Acute promyelocytic leukemia

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Acute promyelocytic leukemia
Gostra promiielotsitarna leikemiia (M3).jpg
Bone marrow smear from a patient with acute promyelocytic leukemia, showing characteristic abnormal promyelocytes. [1]
Specialty Hematology and oncology
Usual onset~40 years old [2]
CausesUncontrolled proliferation of promyelocytes [2]
FrequencyDevelops in about 600 to 800 people per year (United States) [2]

Acute promyelocytic leukemia (APML, APL) is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. [3] In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARA) gene and is distinguished from other forms of AML by its responsiveness to all-trans retinoic acid (ATRA; also known as tretinoin) therapy. Acute promyelocytic leukemia was first characterized in 1957 [4] [5] by French and Norwegian physicians as a hyperacute fatal illness, [3] with a median survival time of less than a week. [6] Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study. [7] [6] [8]

Contents

Signs and symptoms

The symptoms tend to be similar to AML in general with the following being possible symptoms: [9]

Easy bleeding from low platelets may include:

Pathogenesis

Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARA) gene on chromosome 17. [3] In 95% of cases of APL, the RARA gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene (PML) on chromosome 15, a translocation denoted as t(15;17)(q22;q21). [3] The RAR receptor is dependent on retinoic acid for regulation of transcription. [3]

Eight other rare gene rearrangements have been described in APL fusing RARA to promyelocytic leukemia zinc finger (PLZF), [10] nucleophosmin, nuclear matrix associated, signal transducer and activator of transcription 5b (STAT5B), protein kinase A regulatory subunit 1α ( PRKAR1A ), factor interacting with PAPOLA and CPSF1 ( FIP1L1 ), BCL-6 corepressor or oligonucleotide/oligosaccharide-binding fold containing 2A ( NABP1 ) genes. Some of these rearrangements are ATRA-sensitive or have unknown sensitivity to ATRA because they are so rare; STAT5B/RARA and PLZF/RARA are known to be resistant to ATRA. [3]

The fusion of PML and RARA results in expression of a hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC). Although the chromosomal translocation involving RARA is believed to be the initiating event, additional mutations are required for the development of leukemia. [3]

RARA/PLZF gene fusion produces a subtype of APL that is unresponsive to tretinoin therapy and less responsive to standard anthracycline chemotherapy hence leading to poorer long-term outcomes in this subset of patients. [3]

Diagnosis

Acute promyelocytic leukemia may also have a hypogranular variant, which can have very scant Auer rods. Wright's stain. Peripheral blood smear of acute promyelocytic leukemia, hypogranular variant.png
Acute promyelocytic leukemia may also have a hypogranular variant, which can have very scant Auer rods. Wright's stain.

Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of the blood film or a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. The presence of promyelocytes containing multiple Auer rods (termed faggot cells) on the peripheral blood smear is highly suggestive of acute promyelocytic leukemia. Definitive diagnosis requires testing for the PML/RARA fusion gene. This may be done by polymerase chain reaction (PCR), fluorescence in situ hybridization, or conventional cytogenetics of peripheral blood or bone marrow. This mutation involves a translocation of the long arms of chromosomes 15 and 17. On rare occasions, a cryptic translocation may occur which cannot be detected by cytogenetic testing; on these occasions PCR testing is essential to confirm the diagnosis. [3]

Hypogranular variant of APL. Giemsa stain, 1000x. Acute promyelocytic leukemia, hypogranular variant (M3v).jpg
Hypogranular variant of APL. Giemsa stain, 1000x.

Treatment

Initial treatment

Tretinoin Tretinoin2DACS.svg
Tretinoin
Mitozantrone Mitozantrone2DACS.svg
Mitozantrone
Methotrexate Methotrexate2DACS2.svg
Methotrexate

APL is unique among leukemias due to its sensitivity to all-trans retinoic acid (ATRA; tretinoin), the acid form of vitamin A. [3] Treatment with ATRA dissociates the NCOR-HDAC complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. [3] Unlike other chemotherapies, ATRA does not directly kill the malignant cells. [3] ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA alone is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy. [3] As of 2013 the standard of treatment for concurrent chemotherapy has become arsenic trioxide, which combined with ATRA is referred to ATRA-ATO; [12] [13] before 2013 the standard of treatment was anthracycline (e.g. daunorubicin, doxorubicin, idarubicin or mitoxantrone)-based chemotherapy. Both chemotherapies result in a clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile. [7]

