increased (p > 0.05) in untreated leukaemic rats compared with healthy rats, and did not change (p > 0.05) upon treatment with the siRNA. The bifunctional siRNA reduces the hypercoagulable state in APL in addition to its direct anti-leukaemic properties, supporting testing of this small molecule in human APL.
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Kunhikrishnan, Anitha, Abdul Rashid Shah, Ramesh Pandita, Abdul Aziz, Mohan Ram, Mahmoud Maged, Rasha Galal, Nermin Salem, Reneah B, and Ahmad Alhuraiji. "Acute Promyelocytic Leukaemia (APL) in Pregnancy - A Challenge for Physicians." Clinical Lymphoma Myeloma and Leukemia 19 (September 2019): S237—S238. http://dx.doi.org/10.1016/j.clml.2019.07.129.
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Kasinathan, Ganesh, and Jameela Sathar. "Extramedullary disease in acute promyelocytic leukaemia: A rare presentation." SAGE Open Medical Case Reports 8 (January 2020): 2050313X2092607. http://dx.doi.org/10.1177/2050313x20926076.
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Acute promyelocytic leukaemia consists of 7%–8% of cases of acute myeloid leukaemia. Extramedullary manifestations are rare and show distinct biological features. We describe a 22-year-old female of Malay ethnicity who presented with fever and a left axillary swelling for a week. The peripheral blood smear showed abnormal promyelocytes with faggot cells. PML-RAR-alpha t(15;17) (q22; q12) was detected by polymerase chain reaction. The left axillary swelling histology and immunohistochemical staining confirmed granulocytic sarcoma. She was induced with triple agents consisting of all-trans-retinoic-acid, arsenic trioxide and idarubicin. On day 14 of induction, she developed severe neutropenic sepsis in which she responded to ventilation and antimicrobials. She completed her induction, consolidation and maintenance therapy. Currently she is in molecular and morphological remission. Extramedullary disease in acute promyelocytic leukaemia usually has a severe clinical presentation. Granulocytic sarcoma may present as an early feature of acute promyelocytic leukaemia.
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Pearson, E. C., J. G. Matthews, and F. G. J. Hayhoe. "Ultrastructure and cytogenetics in seven cases of acute promyelocytic leukaemia (APL)." British Journal of Haematology 63, no. 2 (March 12, 2008): 247–56. http://dx.doi.org/10.1111/j.1365-2141.1986.tb05547.x.
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Ghavamzadeh, Ardeshir, Kamran Alimoghaddam, Hamidolah Ghaffari, Shahrano Rostami, Yousef Mortazavi, Asadolah Mousavi, Mehrangiz Tootonchi, et al. "Treatment of New Cases of Acute Promyelocytic Leukaemia by Arsenic Trioxide." Blood 104, no. 11 (November 16, 2004): 396. http://dx.doi.org/10.1182/blood.v104.11.396.396.
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Abstract Purpose: Arsenic Trioxide approved for treatment of relapsed or refractory APL to ATRA. We studied the effects of Arsenic Trioxide as first line treatment of new cases of APL and their follow up. Material and methods: we studied 73 new cases of APL diagnosed by morphologic criteria and confirmed by cytogenetic, RT-PCR for PML/RARA and/or FISH and followed patients for MRD by sensitive nested RT-PCR. Our patients were 30 males and 43 females with median age 30+/− 12. Patients treated by infusion of 0.15mg/kg/d of Arsenic Trioxide to complete remission by morphologic criteria or till day +60. In patients who complete remission achieved, after 28 days rest, again we began Arsenic Trioxide 0.15mg/kg/d for 28 days as consolidation. Results: complete remission were achieved in 66 patients( 90.4%) and 7 early mortality. Median time to complete remission was 30+/−6.4 days. Most common cause of mortality was APL maturation syndrome ( 4 cases) Most common toxicities during induction phase were, APL maturation syndrome (10 cases), serositis(6 cases) and hepatotoxicity (19 cases). 63 cases(86.3%) are alive with a median follow up of 17+/−12.65 months. 14 relapses observed in our patients and complete remission achieved with re-treatment by Arsenic trioxide in 11 of them. Also we could control 3 fatal bleeding by infusion of activated factor 7(NovosevenÒ) which stopped hemorrhage . One year and two/three years survival of patients were 86% and 84%. Most common cause of death was APL maturation syndrome in 4 patients and relapse in 3 cases.Conclusion: Arsenic Trioxide is acceptable as first line treatment of APL and its result is comparable to ATRA with chemotherapy.
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Zhao, Jie, Liang Jian-Wei, Shuhong Shen, Jing Chen, Hui-Liang Xue, Ben-Shang LI, and Jing-Yan Tang. "The Genetics and Clinical Characteristics of Children Morphologically Diagnosed As Acute Promyelocytic Leukaemia." Blood 132, Supplement 1 (November 29, 2018): 2801. http://dx.doi.org/10.1182/blood-2018-99-112401.
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Abstract Acute promyelocytic leukaemia (APL) is characterized by t(15;17)(q22;q21), resulting in a PML-RARA fusion that is the master driver of APL. A few cases that can't be identified with PML-RARA by using routine methods (karyotype analysis, FISH, and RT-PCR) involve abnormal promyelocytes that are fully in accordance with APL in morphology, cytochemistry, and immunophenotype. To explore the mechanisms involved in pathogenesis and recurrence of morphologically diagnosed APL, we performed comprehensive variant analysis from structural variants (SVs) to single-nucleotide variants (SNVs) in paediatric patients mophologically diagnosed as APL by next generation sequencing. SV analysis using targeted gene sequencing(TGS) in 120 DNA samples from both diagnosis and relapse stage identified 95 samples with RARA rearrangement (including 94 with PML-RARA and one with NPM-RARA) and two samples with KMT2A rearrangement. In the cases failed to be identified with any RARA rearrangement, transcriptome sequencing was applied in the available 13 RNA samples at diagnosis. One case each with CPSF6-RARG, NPM1-CCDC28A, and TBC1D15-RAB21 and two cases with a TBL1XR1-RARB fusion were discovered, which strongly suggested their contributions to leukemogenesis as driver alternations and APL phenotype is inextricably linked to rearrangement of RARA gene. SNV analysis in 75 primary APL samples with RARA rearrangement showed recurrent alternations in FLT3(27%), WT1(13%), USP9X(9%), NRAS(7%), and ARID1A(4%), with a strong potential for involvement in pathogenesis, and WT1as the only gene recurrently mutated in 4/5 samples(3/4 cases) in relapsed APL. WT1 (17.6%), NPM1 (11.8%), NRAS (11.8%), FLT3 (11.8%), and NSD1 (11.8%) were identified as recurrently mutated in 17 primary samples without RARA rearrangement and WT1(44.4%), NPM1 (33.3%), TP53 (33.3%), and RARA (33.3%)as recurrently mutated in 9 relapsed samples. The retrospective study showed the survival rates of APL without RARA rearrangement(8y-EFS=38.7%±17.8%) were much worse than APL with RARA rearrangement(8y-EFS=90.9%±3.9%), which is similar to AML (non-M3) patients(8y-EFS=57.7%±3.0%). Thus,NGS is necessary in cases failed to be identified with RARA rearrangement by karyotype analysis, FISH, and RT-PCR, which can afford accurate diagnosis and treatment guidance. APL phenotype may arise by abnormities of other members of the nuclear receptor superfamily involved in retinoid signaling(RARB or RARG) or even by mechanisms distinct from the formation of aberrant retinoid receptors. Differences in genetic alternations and survival indicated that APL that cannot be identified as having a RARA rearrangement are more reasonably classified as a subclass of AML other than APL, and an AML treatment regimen or individualized treatment should be considered according to the genetic abnormalities. Figue1. (A)Mutational profile between APL with and without RARA rearrangement. (B)Comparison of estimated probability of EFS and OS among APL with and without RARA rearrangement and AML(non-M3) group . “Typical APL” means APL with RARA rearrangement and “Atypical APL” means APL without RARA rearrangement. Disclosures No relevant conflicts of interest to declare.
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Bai, Yuanyuan, Cheng Chen, Xiaoling Guo, Ting Ding, Xinyun Yang, Jian Yu, Junjun Yang, Jichen Ruan, Xiaoqun Zheng, and Zhanguo Chen. "miR-638 in circulating leukaemia cells as a non-invasive biomarker in diagnosis, treatment response and MRD surveillance of acute promyelocytic leukaemia." Cancer Biomarkers 29, no. 1 (September 25, 2020): 125–37. http://dx.doi.org/10.3233/cbm-190899.
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BACKGROUND: MicroRNA (miRNA) expression has been implicated in leukaemia. In recent years, miRNAs have been under investigation for their potential as non-invasive biomarkers in acute promyelocytic leukaemia (APL). We investigated whether miR-638 in circulating leukaemia cells is a non-invasive biomarker in diagnosis, assessment of the treatment response and minimal residual disease (MRD) surveillance of APL. METHODS: Sixty cases of acute myeloid leukaemia (AML), including 30 cases of APL and 30 cases of non-APL AML, were selected. Thirty healthy controls were also selected. Bone marrow (BM) and peripheral blood (PB) samples were collected from APL patients at diagnosis and post-induction. Microarray analysis and quantitative real-time PCR (qRT-PCR) were performed for miRNA profiling and miR-638 expression analysis, respectively. For statistical analysis, Mann-Whitney U test, Wilcoxon Signed Rank test, receiver operating characteristic (ROC) curve analysis and Spearman’s rho correlation test were used. RESULTS: Both microarray and qRT-PCR data showed that miR-638 was significantly upregulated in BM after APL patients received induction therapy. Moreover, miR-638, which is specifically downregulated in APL cell lines, was upregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation. Receiver operating characteristic (ROC) curve analyses revealed that miR-638 could serve as a valuable biomarker for differentiating APL from controls or non-APL AML. Furthermore, miR-638 expression was sharply increased after induction therapy and complete remission (CR). An inverse correlation was observed between miR-638 and PML-RARα transcripts levels in BM samples, while a positive correlation was revealed between PB miR-638 and BM miR-638 levels in APL patients after induction therapy. CONCLUSIONS: Our study suggested that miR-638 may serve as a potential APL biomarker for diagnosis and assessment of the response to targeted therapy, and PB miR-638 could be used for non-invasive MRD surveillance in APL.