ATRA therapy is associated with the unique side effect of differentiation syndrome. [14] This is associated with the development of dyspnea, fever, weight gain, peripheral edema and is treated with dexamethasone. [15] The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes. [15]

The monoclonal antibody, gemtuzumab ozogamicin, has been used successfully as a treatment for APL, [16] although it has been withdrawn from the US market due to concerns regarding potential toxicity of the drug and it is not currently marketed in Australia, Canada or the UK. [16] [17] Given in conjunction with ATRA, it produces a response in around 84% of patients with APL, which is comparable to the rate seen in patients treated with ATRA and anthracycline-based therapy. [16] It produces less cardiotoxicity than anthracycline-based treatments and hence may be preferable in these patients. [16]

According to recent updates, the combination of ATRA and arsenic trioxide (ATO) is now preferred for induction therapy in many cases, offering at least as effective results with fewer side effects compared to traditional chemotherapy. [18] In cases of relapse, options include re-treatment with ATO or the targeted drug gemtuzumab ozogamicin (Mylotarg). [19]

Maintenance therapy

After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy with methotrexate, mercaptopurine and ATRA. [20] A significant portion of patients relapsed without consolidation therapy. [15] In the 2000, European APL study, the 2-year relapse rate for those that did not receive consolidation chemotherapy (ATRA not included) therapy was 27% compared to 11% in those that did receive consolidation therapy (p<0.01). [21] Likewise, in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance. [22]

However, recent research on consolidation therapy following ATRA-ATO, which became the standard treatment in 2013, has found that maintenance therapy in low-risk patients following this therapy may be unnecessary, although this is controversial. [13]

Relapsed or refractory disease

Arsenic trioxide (As2O3) is currently being evaluated for treatment of relapsed/refractory disease. Remission with arsenic trioxide has been reported. [23] Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein. [23] Arsenic also increases caspase activity which then induces apoptosis. [23] It does reduce the relapse rate for high risk patients. [24] In Japan a synthetic retinoid, tamibarotene, is licensed for use as a treatment for ATRA-resistant APL. [25]

Investigational agents

Some evidence supports the potential therapeutic utility of histone deacetylase inhibitors such as valproic acid or vorinostat in treating APL. [26] [27] [28] According to one study, a cinnamon extract has effect on the apoptotic process in acute myeloid leukemia HL-60 cells. [29]

Prognosis

Prognosis is generally good relative to other leukemias. Because of the acuteness of onset compared to other leukemias, early death is comparatively more common. If untreated, it has median survival of less than a month. It has been transformed from a highly fatal disease to a highly curable one. The cause of early death is most commonly severe bleeding, often intracranial hemorrhage. Early death from hemorrhage occurs in 5–10% of patients in countries with adequate access to healthcare and 20–30% of patients in less developed countries. Risk factors for early death due to hemorrhage include delayed diagnosis, late treatment initiation, and high white blood cell count on admission. [30] Despite advances in treatment, early death rates have remained relatively constant, as described by several groups including Scott McClellan, Bruno Medeiros, and Ash Alizadeh at Stanford University. [31]

Relapse rates are extremely low. Most deaths following remission are from other causes, such as second malignancies, which in one study occurred in 8% of patients. In this study, second malignancies accounted for 41% of deaths, and heart disease, 29%. Survival rates were 88% at 6.3 years and 82% at 7.9 years. [32]

In another study, 10-year survival rate was estimated to be approximately 77%. [7]

Epidemiology

Acute promyelocytic leukemia represents 10–12% of AML cases. [16] The median age is approximately 30–40 years, [33] which is considerably younger than the other subtypes of AML (70 years), however in elderly population APL has peculiar characteristics. [34] Incidence is higher among individuals of Latin American or South European origin. [35] It can also occur as a secondary malignancy in those that receive treatment with topoisomerase II inhibitors (such as the anthracyclines and etoposide) due to the carcinogenic effects of these agents, with patients with breast cancer representing the majority of such patients. [36] [37] [38] Around 40% of patients with APL also have a chromosomal abnormality such as trisomy 8 or isochromosome 17 which do not appear to impact on long-term outcomes. [3]

Related Research Articles

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Tretinoin</span> Medication

Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present and is taken by mouth for up to three months. Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.

<span class="mw-page-title-main">Arsenic trioxide</span> Chemical compound (industrial chemical and medication)

Arsenic trioxide is an inorganic compound with the formula As
2O
3. As an industrial chemical, its major uses include the manufacture of wood preservatives, pesticides, and glass. It is sold under the brand name Trisenox among others when used as a medication to treat a type of cancer known as acute promyelocytic leukemia. For this use it is given by injection into a vein.