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Sheer, D., T. A. Lister, J. Amess, and E. Solomon. "Incidence of the 15q+;17q- chromosome translocation in acute promyelocytic leukaemia (APL)." British Journal of Cancer 52, no. 1 (July 1985): 55–58. http://dx.doi.org/10.1038/bjc.1985.148.
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Zhou, Guang-Biao, Ji Zhang, Zhen-Yi Wang, Sai-Juan Chen, and Zhu Chen. "Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy." Philosophical Transactions of the Royal Society B: Biological Sciences 362, no. 1482 (February 22, 2007): 959–71. http://dx.doi.org/10.1098/rstb.2007.2026.
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To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of all-trans retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90–95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML–RARα fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARα (retinoic acid receptor α) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML–RARα transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable disease. Thus, the story of APL can serve as a model for the development of curative approaches for disease; it suggests that molecularly synergistic targeted therapies are powerful tools in cancer, and dissection of disease pathogenesis or anatomy of the cancer genome is critical in developing molecular target-based therapies.
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Mays, Ashley Nicole, Neil Osheroff, Carolyn Felix, Jo Ann Byl, Kandeepan Saravanamuttu, Andrew Peniket, Robert Corser, et al. "Molecular Characterization of the t(15;17)(q22;21) in Epirubicin-Related Acute Promyelocytic Leukaemia." Blood 112, no. 11 (November 16, 2008): 791. http://dx.doi.org/10.1182/blood.v112.11.791.791.
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Abstract Chromosomal translocations generating chimaeric oncoproteins play an important role in leukaemogenesis, but mechanisms underlying their formation are largely unclear. Substantial insights can be gained from the analysis of therapy-related acute myeloid leukaemias (t-AMLs), which are becoming an increasing healthcare problem as more patients survive their primary cancers. Exposure to agents targeting topoisomerase II (topoII) predisposes to the development of leukaemias with balanced translocations e.g. t(15;17), fusing PML and RARA genes, in therapy-related acute promyelocytic leukaemia (t-APL) which is particularly associated with prior treatment involving mitoxantrone or epirubicin. Using long-range PCR and sequencing to define genomic junction regions we found that in t-APL cases arising in breast cancer patients exposed to the former agent, chromosome 15 breakpoints clustered tightly in an 8 bp “hotspot” region in PML intron 6, which was shown by functional assay to be a preferred site of mitoxantrone-induced DNA topoII cleavage (Mistry et al, NEJM 2005). Subsequent analysis of an independent cohort of t-APL cases arising after mitoxantrone therapy for multiple sclerosis confirmed chromosome 15 breakpoint clustering in the “hotspot” and identified a recurrent breakpoint within RARA intron 2. This hotspot also was shown to be a preferential site of mitoxantrone-induced cleavage in vitro (Hasan et al, Blood 2008). However, the molecular basis of epirubicin-related APL remains uncertain. Therefore we used long-range PCR and sequence analysis to define translocation breakpoints in 6 patients who developed APL after treatment involving epirubicin-containing regimens for prior breast carcinoma. While mitoxantrone-related APL displayed a bias towards breakpoints occurring within PML intron 6 (bcr1), epirubicin-related breakpoints fell within intron 3 (n=2) or intron 6 (n=4) and were outside the mitoxantrone-related “hotspot” (located at position 1484 according to accession number S57791). Breakpoints within the RARA locus were distinct from those observed in mitoxantrone-related APL. Interestingly, the chromosome 15 or chromosome 17 breakpoints of 4 of the epirubicin-related t-APLs fell in close proximity (within 1–4bp) to one of the other cases. Two shared a breakpoint location in PML intron 6 that occurred at bases 1185 and 1186 (accession number S57791) and two fell within RARA intron 2 at base numbers 16193 and 16197 (accession number AJ297538). Given that PML intron 6 and RARA intron 2 are ~1kb and 17kb in length, respectively, such breakpoint clustering was unlikely to have occurred by chance and consistent with functional sites of topoII cleavage. In addition, in vitro DNA cleavage assays demonstrated that heat stable topoII cleavage complexes are formed at the exact location of the breakpoint identified in one of the other patients, at position 1969 in PML intron 6, which were enhanced by the presence of epirubicin. This study suggests that mitoxantrone and epirubicin exhibit preference differences in sites of DNA damage induced by topoisomerase II, which may underlie the propensity to develop specific molecularly-defined subtypes of t-AML according to the nature of the particular chemotherapeutic agent used.
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Jiang, Yan, and Linhua Ji. "Severe Wernicke encephalopathy and acute pancreatitis due to all-trans-retinoic acid and arsenic trioxide during treatment of acute promyelocytic leukaemia: a case report." Journal of International Medical Research 48, no. 9 (September 2020): 030006052095948. http://dx.doi.org/10.1177/0300060520959487.
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A 55-year-old woman developed acute promyelocytic leukaemia during treatment with all-trans-retinoic acid and arsenic trioxide. Initially, she presented with symptoms of epigastric pain, vomiting, and nausea, and she developed acute pancreatitis. She was treated with parenteral nutritional supplementation for 20 days. However, the patient continued to develop refractory hyponatraemia, hypotension, and apathy. Finally, the patient was diagnosed with Wernicke encephalopathy (WE) using head magnetic resonance imaging. The patient underwent high-dose intravenous thiamine administration, and her symptoms were alleviated. WE is a rare adverse event during acute pancreatitis therapy. Acute pancreatitis that is caused by all-trans-retinoic acid and arsenic trioxide is a rare complication of acute promyelocytic leukaemia during chemotherapy. Further study is essential to improve our comprehension of the risk factors for complications in patients with acute promyelocytic leukaemia, considering that the associated complications were potentially caused by multiple etiological factors. A better understanding of these risk factors may help to improve the prognosis of patients with acute promyelocytic leukaemia at an early stage.
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Campbell, Lynda J., Paul Oei, Ross Brookwell, Jake Shortt, Nicola Eaddy, Ashley Ng, Edward Chew, and Peter Browett. "FISH Detection ofPML-RARAFusion in ins(15;17) Acute Promyelocytic Leukaemia Depends on Probe Size." BioMed Research International 2013 (2013): 1–4. http://dx.doi.org/10.1155/2013/164501.
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The diagnosis of acute promyelocytic leukaemia (APL) is usually confirmed by cytogenetics showing the characteristic t(15;17), but a minority of patients have a maskedPML/RARAfusion. We report ten patients with APL and no evidence of the t(15;17), in whom the insertion ofRARAintoPMLcould not be demonstrated by initial FISH studies using a standard dual fusion probe but was readily identified using smaller probes. Given the need for rapid diagnosis of APL, it is important to be aware of the false negative rate for largePML/RARAFISH probes in the setting of masked rearrangements.
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Wadley, Alex J., Paul Hole, Alex Tonks, Richard Darley, Dr Omidvar, Rhys Gareth Morgan, Keane Gary, and Steven John Coles. "Intracellular Thiol Oxidation Is Linked with Loss of Δψm and Disease Progression in Acute Promyelocytic Leukaemia." Blood 132, Supplement 1 (November 29, 2018): 2751. http://dx.doi.org/10.1182/blood-2018-99-118646.
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Abstract Acute promyelocytic leukaemia (APL) is a type of myeloid malignancy defined by the chromosomal translocation t(15;17) and subsequent expression of the PML-RARα fusion protein. Long term remission in APL is achieved through a combination of high dose all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the latter of which has potential to induce mitochondrial derived oxidative stress and initiate the intrinsic apoptosis pathway. ATO is particularly effective in the treatment of APL when compared with acute myeloid leukaemia (AML), suggesting that the mitochondrial membrane potential (Δψm) of APL cells is compromised. Here we show that loss of Δψm is associated with intracellular thiol oxidation and disease progression in APL. The mitochondrial probe 3,3'-diethyloxacrbocyanine iodide (DiOC2(3)) was used to evaluate MRP8-PML/RARA transgenic mice Δψm in bone marrow mononuclear cells (BMMC) at three disease stages: 1) pre-APL, 2) APL and 3) ATRA treated APL. Our data show that MRP8-PML/RARA BMMC cells during the APL stage accumulate significantly less DiOC2(3) compared with pre-APL cells (0.05±0.02 vs 0.24±0.05, p<0.05; data are normalised FL1/FL3 MFI ratio). The DiOC2(3) accumulation in BMMC from ATRA treated APL mice was equivalent to that of pre-APL cells (p>0.05). This finding indicates a loss of Δψm in APL. This may result in free radical leakage from the mitochondria, which in turn could oxidise intracellular thiols. To evaluate intracellular thiol oxidation, a previously optimised flow cytometric assay that incorporates the thiol reactive probe fluorescein-5 maleimide (F5M) was used. Our data show a significant decrease in F5M MFI for MRP8-PML/RARA BMMC cells during the APL stage, compared with pre-APL cells (219.01±47.67 vs 672.66±131.04, p<0.05; data are F5M MFI relative to unstained controls). This finding signifies that there is more thiol oxidation at the APL stage. ATRA treated APL mice showed an equivalent F5M MFI to that of pre-APL cells. Confocal microscopy confirmed that the F5M signal was intracellular. This observation shows that there is an increase in intracellular thiol oxidation in APL, which may be tracked during disease progression and treatment course. This finding may explain why APL cells are more sensitive to pro-oxidant treatments i.e. ATO. To understand these observations further, the APL cell line (NB4) was subjected to glucose oxidase (GOX) mediated oxidative stress in cell culture over a 4 hour time-course. F5M MFI signal was compared with the THP1 and Kasumi-1 AML cell lines subjected to the same treatment. All cell lines showed similar significant increases in F5M MFI after 1 hour GOX treatment relative to control (p<0.05), indicating an increase in 'reduced' cellular thiol i.e. reductive stress. However, after 4 hours NB4 cells showed a significant decrease in F5M MFI relative to control (p<0.05), indicating an increase in 'oxidised' cellular thiol i.e. oxidative stress. In contrast, THP1 cells showed no difference in MFI after 4 hours (p>0.05), whereas F5M MFI Kasumi-1 remained significantly increased after 4 hours (p<0.05) relative to control. This finding indicates differences in the sensitivity to oxidative stress between APL and AML cells. Taken together, this study shows that APL cells are more sensitive to oxidative stress compared with AML cells. Our F5M flow cytometric assay illustrates that an increase in cellular thiol oxidation is linked to disease progression in APL, with loss of Δψm associated with this process. Our F5M flow cytometric assay may therefore have clinical utility in monitoring treatment efficacy in APL. Disclosures No relevant conflicts of interest to declare.
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Di Bona, Eros, Felicetto Ferrara, Giorgina Specchia, Franco Leoni, Lorella Melillo, Anna Falanga, Giuseppe Rossi, Paola Fazi, Francesco Lo Coco, and Franco Mandelli. "“Fulminant” Acute Promyelocytic Leukemia: Clinical and Biological Features." Blood 108, no. 11 (November 16, 2006): 4586. http://dx.doi.org/10.1182/blood.v108.11.4586.4586.
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Abstract Acute promyelocytic leukemia (APL) is associated with severe hemorrhagic coagulopathy, which is the main cause of early death. The introduction of ATRA ameliorated the complete remission rate and improved the overall survival compared to treatment with chemotherapy alone. However, the pioneristic large randomized trials comparing ATRA alone versus chemotherapy alone in previously untreated patients failed to demonstrate a significant reduction of early hemorrhagic deaths, notwithstanding ATRA capability to quench the ongoing coagulopathy. Nevertheless, the incidence of such very early deaths remains unsettled, leading to a bias in the evaluation of real impact of ATRA in clinical outcome of APL. We have retrospectively collected and examined a total of 31 very early deaths from APL from the database of 7 Italian Centres. Very early death was defined as death occurring within 72 hours from the first clinical observation. The incidence was 9.7% (31 of 318 APL enrolled in the same period in GIMEMA APL trials). Median age was 53 years (21–88), M/F ratio 0.9, 13 were variant forms of APL, median peripheral blood cell count was: WBC 41.2 ×109/L (0.68–181), with 94% of blast cells, platelets 24 ×109/L (6–96); BCR type 1, 2, 3 were observed in 10, 2, and 7 cases, respectively; clinical features of disseminated intravascular coagulopathy (DIC) were present in all but two patients, while median WHO grade of hemorrhage was 3. Median time from symptoms onset to diagnosis and from diagnosis to death was respectively 72 and 44 hours. One third of the patient did not receive any therapy, the others received some doses of ATRA with or without chemotherapy. The majority of these patients was not enrolled in any clinical trial. These preliminary data suggest that a relevant percentage of APL patients died before starting any effective treatment. Every clinical trial should include this slice of patients to give realistic clinical outcome of APL therapies. Seventy-two percent of patients showed WBC≥10×109/L and variant form was more frequent (42%) than expected (usually 20–25% of APL). Based on the possible confused morphological features with monocytic leukaemia, diagnosis required rapidly confirmative molecular methods and heavy supportive and transfusional therapies. Moreover, underlying APL should be considered as a differential diagnosis when apparently spontaneous cerebral hemorrhage occurs; in some instance, a prompt supportive and differentiating therapy could be lifesaving.
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Ng, Chin-Hin, and Wee-Joo Chng. "Recent advances in acute promyelocytic leukaemia." F1000Research 6 (July 28, 2017): 1273. http://dx.doi.org/10.12688/f1000research.10736.1.
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Acute promyelocytic leukaemia (APML) is a subtype of leukaemia arising from a distinct reciprocal translocation involving chromosomes 15 and 17, which results in thePML-RARAfusion gene. Over the past three decades, APML has been transformed from a highly fatal disease to a highly curable one. This drastic improvement is because of the introduction of a new treatment strategy with all-trans retinoic acid and, more recently, arsenic trioxide. The revolutionary treatment of APML has also paved the way for a new cancer treatment, which is genetically targeted therapy. In this review, we look into this amazing journey of transformation and provide recent advances in the management of APML.
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Chatterjee, Tathagata, Srishti Gupta, Ajay Sharma, Sanjeevan Sharma, and Prosenjit Ganguli. "DISTRIBUTION OF DIFFERENT PML/RARΑ BCR ISOFORMS IN INDIAN ACUTE PROMYELOCYTIC LEUKAEMIA (APL) PATIENTS AND CLINICOHEMATOLOGICAL CORRELATION." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (December 31, 2013): e2014004. http://dx.doi.org/10.4084/mjhid.2014.004.
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Context: Acute promyelocytic leukemia (APL), an AML subtype, is characterized morphologically by abnormal promyelocytes. Molecular studies show three possible bcr isoforms of PML- RARα fusion gene . This study undertakes analysis of PML-RARα bcr isoforms and their correlation with hematological parameters and response to treatment in Indian patients. Aims: To study different bcr isoforms in Indian patients and to find any correlation with various hematological parameters and response to treatment Settings and Design: Patients diagnosed as APL on morphology or flowcytometry and confirmed by RQ PCR were included in the study. Treated APL patients or patients with relapse and on follow up were excluded from the study. Methods and Material: Twenty patients over thirty one months period were included. The clinical, hematological & morphological features were analysed, the latter using routine & special cytochemical stains on blood and bone marrow . Flow cytometric evaluation using 4-color Beckman Coulter FC 500 and molecular studies using RT PCR FusionQuant® kits for bcr-1, bcr-2 and bcr-3 on the instrument Rotor Gene™ 3000 were performed . Statistical analysis used: Student t test was applied to correlate different bcr isoforms with various haematological parameters and response to treatment. Results: In our study , M:F ratio was 1.5:1 with median age 42 years, Hb - 8.0 g/dl, TLC-7900/μl, and platelet – 35000/ μl and varied clinical presentation. Four patients were microgranular variants and rest hypergranular . MPO and CAE positivity was 100% and 33.33% for NSE. Molecular analysis revealed bcr1 in 42.85% , bcr2 in 14.28% and bcr 3 in 38.09 % patients. No correlation was found between bcr isoforms , different hematological parameters and response to treatment. Conclusions: Higher incidence of bcr-1 was found in Indian APL patients with no significant correlation between different hematological parameters and response to treatment.
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Gupta, Vikas, Qi-long Yi, Joseph Brandwein, Jeffrey H. Lipton, Hans A. Messner, Andre C. Schuh, Richard A. Wells, and Mark D. Minden. "Role of all-trans-retinoic acid (ATRA) in the consolidation therapy of acute promyelocytic leukaemia (APL)." Leukemia Research 29, no. 1 (January 2005): 113–14. http://dx.doi.org/10.1016/j.leukres.2004.05.006.
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Islam, AKM Mynul, Mohammad Ali, Mohammad Abdullah Al Anis, Ahmad Monzurul Aziz, Syeda Subrina Siddika, Salina Haque, Zulfia Zinat Chowdhury, et al. "Treatment Outcome of Newly Diagnosed Acute Promyelocytic Leukaemia by All-Trans Retinoic Acid followed by Arsenic Tri-Oxide." Haematology Journal of Bangladesh 2, no. 01 (January 21, 2018): 3–7. http://dx.doi.org/10.37545/haematoljbd201810.
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Background: Acute promyelocytic leukaemia (APL) is curable with carefully selected treatment protocol. Reduction of early fatal haemorrhage in initial phase of induction with cost effective combination of chemotherapeutic agents is considered to be the main challenge for successful outcome in APL. Objective: The study was conducted to see the effectiveness of the use of all-trans retinoic acid (ATRA) followed by single agent Arsenic tri oxide (ATO) in the induction phase of the management of APL. Methodology: This is an observational study and was conducted from October 2012 to September 2013, in department of Haematology and BMT of Dhaka Medical College Hospital, Dhaka, Bangladesh. Total 17 patients with PML/RARA positive APL were enrolled and all patients were treated with sequential use of ATRA in a dose of 45mg/m2 for initial 2-3 weeks up to differentiation and then ATO in a dose of 0.15mg/kg daily was used in induction up to 60 days after taking informed written consent. Outcome was drawn after consolidation of therapy. Results: The morphologic complete remission rate was 88.2%. Remission failure was in observed in 2 cases (11.8%) that died at day 12 and day 51 due to differentiation syndrome and arrhythmia respectively. No death observed within first 10 days of treatment initiation. Complications observed during management were weight gain (11, 64.7%), hyper leucocytosis (10, 58.8%), ATRA syndrome (9, 52.9%), headache (6, 35.3%), tachycardia (5, 29.4%), hypomagnesaemia (3, 17.7%) and supra ventricular tachycardia (1, 5.8%). Conclusion: Initial use of ATRA up to differentiation of promyelocytes before use of single agent ATO induction and consolidation can be a cost-effective alternative against newly diagnosed APL in reduction of early haemorrhagic death.