Retinoic acid syndrome (RAS) is a potentially life-threatening complication observed in people with acute promyelocytic leukemia (APML) and first thought to be specifically associated with all-trans retinoic acid (ATRA) treatment. Subsequently, so-called RAS was recognized in APML patients who had been treated with another highly efficacious drug, arsenic trioxide, and yet did not appear in patients treated with tretinoin for other disorders. These facts and others support the notion that RAS depends on the presence of the malignant promyelocytes. This has led to the growing deprecation of the term 'retinoic acid syndrome' and to an increasing use of the term differentiation syndrome to signify this APML treatment complication.

<span class="mw-page-title-main">Acute myeloid leukemia</span> Cancer of the myeloid line of blood cells

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated.

<span class="mw-page-title-main">Promyelocyte</span> Granulocyte precursor cell

A promyelocyte is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte. Promyelocytes measure 12–20 microns in diameter. The nucleus of a promyelocyte is approximately the same size as a myeloblast but their cytoplasm is much more abundant. They also have less prominent nucleoli than myeloblasts and their chromatin is more coarse and clumped. The cytoplasm is basophilic and contains primary red/purple granules.

<span class="mw-page-title-main">Acute monocytic leukemia</span> Medical condition

Acute monocytic leukemia is a type of acute myeloid leukemia. In AML-M5 >80% of the leukemic cells are of monocytic lineage. This cancer is characterized by a dominance of monocytes in the bone marrow. There is an overproduction of monocytes that the body does not need in the periphery. These overproduced monocytes interfere with normal immune cell production which causes many health complications for the affected individual.

<span class="mw-page-title-main">Acute myeloblastic leukemia with maturation</span> Medical condition

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein found in humans

Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.

<span class="mw-page-title-main">Zinc finger and BTB domain-containing protein 16</span> Protein found in humans

Zinc finger and BTB domain-containing protein 16 is a protein that in humans is encoded by the ZBTB16 gene.

<span class="mw-page-title-main">FIP1L1</span> Protein-coding gene in humans

Factor interacting with PAPOLA and CPSF1 is a protein that in humans is encoded by the FIP1L1 gene. A medically important aspect of the FIP1L1 gene is its fusion with other genes to form fusion genes which cause clonal hypereosinophilia and leukemic diseases in humans.

<span class="mw-page-title-main">PRAM1</span> Protein-coding gene in the species Homo sapiens

PML-RARA-regulated adapter molecule 1 is a protein that in humans is encoded by the PRAM1 gene.

Acute myelomonocytic leukemia (AMML) is a form of acute myeloid leukemia that involves a proliferation of CFU-GM myeloblasts and monoblasts. AMML occurs with a rapid increase amount in white blood cell count and is defined by more than 20% of myeloblast in the bone marrow. It is classified under "M4" in the French-American-British classification (FAB). It is classified under "AML, not otherwise classified" in the WHO classification.

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<span class="mw-page-title-main">Childhood leukemia</span> Medical condition

Childhood leukemia is leukemia that occurs in a child and is a type of childhood cancer. Childhood leukemia is the most common childhood cancer, accounting for 29% of cancers in children aged 0–14 in 2018. There are multiple forms of leukemia that occur in children, the most common being acute lymphoblastic leukemia (ALL) followed by acute myeloid leukemia (AML). Survival rates vary depending on the type of leukemia, but may be as high as 90% in ALL.

"7+3" in the context of chemotherapy is an acronym for a chemotherapy regimen that is most often used today as first-line induction therapy in acute myelogenous leukemia, excluding the acute promyelocytic leukemia form, which is better treated with ATRA and/or arsenic trioxide and requires less chemotherapy.

<span class="mw-page-title-main">Anne Dejean-Assémat</span> French biologist (born 1957)

Anne Dejean-Assémat is a French molecular biologist working on the mechanisms leading to the development of human cancers. Professor at the Pasteur Institute and Research Director at Inserm, she heads the laboratory of Nuclear Organization and Oncogenesis at the Pasteur Institute.

Realgar/Indigo naturalis (RIF), also known as Compound Huangdai (复方黄黛), is a medication used to treat acute promyelocytic leukemia. Effectiveness appears similar to arsenic trioxide. It is generally used together with all-trans-retinoic acid (ATRA). It is taken by mouth.

Hugues de Thé, is a French doctor and researcher. He is currently a hospital doctor and professor at the Collège de France, holder of the chair of cellular and molecular oncology (2014), member of the French Academy of sciences since 2011. His work, at the interface between biology and medicine, has radically transformed the management of a rare form of leukaemia, which has become the paradigm for targeted cancer treatments.