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Arruda, Walter Oleschko, María Belén Montú, Marcelo de Souza R. de Oliveira, and Ricardo Ramina. "Acute myeloid leukaemia induced by mitoxantrone: case report." Arquivos de Neuro-Psiquiatria 63, no. 2a (June 2005): 327–29. http://dx.doi.org/10.1590/s0004-282x2005000200024.
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Mitoxantrone (MX) is an immunosupressant drug used in secondarily progressive multiple sclerosis (SPMS) and in relapsing-remitting multiple sclerosis (RRMS). It has a leukemogenesis potential induced by cytogenetic abnormalities, though with a low incidence. Promyelocitic leukaemia (type M3) and other forms of acute myeloblastic leukaemias (M4 and M5) have been described in a few MS patients who received MX during their treatment. We describe a white female patient, 47 year-old, with SPMS (EDSS = 4) with 14 years of disease. She received MX during her disease and developed acute promyelocytic leukaemia (M3), with severe thrombocytopenia 30 months later. She ultimately died due to intracerebral hemorrhage. Other cases of treatment related to AML are reviewed and discussed.
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Avvisati, Giuseppe, and Martin S. Tallman. "All-trans retinoic acid in acute promyelocytic leukaemia." Best Practice & Research Clinical Haematology 16, no. 3 (September 2003): 419–32. http://dx.doi.org/10.1016/s1521-6926(03)00057-4.
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Aziz, Md Abdul, Naseeb M. Irshadullah, Mohammad Ali, Shafiqul Islam, Sirajul Islam, Masuda Begum, Rafia Afrose, and Abul Fazal Mohammad Helal. "Maintenance Therapy for Acute Myelogenous Leukaemia." Journal of Dhaka Medical College 24, no. 1 (September 7, 2016): 67–72. http://dx.doi.org/10.3329/jdmc.v24i1.29567.
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Acute myelogenous leukaemia (AML) is one of the deadliest malignancies of mankind. With optimum treatment long term survival is still less than half the patients treated. Except acute promyelocytic leukaemia (AML M3), maintenance therapy in recent protocols are not recommended. This article discusses potential benefit of maintenance therapy for all AML patients, especially in facilities available in developing countries like Bangladesh.J Dhaka Medical College, Vol. 24, No.1, April, 2015, Page 67-72
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Duprez, E., A. J. Saurin, J. M. Desterro, V. Lallemand-Breitenbach, K. Howe, M. N. Boddy, E. Solomon, H. de The, R. T. Hay, and P. S. Freemont. "SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation." Journal of Cell Science 112, no. 3 (February 1, 1999): 381–93. http://dx.doi.org/10.1242/jcs.112.3.381.
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PML is a nuclear phosphoprotein that was first identified as part of a translocated chromosomal fusion product associated with acute promyelocytic leukaemia (APL). PML localises to distinct nuclear multi-protein complexes termed ND10, Kr bodies, PML nuclear bodies and PML oncogenic domains (PODs), which are disrupted in APL and are the targets for immediate early viral proteins, although little is known about their function. In a yeast two-hybrid screen, we first identified a ubiquitin-like protein named PIC1 (now known as SUMO-1), which interacts and co-localises with PML in vivo. More recent studies have now shown that SUMO-1 covalently modifies a number of target proteins including PML, RanGAP1 and IkappaBalpha and is proposed to play a role in either targeting modified proteins and/or inhibiting their degradation. The precise molecular role for the SUMO-1 modification of PML is unclear, and the specific lysine residues within PML that are targeted for modification and the PML sub-domains necessary for mediating the modification in vivo are unknown. Here we show that SUMO-1 covalently modifies PML both in vivo and in vitro and that the modification is mediated either directly or indirectly by the interaction of UBC9 with PML through the RING finger domain. Using site-specific mutagenesis, we have identified the primary PML-SUMO-1 modification site as being part of the nuclear localisation signal (Lys487 or Lys490). However SUMO-1 modification is not essential for PML nuclear localisation as only nuclear PML is modified. The sequence of the modification site fits into a consensus sequence for SUMO-1 modification and we have identified several other nuclear proteins which could also be targets for SUMO-1. We show that SUMO-1 modification appears to be dependant on the correct subcellular compartmentalisation of target proteins. We also find that the APL-associated fusion protein PML-RARA is efficiently modified in vitro, resulting in a specific and SUMO-1-dependent degradation of PML-RARA. Our results provide significant insights into the role of SUMO-1 modification of PML in both normal cells and the APL disease state.
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Alzaabi, Mariam Rashed, Inaam bashir Hassan, Martin S. Tallman, Arif Alam, Khalid Al qawasmeh, and Jorgen Kristensen. "Patient Characteristics and Early Death Predictors in Acute Promyelocytic Leukaemia Patients; Experience from United Arab Emirates (UAE)." Blood 126, no. 23 (December 3, 2015): 4963. http://dx.doi.org/10.1182/blood.v126.23.4963.4963.
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Abstract Background: Acute promyelocytic leukemia (APL) is a highly curable subtype of acute myeloid leukemia (AML). APL has unique morphological, cytogenetic and molecular characteristics. Although extensive data regarding APL are available from developed countries only few studies have been published from developing countries. They describe higher early death rates with lower complete remission rate compared to patients from developed countries. In a retrospective analysis, we evaluated the characteristics features at presentation and predictor of early death in 67 patients with APL diagnosed between 2000 and 2015 at two centers in UAE. To our knowledge there are no published data on APL early death rates from the United Arab Emirates (UAE) Patients and Methods: All patients age >15 years with a newly diagnosis of APL between January 2000 and January 2013 at Tawam hospital and Sheikh Khalifa Medical City (SKMC) were included. The initial diagnosis was typically based on clinical, morphological & phenotypic (negative expression of CD34 and HLA-DR but positive expression of CD2 and CD9) suspicion of APL. Subsequently the diagnosis was confirmed with genetic study for detection of t(15:17). Oral ATRA was immediately started at the standard dose 45 mg/m2 per day in addition to supportive care to correct the coagulopathy (fresh-frozen plasma, cryoprecipitate to maintain fibrinogen at >1.5 g/l, and platelets was maintained at >30x109/l). Early death was defined as death within 30 days of a patient being diagnosed with APL. Data were analyzed using SPSS version 21 (IBM SPSS Inc., Chicago, IL). Results: The median age was 33 years (15 - 57) with only 18 (26.9%) of the patients were older than 40 years. Patients were more likely to be male (42, 62.7%), present with bleeding (53, 80.3%) at the time of diagnosis, have a WBC count greater than 10x109/L in 59.9% while in 40% of the patients it was < 5 x109/L. They tend to have platelet count < 30x109/L in 76.1%, high INR in 66.7% and < 1.5g/L fibrinogen in two third of them. 69.2% of them had bcr1 and 10 of the patients (14.9%) had t(15:17) with additional chromosomal abnormalities include monosomy7 (2 patients), trisomy 8 (1 patients), del 9 (1 patients), ring chromosome 6 (2 patients), der 21 (1 patients) and complex karyotype (3 patients). Early death rate was 11.9%(8/67 patients). In a univariate analysis of the prognostic factors, early-deaths occurred significantly more frequent in patients who were >40 years of age (27.8% versus 6.1%; p= 0.015), those who presented with fever (21.2% versus 2.3%; p=0.030), WBC count >20 x 109/L (26.1% versus 4.5%; p=0.010), high INR (17.7% versus 0.0%; p=0.047), high APTT (40% versus 7.4%; p=0.021) at the time of diagnosis. Although fibrinogen level <1.5g/L was not identified as a significant predictor (21.1% versus 5.1%; p=0.062) of early death, a level of <1.0 g/L emerge as a significance (30.0% versus 4.3%; p=0.010) predictor in addition to the breakpoints other than bcr1 (25.0% versus 3.7%; p=0.043). Time to start of ATRA (>24h versus within 24h) therapy failed to show statistical significance (13.3% versus 12.5%; p=0.9). Patients with WBC count <5.0x109/L have tendency to less frequent early death (3.7% versus 17.5%; p=0.08). None of the patients with additional chromosomal abnormalities experienced early death (0.0% versus 14.0%). However the difference was not statistically significant (p=0.26). Conclusion: The patient characteristics of UAE APL patients at presentation are similar to other published data. Early death rate is comparable to that published from developed countries. Our data support that coagulopathy at presentation is a major contributor to early death and that treatment of APL with improvement of early death rate is feasible at centers in developing countries provided access to facilities for aggressive supportive care. Disclosures No relevant conflicts of interest to declare.
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Suzuki, Rikio, Makoto Onizuka, Minoru Kojima, Masako Shimada, Satomi Fukagawa, Kosuke Tsuboi, Hiroyuki Kobayashi, et al. "Preferential Hypermethylation of the DKK-1 Promoter in Core-Binding Factor Leukaemia." Blood 110, no. 11 (November 16, 2007): 4136. http://dx.doi.org/10.1182/blood.v110.11.4136.4136.
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Abstract The Dickkopf-1 (DKK-1) gene product is an extracellular Wnt inhibitor. Hypermethylation of the DKK-1 promoter results in transcriptional silencing and may play an important role in cancer development. Here, we investigated hypermethylation of the DKK-1 promoter in patients with acute myeloid leukaemia (AML), especially core-binding factor (CBF) leukaemia. The methylation status of DKK-1 was analyzed by methylation-specific polymerase chain reaction in 47 patients with AML. DKK-1 methylation was found in 14 (29.8%) of the patients, and more frequently in those with CBF leukaemia (6 of 12 patients), than in those with acute promyelocytic leukaemia (0 of 6 patients) (P = .03). In contrast, Wnt inhibitory factor-1 methylation was found in acute promyelocytic leukaemia (4 of 6 patients) but not in CBF leukaemia (0 of 12 patients) (P = .001). Multivariate analyses suggested that DKK-1 methylation was a risk factor for poorer overall survival. Sequential analysis using 4 paired samples obtained at diagnosis and relapse suggested that DKK-1 methylation was involved in the progression of leukaemia. DKK-1 methylation may therefore be involved in leukaemogenesis, especially in CBF leukaemia, and may be a useful prognostic marker in AML.
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de Botton, Stephane, Sylvie Chevret, Miguel Sanz, Herve Dombret, Xavier Thomas, Agnes Guerci, Martin Fey, et al. "Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial." British Journal of Haematology 111, no. 3 (December 2000): 801–6. http://dx.doi.org/10.1046/j.1365-2141.2000.02442.x.
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de Botton, Stéphane, Sylvie Chevret, Miguel Sanz, Hervé Dombret, Xavier Thomas, Agnès Guerci, Martin Fey, et al. "Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial." British Journal of Haematology 111, no. 3 (December 2000): 801–6. http://dx.doi.org/10.1111/j.1365-2141.2000.02442.x.
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Sobas, Marta, Maria Carme Talarn-Forcadell, David Martínez-Cuadrón, Lourdes Escoda, María J. García-Pérez, Jose Mariz, María J. Mela-Osorio, et al. "PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review." Cancers 12, no. 5 (May 21, 2020): 1313. http://dx.doi.org/10.3390/cancers12051313.
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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)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα 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-RARα and 2 NPM1-RARα), 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.
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Micol, Jean Baptiste, Emmanuel Raffoux, Nicolas Boissel, Etienne Lengliné, Emmanuel Canet, Marie Thérèse Daniel, Adrienne de Labarthe, et al. "Management and treatment results in patients with acute promyelocytic leukaemia (APL) not enrolled in clinical trials." European Journal of Cancer 50, no. 6 (April 2014): 1159–68. http://dx.doi.org/10.1016/j.ejca.2013.11.023.
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Furtado, Vanessa Fiorini, Felipe Batalini, Pedro Staziaki, Andrey Prilutskiy, and John Mark Sloan. "Acute promyelocytic leukaemia presenting as necrotising fasciitis of the perineum (Fournier gangrene)." BMJ Case Reports 11, no. 1 (December 2018): e226837. http://dx.doi.org/10.1136/bcr-2018-226837.
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We present a case of an unusual presentation of acute promyelocytic leukaemia (APML), which presented with Fournier gangrene (FG). A 38-year-old man presented with malaise, groin swelling, anal bleeding, fever and was found to have FG. Initial workup revealed pancytopaenia, borderline low fibrinogen, prolonged international normalized ratio (INR), which raised the suspicion for leukaemia. The peripheral blood differential revealed leucopaenia with absolute neutropaenia and a 5% abnormal promyelocytes but no blasts, suspicious for APML. Bone marrow biopsy was performed and fluorescence in situ hydridization (FISH), karyotype and PCR confirmed a t(15;17) translocation, establishing a diagnosis of APML. After 1 month of therapy for intermediate risk APML with All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), repeat chromosomal analysis and repeat bone marrow biopsy revealed no evidence of residual APML. After the consolidation phase was started with ATRA and ATO regimen, the wound healed after 2 months and the patient achieved complete remission.
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ROBERTS, A. W., W. P. SHERIDAN, and A. P. GRIGG. "All-trans retinoic acid – chemotherapy interactions in acute promyelocytic leukaemia." Internal Medicine Journal 22, no. 6 (December 1992): 704. http://dx.doi.org/10.1111/j.1445-5994.1992.tb00512.x.
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ROBERTS, A. W., W. P. SHERIDAN, and A. P. GRIGG. "All-trans retinoic acid - chemotherapy interactions in acute promyelocytic leukaemia." Australian and New Zealand Journal of Medicine 22, no. 6 (December 1992): 704. http://dx.doi.org/10.1111/j.1445-5994.1992.tb04879.x.
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Law, Man Fai, Sze-Fai Yip, Hay Nun Chan, Yiu Ming Yeung, and Wai Choi. "Comparing Induction and Consolidation with or without Cytarabine In the Treatment of Acute Promyelocytic Leukaemia In Hong Kong Chinese." Blood 116, no. 21 (November 19, 2010): 4366. http://dx.doi.org/10.1182/blood.v116.21.4366.4366.
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Abstract Abstract 4366 Previous studies suggested that cytarabine was not required in the treatment of newly diagnosed acute promyelocytic leukaemia (APL). They suggested that omitting cytarabine in the treatment of APL could reduce treatment toxicity without increasing relapses and affecting survival. No previous study assessed the effect of cytarabine in the treatment of Chinese APL patients. We compared the outcome of APL patients with or without cytarabine in induction and consolidation therapy in Hong Kong Chinese in a local hospital. Method It was a retrospective study of newly diagnosed APL patients from Jan 1996 to Dec 2009. They were divided into two groups. One group was given ATRA (All-trans-retinoic acid) 45mg/m2/day combined with daunorubicin 60mg/m2/day for 3 days plus cytarabine 200mg/m2/day for 7 days as induction therapy. It was followed by two courses of consolidation with daunorubicin and cytarabine and then 2-year maintenance with low dose chemotherapy and intermittent ATRA. Another group was given the same treatment without cytarabine. The remission rate, relapse rate, overall survival and event-free survival were compared in the two groups of patients. Results Eighteen patients with median age of 41 (range 24–62) received cytarabine. 22% of them had initial WBC count >10,000/uL. Eight patients with median age of 42 (range 16–57) received no cytarabine. 25% of them had WBC count >10,000/uL. The complete remission rates were 100% in both groups. The two-year relapse rate was 5.5% (1/18) for cytarabine group and 62% (5/8) for no cytarabine group (p=0.004, Fisher's exact test). The two-year event-free survival was 82% for cytarabine group and 37% for no cytarabine group (p=0.0017). The two-year overall survival was 89% for cytarabine group and 75% for no cytarabine group (p=0.18). The adverse effects profile was similar in both groups. Conclusion The results support a role of cytarabine in addition to ATRA and daunorubicin in the treatment of newly diagnosed APL. The relapse rate was much lower in patients receiving cytarabine. The two-year event-free survival and two-year overall survival were also significantly better in the cytarabine group. Disclosures: No relevant conflicts of interest to declare.
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Rahman, F., AL Kabir, MR Khan, A. Aziz, MN Baqui, TF Dipta, and ABM Yunus. "Disseminated intravascular coagulation in acute promyelocytic leukaemia and its impact on the induction failure: a single centre study." Bangladesh Medical Research Council Bulletin 39, no. 2 (July 23, 2014): 57–60. http://dx.doi.org/10.3329/bmrcb.v39i2.19642.
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Life-threatening coagulopathy associated with acute promyelocytic leukemia (APL) has been the defining clinical characteristic and is an important risk factor for fatal haemorrhage and early death. Pathogenesis of coagulopathy in APL is complex and mainly includes disseminated intravascular coagulation (DIC). The study was done to see the status of DIC and its impact on the outcome of APL in our setting. Among the total 60 patients, induction mortality rate was 30% and remission rate was 70%. The main cause of induction mortality was bleeding that accounts for 66.7% of mortality. DIC was present among 32 out of 60 patients (53.33%). Induction mortality has significant relationship to DIC as the induction mortality rate is 47% in patients with DIC and 11% in patient without DIC (P value 0.0009 ). Induction motality rate in low, intermediate and high risk group is 6.7%, 24% and 58% respectively (p value <0.0001). Finally, risk group subclassification revealed presence of DIC in high risk group has the highest early mortality rate DOI: http://dx.doi.org/10.3329/bmrcb.v39i2.19642 Bangladesh Med Res Counc Bull 2013; 39: 57-60
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Montesinos, Pau, Jose D. Gonzalez, Chelo Rayon, Javier de la Serna, Juan Bergua, Jordi Esteve, Mar Tormo, et al. "Secondary Acute Myeloid Leukemia and Myelodysplastic Syndromes Following ATRA and Anthracycline Monochemotherapy Treatment for Acute Promyelocytic Leukemia." Blood 110, no. 11 (November 16, 2007): 1838. http://dx.doi.org/10.1182/blood.v110.11.1838.1838.