The RARA gene, also known as NR1B1, is a protein coding gene located on chromosome 17 that provides the instructions required to make transcription factor Retinoic Acid Receptor Alpha.

References

  1. ↑ Image by Mikael Häggström, MD. Reference for findings: Syed Zaidi, M.D. "APL with PML-RARA". APL with PML-RARA. Last author update: 1 February 2013
    Source image: File:Faggot cell in AML-M3.jpg from PEIR Digital Library (Pathology image database) Archived 2009-03-01 at the Wayback Machine (Public Domain)
  2. 1 2 3 "Acute Promyelocytic Leukemia". National Organization for Rare Disorders . Retrieved March 9, 2023.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Kotiah, SD; Besa, EC (3 June 2013). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; McKenna, R; Besa, EC (eds.). "Acute Promyelocytic Leukemia". Medscape Reference. WebMD. Retrieved 14 January 2014.
  4. ↑ Tallman MS, Altman JK (2008). "Curative strategies in acute promyelocytic leukemia". Hematology Am Soc Hematol Educ Program. 2008: 391–9. doi: 10.1182/asheducation-2008.1.391 . PMID   19074116.
  5. ↑ Hillestad, LK (November 1957). "Acute promyelocytic leukemia". Acta Med Scand. 159 (3): 189–94. doi:10.1111/j.0954-6820.1957.tb00124.x. PMID   13508085.
  6. 1 2 Coombs, C. C.; Tavakkoli, M.; Tallman, M. S. (2015-04-17). "Acute promyelocytic leukemia: where did we start, where are we now, and the future". Blood Cancer Journal. 5 (4): e304. doi:10.1038/bcj.2015.25. PMC   4450325 . PMID   25885425.
  7. 1 2 3 Adès, L; Guerci, A; Raffoux, E; Sanz, M; Chevallier, P; Lapusan, S; Recher, C; Thomas, X; Rayon, C; Castaigne, S; Tournilhac, O; de Botton, S; Ifrah, N; Cahn JY; Solary E; Gardin, C; Fegeux, N; Bordessoule, D; Ferrant, A; Meyer-Monard, S; Vey, N; Dombret, H; Degos, L; Chevret, S; Fenaux, P; European APL Group (March 2010). "Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience". Blood. 115 (9): 1690–1696. doi: 10.1182/blood-2009-07-233387 . PMID   20018913. S2CID   18553186.
  8. ↑ C C, Coombs (17 April 2015). "Acute promyelocytic leukemia: where did we start, where are we now, and the future". Blood Cancer Journal. 5 (4): 304. doi:10.1038/bcj.2015.25. PMC   4450325 . PMID   25885425.
  9. ↑ Kotiah, SD; Besa, EC (3 June 2013). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; McKenna, R; Besa, EC (eds.). "Acute Promyelocytic Leukemia Clinical Presentation". Medscape Reference. WebMD. Retrieved 14 January 2014.
  10. ↑ Chen Z, Brand NJ, et al. (March 1993). "Fusion between a novel Krüppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia". EMBO J. 12 (3): 1161–7. doi:10.1002/j.1460-2075.1993.tb05757.x. PMC   413318 . PMID   8384553.
  11. ↑ Image by Mikael Häggström, MD. Source for findings: Syed Zaidi, M.D. "Bone marrow neoplastic, APL with PML-RARA". Pathology Outlines. Last author update: 1 February 2013 Last staff update: 29 November 2022
  12. ↑ Francesco Lo-Coco, M.D.; et al. (July 2013). "Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia". New England Journal of Medicine. 369 (2): 111–121. doi: 10.1056/NEJMoa1300874 . hdl: 11380/980318 . PMID   23841729.
  13. 1 2 Cingam, Shashank R.; Koshy, Nebu V. (2018), "Cancer, Leukemia, Promyelocytic, Acute (APL, APML)", StatPearls, StatPearls Publishing, PMID   29083825 , retrieved 2018-12-11, Hence, ATRA-ATO for induction and consolidation has emerged as the new standard of care for patients with low-(to-intermediate) risk acute promyelocytic leukemia. ATRA-ATO therapy is also a reasonable choice for patients with severe comorbidities, older adults, patients with cardiac dysfunction who cannot tolerate anthracycline-based regimens or overall poor functional status. Maintenance therapy after the initial consolidation is widely debated. Maintenance may not be necessary for patients receiving intensive induction/consolidation including ATO.