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Abstract Background: With the improved survival of patients with acute promyelocytic leukemia (APL) treated with all trans retinoic acid (ATRA) combined to anthracycline chemotherapy, acquired therapy-related myelodysplasia (tMDS), acute myelogenous leukaemia (tAML), or both, can be an emerging problem. Objectives: Analyze the incidence and characteristics of tMDS/tAML in 740 patients with newly diagnosed APL enrolled in the PETHEMA LPA96 and LPA99 trials. Methods: From 1996 to 2005, 740 patients (median age 40 years, range 2–83) were included in the LPA96 and LPA99 trials (176 and 564 patients, respectively). Induction therapy consisted of ATRA and idarubicin, followed by three consolidation courses of anthracycline monochemotherapy with or without ATRA. Maintenance therapy consisted of low-dose oral chemotherapy (mercaptopurine and methotrexate with ATRA). We measured the cumulative incidence (CI) of tMDS/tAML during the course of APL patients who achieved the complete remission (CR). Results: CR was achieved in 667 patients (90%). The median follow-up of the cohort was 66 months (range 20–127 months). Overall, 12 patients presented a tMDS/tAML, after a median of 43 months (range 23–55) from the achievement of CR. Six patients were diagnosed of tAML and 6 were diagnosed of tMDS. In all patients, RT-PCR monitoring and/or cytogenetic analysis indicated first complete remission of APL at the time of diagnosis of tMDS/tAML. Cytogenetic characterization revealed −5/del(5q) and/or −7/del(7q) abnormalities in 7 of 12 patients, whereas 11q23 rearrangements were observed in 2 patients. In spite of intensive chemotherapy (with allogeneic stem-cell transplantation in 3 patients), the course of tAML was aggressive (5 of 6 patients dead after a median of 7 months from diagnosis). Five patients with tMDS received only supportive treatment, and the remaining patient received chemotherapy and allogeneic stem-cell transplantation. Survival was also poor, with 4 patients dead after a median of 6 months, and 2 patients alive after 3 and 5 months from tMDS diagnosis. The median age at diagnosis of tMDS/tAML was 58 years (range 29–68). Four and 8 patients followed the LPA96 and the LPA99 trial, respectively. At the initial diagnosis, APL were classified, according to the Sanz score, as high-, intermediate- and low-risk, in 0, 7, and 5 patients, respectively. The overall 5 year CI of tMDS/tAML was 2.1%. The 5 year CI of tMDS/tAML in high-, intermediate- and low-risk patients was 0%, 2.2% and 4.2%, respectively (low- vs high-risk log-rank test; p=0.06). The 5 year CI of tMDS/tAML in patients <50 years and ≥50 years was 1% and 4.6%, respectively (p=0.009). Conclusion: In this large series of APL patients treated with ATRA and anthracycline monochemotherapy, the 5 year CI of tMDS/tAML was 2.1%. tMDS/tAML can be a long-term therapeutic complication, affecting more frequently patients aged ≥50 years and conferring a poor prognosis. Despite the lack of alkylating agents in the therapy of APL, cytogenetic abnormalities involving chromosomes 5 and 7 were frequently observed.
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Bain, Barbara J., and Marie C. Béné. "Morphological and Immunophenotypic Clues to the WHO Categories of Acute Myeloid Leukaemia." Acta Haematologica 141, no. 4 (2019): 232–44. http://dx.doi.org/10.1159/000496097.
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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.
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Gyi, Aye Aye, Aung Aung, Khin Thida Htut, Yin Nwe Han, and Mee Mee Khaing. "Preliminary Report for Outcome of Treatment with Differentiation Agents Plus Combination Chemotherapy during Induction Phase in High Risk Acute Promyelocytic Leukaemia." Blood 128, no. 22 (December 2, 2016): 5175. http://dx.doi.org/10.1182/blood.v128.22.5175.5175.
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Abstract BACKGROUND: With the advent of differentiating agents like all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), acute promyelocytic leukemia (APL) nowadays has achieved highest cure rate among acute myeloid leukemias worldwide. However, in Myanmar, remission rate is relatively low (less than 60%) due to high early deaths from coagulopathy, infection and differentiation syndrome (DS). Resource constraints in molecular diagnosis also delay the treatment. High abandonment is also a major problem. As beneficial effects of ATO and ATRA as well as anthracycline and cytarabine on outcome of APL have been reported in recent literatures, they all are combined in local protocol developed to achieve maximum benefit during induction particularly for high risk patients. This preliminary study report the induction outcome of combination of both ATRA and ATO plus two chemotherapeutic agents in high risk APL patients treated at North Okkalapa General Hospital of Myanmar. METHODS: Molecularly or cytogenetically confirmed newly diagnosed APL patients presented during January 2014 to June 2016 were stratified into high and low or intermediate risk groups according to the Sanz's risk score. High risk patients were treated with oral ATRA 45mg/m2 /day started once diagnosis was suspected together with combined chemotherapy (IV Daunorubicin 45mg/m2 /day x 3 days plus IVI Cytarabine 100mg/m2 /day for 7 days). After receiving molecular or cytogenetic confirmation of PML-RARA fusion transcript, IVI ATO 0.15mg/kg/day was added until complete remission (CR). Low and intermediate risk patients were considered as high risk and chemotherapy was added when WBC count was rapidly raised above 10 x 10⁹/L during first 10 days of induction. Prednisolone 0.5mg/kg/day was added during first 10 days in all patients. Transfusion support was given according to standard transfusion guidelines. Remission assessment by morphology and RT-PCR for molecular remission (mCR) was done at the end of induction. Second induction was repeated if there was no molecular remission after first induction. RESULTS: Among21 APL remained after 4 early deaths, 18 were treated with high risk protocol where 8 cases (44%) were classified as high risk at entry and 10 intermediate patients (56%) were added due to rapid rise in white cell counts. Median age was 29 years (range 12 to 56 years). Male to female ratio was 1.6:1. Five (28%) were variant form and 13 (72%) were typical APL. Median white cell and platelet count were 21.8 x 109/L and 31 x 109/L respectively. The most common grade 3 or 4 complication during induction period was infection, especially blood stream and catheter related infection (9 patients) and respiratory tract infection (7 patients) followed by differentiation syndrome (6 patients). Fourof 18 high risk APL patients (22%) died during induction period due to documented severe respiratory tract infection. Remaining 14 patients who completed induction achieved CR (77.78%). Of 14 who achieved haematologic remission at the end of first induction, 10 (71.43%) had molecular remission. The remaining 4 patients who were also in morphologic CR achieved mCR after second induction. All proceeded to consolidation without chemotherapy and remained in remission till the time of this report. CONCLUSION: Although induction mortality rate of 22% is still high in this combination treatment due to limitation in intensive care support, there were no mortality from coagulopathy or DS. All high risk APL who completed induction in this study achieved high rate of early molecular remission (mCR). As the molecular remission status is documented to be associated with lower relapse, those patients are still hopeful of prolonged survival even if they are unable to attend follow-up frequently. By improving supportive care, and survival could be improved with minimal chemotherapy in even in high risk disease. Disclosures No relevant conflicts of interest to declare.
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Troitskaya, V. V., E. N. Parovichnikova, A. A. Semenova, Z. T. Fidarova, A. N. Sokolov, G. M. Galstyan, M. V. Spirin, et al. "Risk-adapted combined therapy with arsenic trioxide and all-trans-retinoic acid for de novo acute promyelocytic leuкaemia." Russian journal of hematology and transfusiology 66, no. 2 (September 2, 2021): 168–91. http://dx.doi.org/10.35754/0234-5730-2021-66-2-168-191.
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Introduction. Non-chemotherapy for acute promyelocytic leukaemia (APL) with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) provides for a high patient survival rate at lesser toxicity as effectively or superior to standard chemotherapy programmes.Aim — assessment of the ATO–ATRA risk-adapted exposure protocol in management of de novo acute promyelocytic leucaemia.Materials and methods. A prospective study included 51 primary APL patients aged 18–76 years. The program included remission induction (ATO 0.15 mg/kg intravenously, ATRA 45 mg/m2 orally) for 30–60 days in a low-risk (until remission) and 60 days — in a high-risk cohort that had idarubicin therapy added on days 2 and 4. Remission consolidation was attained with four (low-risk) or five (high-risk) courses. Minimal residual disease was monitored with real-time PCR at all phases.Results. The high-risk cohort was assigned 15 (29.4 %), the low-risk cohort — 36 (70.6 %) patients. Therapy induction till APL morphological remission was performed in 48/51 (94 %) patients. Molecular APL remission was achieved in 47 (92 %) patients, 100 % in the low-risk and 80 % in high-risk cohort. Early mortality was 6 % (n = 3), death in remission — 2 % (n = 1). Differentiation syndrome (DS) occurred in 16 (31.7 %) patients, more frequently in the high-risk vs. low-risk cohort (53.3 % and 22.2 %, respectively, p = 0.05; odds ratio 4.0 [1.1–14.4]). DS developed on days 1–20 (3 days median) of therapy. DS risk factors: a high-risk status, haemorrhagic syndrome and infection at the disease onset. A median follow-up time in survivors was 12.9 months (2.5–34.3), a six-month overall survival — 92 % (95 % CI: 85–100 %). A six-month overall survival was 100 and 73 % in the low- and high-risk cohorts, respectively (95 % CI: 54–100 %, p = 0.001). APL relapse not registered, 47 (92 %) patients survived and achieved the first molecular remission.Conclusion. A differentiated risk-adapted approach to APL therapy with cytostatic treatment added in high-risk patients only provided for a 100 % molecular remission and relapse-free survival. Therapy failures (early mortality and death in remission) affected high-risk patients due to a severe individual condition at the time of APL diagnosis.
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Keane, Colm G., Peter Mollee, Paula Marlton, and Devinder Gill. "Treatment of Acute Promyelocytic Leukaemia in Jehovah’s Witness(JW) Population." Blood 112, no. 11 (November 16, 2008): 4014. http://dx.doi.org/10.1182/blood.v112.11.4014.4014.
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Abstract Treatment Of Acute Promyelocytic Leukemia (APML) In The Jehovah’s Witness (JW) Population. Colm Keane, Peter Mollee, Paula Marlton, Devinder Gill. Background: Treatment of acute myeloid leukaemia in JW patients is challenging. The refusal to accept blood products is usually a contraindication to intensive chemotherapy and a potential cure. Methods: We review three cases of APML occurring in JW patients treated at our institution which demonstrate the benefit of newer targeted combination therapies that induce less marrow suppression. Suggested management principles are derived from these anecdotal rare cases. Case 1 was a 39 year old male who was initially treated with ATRA (25 mg/m2) and Darbopoietin 100μg twice weekly with arsenic added on day 10 (0.15mg/kg/day). He initially tolerated therapy well despite severe pancytopenia until (day 20) the hemoglobin fell to 52g/L when he developed chest pain. He was diagnosed to have had a myocardial infarct in the setting of fluid retention. His WCC was 10.4 × 109/L with platelet count of 20 × 109/L. He was managed conservatively with no anticoagulation. His hemoglobin nadir was 44 g/L before rising above 80 g/L by day 38 of therapy at which time he was in cytogenetic and molecular remission. He completed a further 28 weeks of consolidation with ATRA (45mg/m2 for 2 weeks every 4 weeks) and arsenic (0.15mg/kg/day Mon-Fri, d1-28 every 2 months for 4 cycles). He has completed 9 months of planned 2 yrs oral maintenance chemotherapy (ATRA, 6MP, MTX) without further incident. Case 2 was a 62 year old female who was treated with ATRA induction (initially at 25mg/m2 but increased to 45mg/m2 on day 18), plus Erythropoietin (Epo) 4,000U × 3 per week s/c. She was in complete cytogenetic remission on day 37 and complete molecular remission by day 87. She had a hemoglobin nadir of 60 g/L but remained asymptomatic. Consolidation therapy commenced on day 106 consisting 3 cycles of combination therapy with ATRA (45mg/m2/d po for 4 weeks) and arsenic (0.15mg/m2/d iv for 5d/week for 4 weeks). Between consolidation cycles there was a 3-week interval during which all therapy was ceased. This regimen was well tolerated. She remains in complete remission after 8 years. Case 3 was a 28-year-old male who was initially treated with ATRA, low dose cytarabine and Epo 4000U 3-times/week s/c. He developed symptoms of severe anemia when his hemoglobin dropped to 25g/L with syncopal episodes and hypotension. He was subsequently found to have t (11:17) mutation and the leukemia did not respond to ATRA. He died from severe anemia fourteen days after presentation. Case reports published subsequently have shown that ATRA resistance in t(11:17) APML may occasionally be overcome if combined with standard chemotherapy or GCSF. However to date Arsenic has not been useful in this variant form of APML. Recommendations: Therapy. Induction with ATRA 25mg/m2 followed on day 10 by arsenic 0.15mg/kg/day until morphologic remission. Consolidation with alternating cycles of ATRA and arsenic as per Case 1. Maintenance therapy with ATRA, 6MP and MTX for 2 years. Anemia. Our patients tolerated severe anemia reasonably well until hemoglobin dropped to approximately 50g/L (most deaths in the literature due to anemia in the JW population have occurred below this threshold). All JW patients receive maximal erythropoietin stimulation and sparing phlebotomy episodes using paediatric blood collection tubes. Thrombocytopenia and coagulopathy. Antifibrinolytics, DDAVP and newer agents such as FVIIa have been used successfully in JW patients undergoing high risk surgery and may be of benefit in the APML setting for patients with haemorrhagic complications. Differentiation syndrome (DS) Case 1 may have developed DS. The standard management of DS is to commence chemotherapy such as idarubicin, cytarabine or gemtuzumab ozogamicin but because of the potential prolonged myelosuppression such agents are not suitable options for JW patients. We would advocate corticosteroids for DS prophylaxis and if treatment of DS is required, hydroxyurea may be a safer option because of its limited and shorter duration of myelosuppression. Conclusion: Our series demonstrates the benefit of more targeted therapy in APML allowing patients who refuse transfusion of blood products a realistic chance of cure.
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Fulghieri, Paola, Lucia Anna Stivala, and Virginie Sottile. "Modulating cell differentiation in cancer models." Biochemical Society Transactions 49, no. 4 (August 26, 2021): 1803–16. http://dx.doi.org/10.1042/bst20210230.
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Cancer has been traditionally viewed as a disease characterised by excessive and uncontrolled proliferation, leading to the development of cytotoxic therapies against highly proliferating malignant cells. However, tumours frequently relapse due to the presence of slow-cycling cancer stem cells eluding chemo and radiotherapy. Since these malignant stem cells are largely undifferentiated, inducing their lineage commitment has been proposed as a potential intervention strategy to deplete tumours from their most resistant components. Pro-differentiation approaches have thus far yielded clinical success in the reversion of acute promyelocytic leukaemia (APL), and new developments are fast widening their therapeutic applicability to solid carcinomas. Recent advances in cancer differentiation discussed here highlight the potential and outstanding challenges of differentiation-based approaches.
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Sanz, Miguel A., Jesús A. Martínez, Eva Barragán, Guillermo Martín, and Francesco Lo Coco. "All-Trans Retinoic ACID and Low-Dose Chemotherapy For Acute Promyelocytic Leukaemia." British Journal of Haematology 109, no. 4 (June 2000): 896–97. http://dx.doi.org/10.1046/j.1365-2141.2000.109004896.x.
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Charles, K. S., M. Kanaa, D. A. Winfield, and J. T. Reilly. "Scrotal ulceration during all-trans retinoic (ATRA) therapy for acute promyelocytic leukaemia." Clinical & Laboratory Haematology 22, no. 3 (June 2000): 171–74. http://dx.doi.org/10.1046/j.1365-2257.2000.00306.x.
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Takam Kamga, Paul, Giada Dal Collo, Adriana Cassaro, Annalisa Adamo, Alessandro Gatti, Roberta Carusone, Mariano Di Trapani, et al. "Inhibition of GSK-3 Signalling Enhances Sensitivity of Non-Promyelocitic Acute Myeloid Leukemia (AML) Cell to Chemotherapy." Blood 128, no. 22 (December 2, 2016): 1582. http://dx.doi.org/10.1182/blood.v128.22.1582.1582.
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Abstract Background: GSK-3 is a serine-threonine kinase involved in metabolic regulation as well as in the control of many pathways associated to cancer development, including Notch Wnt/β-catenin, Hedgehog, and AKT. It has been demonstrated that association of GSK-3 inhibitors with All-trans-retinoic acid (ATRA) significantly improves ATRA-mediated differentiation and cell death of acute promyelocytic (APL) leukaemia cells. However, little is currently known about the contribution of GSK-3 role to non-promyelocytic AML cell response to treatment with chemotherapeutic agents. Aims: In this study, we aim to validate GSK-3 signalling as potent successful therapeutic target in non-promyelocytic AML. For this purpose we tested different GSK-3 for their ability to influence AML cells proliferation and response to Cytarabine (Ara-C) or Idarubicin treatments. Methods: GSK-3 expression was analyzed by Western blot or flow cytometry inAML cell lines (HL-60, THP1, U937) or primary non-promyelocyticAML blast cells (30 samples). AML cellscultured alone or in presence ofhuman bone marrow mesenchymal stromal cells (hBM-MSCs) were treated with GSK-3 inhibitors, including LiCL, AR-A014418, SB 216763, in association or not with Cytarabine (Ara-C) or Idarubicin. Cell proliferation and cell death were measured by CFSE dilution and TOPRO-3/Annexin-V staining, respectively. Results: Flow cytometry and Western blot analysis in AML samples revealed high expression levels of all GSK-3forms, including total GSK-3α, (Ser21) GSK-3α, total GSK-3β, and (Ser 21) GSK-3β; theseforms were all down-modulated when AML cells were cultured in presence of hBM-MSCs, thus suggesting that GSK-3 plays an important role in transducting micro-environmental signals in AML cells interacting with bone marrow stroma. The treatment of AML cells with increasing concentrations of each GSK-3 inhibitors decreased AML cell viability in a dose-dependent manner; interestingly, hBM-MSCs or peripheral blood mononuclear cells were less sensitive to GSK-3inhibitors. The addition of each inhibitor increased dramatically the AML cell apoptotic rate induced by the addition of Ara-C or Idarubicin in vitro. Notably, LiCl and AR-A014418 were capable of abrogating hBM-MSC-mediated AML cell resistance to apoptosis induced by Ara-C or Idarubicin. Conclusion: Overall our data clearly demonstrated that inhibition of GSK-3 reduced proliferation and chemoresistance of non promyelocytic AML cells. Thus GSK-3 inhibition represents a therapeutic strategy not only for APL but also for other AML subtypes. Disclosures Bonifacio: Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Amgen: Consultancy.
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Navarrete, Maida, Teresa Vallespi, Anny Jaramillo, Carmen Sánchez-Morata, Carlos Palacio, Noemí Martínez-Morgado, Ángel Guerra-Moreno, Margarita Ortega, and Javier Bueno. "Therapy-Related PML-RARα Leukemia: An Emerging Disease. Report of 10 Cases From One Department of Hematology." Blood 114, no. 22 (November 20, 2009): 1016. http://dx.doi.org/10.1182/blood.v114.22.1016.1016.
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Abstract Abstract 1016 Poster Board I-38 Introduction: Therapy-related acute myeloid leukemia (t-AML) following chemotherapy is a distinct diagnostic entity in the WHO classification of hematopoietic malignacies. t-AML with monosomy 5 and 7 (or 5q-/7q-) usually occur late after exposure to alkylating agents, whereas those with balanced translocations, especially involving 11q 23 are associated with exposure to epipodophyllotoxin and shorter latency. The occurrence of acute promyelocytic leukaemia (APL) with PML-RARa rearrangement after treatment of a preceding malignancy is a rare event. APL constitutes 10 % of all AML but only 2.7% are t-APL. Patients, Methods and Results: We reported on a single-center experience about of 10 cases of t-APL; patients were observed between October of 1997 until Abril of 2007. There were 6 males and 4 females. Previous diseases were: 6 solid organ malignancies (3 breast cancer, 1 colon cancer, 1 prostate adenocarcinoma and 1 oral cancer), 3 hematologic malignancies (1 Hodgkin disease, 1 follicular lymphoma and 1 polycytemia vera), and 1 multiple sclerosis. Treatment: all of 6 solid tumors received radiotherapy, besides, 3 breast cancers were treated with topoisomerase II inhibitors and anthracyclines, the prostate adenocarcinoma got hormonal therapy and antimetabolite, two lymphomas and the oral cancer received alkylants agents, polycytemia vera was treated with phosphorus 32 and hydroxiurea, and multiple sclerosis with mitoxantrone. Mean age at diagnosis of first cancer was 52.2 years (range: 19-74) and 59.7 years (range: 34-80) at the second. The mean time between the treatment and diagnosis of t-APL was 69.6 months (range: 12-180) being longer in patients treated with alkylants agents (mean: 84 months). Morphologically, all patients presented with hypergranular or typical promyelocytic leukaemia; moreover, two showed Chèdiak granulation and only in one patient bundles of Auer rods (faggot cells) were not observed. By conventional cytogenetics, 3 out of 10 patients presented with complex karyotype: +4, ider(17)(q10) and del(3)(q23q26),t(9;22) (p24;q12),del(14)(q23q32). In all patients the presence of PML/RARa fusion gene was confirmed by RT-PCR. Patients were treated according to Spanish PHETEMA protocol. Regarding to the prognosis they were classified as: high- risk 2, intermediate-risk: 7 and low-risk: 1 (Sanz et al, Blood 2000; 96:1247). A complete remission (CR) was achieved in 8 patients that received treatment. Two patients died of bleeding at diagnosis. Only one patient had molecular relapse and received arsenic trioxide; currently he is in complete remission. Comments: Therapy-related AML has poor prognosis because of the short duration of response. In contrast, several retrospective studies have described that responses to chemotherapy and prognosis of t-APL is similar to that of de novo APL. Last years, we have observed an increment of t-APL diagnosis, 6 out of 10 of our patients were diagnosed over period of 24 months. Disclosures: Guerra-Moreno: Celgene: Research Funding.
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Iacobucci, Ilaria, Emanuela Ottaviani, Federica Salmi, Viviana Guadagnuolo, Nicoletta Testoni, Annalisa Lonetti, Cristina Papayannidis, et al. "Genome-Wide Analysis by High-Resolution SNP Array Identifies Novel Genomic Alterations in Acute Promyelocytic Leukemia (APL)." Blood 114, no. 22 (November 20, 2009): 167. http://dx.doi.org/10.1182/blood.v114.22.167.167.
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Abstract Abstract 167 Introduction: Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17), resulting in the fusion of the promyelocytic leukemia (PML) gene and retinoic acid receptor α (RARA) gene (PML-RARA). Experimental evidence obtained in transgenic mice revealed that PML-RARA is necessary but not sufficient for the development of APL, suggesting that additional genetic mutations are also required for the development of APL. Aim: To define whether additional submicroscopic genomic alterations may characterize APL and be used to better classify the disease by dissection of genomic subsets. Methods: At the time of writing, DNA from the bone marrow of 21 cases of t(15;17) APL at diagnosis were examined. Genomic DNA was isolated from mononuclear APL cells and applied to Genome-Wide Human SNP 6.0 array microarrays (Affymetrix, Santa Clara, CA) following the manufacturer's instructions. Copy number aberrations were scored using the Hidden Markov Model and the segmentation approach available within the Partek software package as well as by visual inspection. All aberrations were calculated with respect to a set of 270 Hapmap normal individuals and a set of samples obtained from acute leukaemia cases in remission in order to reduce the noise of raw copy number data. When available, in order to exclude inherited copy number variants a comparison to paired constitutional DNA and to paired remission DNA was performed. Fluorescence in situ hybridization, quantitative PCR and nucleotide sequencing were used to confirm genomic alterations. Results: In all patients we identified one or more genomic abnormalities ranging from loss or gain of complete chromosome arms (trisomy 8, loss of 20q and loss of 6q) to submicroscopic genomic intervals. Focal genetic alterations were detected at the breakpoints of t(15;17)(q22;q21) in PML and RARA genes. Hemizygous deletions were identified at 1p13.3 affecting the glutathione S-transferase mu 1 (GSTM1), at 2q33.3–q34 involving ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4 avian), at 3p11.2 (EPHA3), at 12p13 (ETV6), and at 17q12 (NF1). Deletions also affected genes involved in cell regulations as CDKN2A (9p21) and RB1 (13q14.2). Most frequent gains affected the TP73 gene at 1p36.3, the oncogene MYC at 8q24 (4.33 Mb), the oncogene ETS1 (11q23.3), the RAS p21 protein activator 3 (RASA3) at 13q34 and PRAME at the 22q11.22. Interestingly, in 2 cases we observed a gain of the region (5p15.33) containing the telomerase reverse transcriptase (TERT) which is important for maintenance of telomere ends. Other recurring genetic lesions were uncommon and were identified only in single cases. Some lesions affected regions lacking annotated genes and they are under investigation for miRNAs. For each alteration we interrogated a collated library of copy-number variants (CNVs, Database of Genomics Variants and USCS Genome Browser) to assure that these regions were not known as CNVs. Conclusion: These data demonstrate that different cooperating events may be involved in the generation of APL. These novel findings may be used to stratify patients according to genomic changes and to facilitate the screening for novel therapeutic targets. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, PIO project 2007, Strategico di Ateneo. Disclosures: No relevant conflicts of interest to declare.
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Clarke, Nicole, Pierre Germain, Lucia Altucci, and Hinrich Gronemeyer. "Retinoids: potential in cancer prevention and therapy." Expert Reviews in Molecular Medicine 6, no. 25 (November 30, 2004): 1–23. http://dx.doi.org/10.1017/s1462399404008488.
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Retinoids (derivatives of vitamin A) are signalling molecules that play important roles in cell growth, differentiation and death. Retinoids act through two types of receptors – retinoic acid receptors (RARα, RARβ and RARγ) and retinoid X receptors (RXRα, RXRβ and RXRγ) – which themselves act as ligand-dependent transcription factors. Retinoids are of special interest in cancer research owing to their antiproliferative and cancer-preventative properties. They have been used successfully to cure acute promyelocytic leukaemia (APL) and can suppress carcinogenesis in a variety of tissue types (e.g. skin, lung, breast and oral cancers). Extensive research efforts have been dedicated to elucidating the molecular and cellular networks that are induced by retinoids, and this has recently yielded novel insights into how retinoids can both prevent and combat cancer.
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Yamasaki, Yoshihiro, Yoichiro Izumi, Hitoshi Sawada, and Kazuyuki Fujita. "PROBABLE IN VIVO INDUCTION OF DIFFERENTIATION BY RECOMBINANT HUMAN GRANULOCYTE COLONY STIMULATING FACTOR (rhG-CSF) IN ACUTE PROMYELOCYTIC LEUKAEMIA (APL)." British Journal of Haematology 78, no. 4 (August 1991): 579–80. http://dx.doi.org/10.1111/j.1365-2141.1991.tb04498.x.
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Zhou, Jin, Ran Meng, Xinhua Sui, Guosheng Feng, and Baoyu Li. "Arsenic Trioxide Entered Cerebrospinal Fluid with the Help of Mannitol Overwhelm the Meningeal Relapse of Acute Promyelocytic Leukemia." Blood 112, no. 11 (November 16, 2008): 946. http://dx.doi.org/10.1182/blood.v112.11.946.946.
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Abstract Background and objective Central nervous system (CNS) relapse of acute promyeloytic leukemia (APL) is increasingly reported after treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3), the optimal therapy for these cases remains unclear. As2O3 highly effective in APL marrow relapse, but its efficacy in APL CNS relapse is undefined. Recent researches showed that little As2O3 could pass through the intact blood- brain-barrier (BBB), which limits its use in prevention and treatment of central nervous system acute promyelocytic leukaemia (CNSAPL). After discovered the different tolarance between NB4 cell line and human cortex neuron to As2O3in vitro, and primarily cleared the safe range of As2O3 level in central nervous system (CNS), we created a non-invasive method to help As2O3 enter into CNS effectively. Methods Five volunteers with isolated meningle APL relapse received the new As2O3 regimen (mannitol helped As2O3 penetration) after accepted the conventional treatment: As2O3 0.16mg/kg/d diluted with 5%glucose 250ml common speed intravenous infusion with intensive intrathecal chemotherapy (MTX 12mg/dose + cytarabine 50mg / dose + Dexamethasone 10mg/dose) and showed chemotherapy resistance. The new regimen included 125ml of 20% mannitol bolus through medial cubital vein with the speed of 12„d`30ml / min, followed by As2O3 0.08mg/kg/d diluted with 250ml-20% mannitol intravenous infusion with the speed of 6ml /min, and then followed by As2O3 0.08mg/kg/d diluted with 5%glucose 250ml intravenous infusion with the speed of 0.5ml/min, meanwhile, associated with intensive intrathecal chemotherapy. The elemental arsenic levels in CSF and plasma during the new regimen performance were dynamic monitored with atomic fluorescence, and the differentiation and apoptosis of the blast cells in CSF were detected with flow cytometry assay. Results The elemental arsenic level in the CSF treated with mannitol helped As2O3 penetration was fluctuated between 0.04 mg /L (0.2 micromol /L) and 0.05mg / L(0.25 micromol /L), which was much higher than that with common speed As2O3 intravenous infusion, and reached to the As2O3 effectively therapeutic level. The blast cells in CSF showed significant differentiation and apoptosis after treated with mannitol helped As2O3 penetration. Three of the five patients obtained complete remission, two of them reached partial remission. Conclusions The new regimen of mannitol helped As2O3 penetration promoted the entrance of elemental arsenic to CNS, which might be benefit to prevent and cure CNS APL, especially to chemotherapy resistant CNS APL.