  14. ↑ Breccia, M; Latagliata, R; Carmosino, I; Cannella, L; Diverio, D; Guarini, A; De Propris, MS; Petti, MC; Avvisati, G; Cimino, G; Mandelli, F; Lo-Coco, F (December 2008). "Clinical and biological features of acute promyelocytic leukemia patients developing retinoic acid syndrome during induction treatment with all-trans retinoic acid and idarubicin". Haematologica. 93 (12): 1918–20. doi: 10.3324/haematol.13510 . PMID   18945746.
  15. 1 2 3 Kotiah, SD; Besa, EC (3 June 2013). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; McKenna, R; Besa, EC (eds.). "Acute Promyelocytic Leukemia Treatment & Management". Medscape Reference. WebMD. Retrieved 14 January 2014.
  16. 1 2 3 4 5 Ravandi, F; Estey, EH; Appelbaum, FR; Lo-Coco, F; Schiffer, CA; Larson, RA; Burnett, AK; Kantarjian, HM (November 2012). "Gemtuzumab Ozogamicin: Time to Resurrect?". Journal of Clinical Oncology. 30 (32): 3921–3923. doi:10.1200/JCO.2012.43.0132. PMC   4874205 . PMID   22987091.
  17. ↑ Martindale: The Complete Drug Reference. Pharmaceutical Press. 23 September 2011.
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  19. ↑ "FDA approves Mylotarg for treatment of acute myeloid leukemia" (Press release). United States Food and Drug Administration. 2017-09-17. Archived from the original on 2024-03-07.
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  22. ↑ Tallman, MS; Andersen, JW; Schiffer, CA; Appelbaum, FR; Feusner, JH; Woods, WG; Ogden, A; Weinstein, H; Shepherd, L; Willman, C; Bloomfield, CD; Rowe, JM; Wiernik, PH (December 2002). "All-transretinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol". Blood. 100 (13): 4298–4302. doi: 10.1182/blood-2002-02-0632 . PMID   12393590.
  23. 1 2 3 Soignet SL, Maslak P, Wang ZG, et al. (November 1998). "Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide". N. Engl. J. Med. 339 (19): 1341–8. doi: 10.1056/NEJM199811053391901 . PMID   9801394.
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  25. ↑ Miwako, I; Kagechika, H (August 2007). "Tamibarotene". Drugs of Today. 43 (8): 563–568. doi:10.1358/dot.2007.43.8.1072615. PMID   17925887.
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  27. ↑ Leiva, M; Moretti, S; Soilihi, H; Pallavicini, I; Peres, L; Mercurio, C; Dal Zuffo, R; Minucci, S; de Thé, H (July 2012). "Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL". Leukemia. 26 (7): 1630–1637. doi: 10.1038/leu.2012.39 . PMID   22333881.
  28. ↑ He LZ; Tolentino T; Grayson P; et al. (November 2001). "Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia". Journal of Clinical Investigation. 108 (9): 1321–1330. doi:10.1172/JCI11537. PMC   209432 . PMID   11696577.
  29. ↑ Assadollahi V, Parivar K, Roudbari NH, Khalatbary AR, Motamedi M, Ezatpour B, Dashti GR (2013). "The effect of aqueous cinnamon extract on the apoptotic process in acute myeloid leukemia HL-60 cells". Adv Biomed Res. 2: 25. doi: 10.4103/2277-9175.108001 . PMC   3748636 . PMID   23977653.
  30. ↑ Breccia, Massimo; Latagliata, Roberto; Cannella, Laura; Minotti, Clara; Meloni, Giovanna; Lo-Coco, Francesco (2010-05-01). "Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation". Haematologica. 95 (5): 853–854. doi:10.3324/haematol.2009.017962. ISSN   0390-6078. PMC   2864399 . PMID   20015875.
  31. ↑ McClellan, James Scott; Kohrt, Holbrook E.; Coutre, Steven; Gotlib, Jason R.; Majeti, Ravindra; Alizadeh, Ash A.; Medeiros, Bruno C. (2012-01-01). "Treatment advances have not improved the early death rate in acute promyelocytic leukemia". Haematologica. 97 (1): 133–136. doi:10.3324/haematol.2011.046490. ISSN   0390-6078. PMC   3248942 . PMID   21993679.
  32. ↑ Shetty, Aditya Vittal; Ravandi, Farhad; Alapati, Naga; Borthakur, Gautam; Garcia-Manero, Guillermo; Kadia, Tapan M.; Wierda, William; Estrov, Zeev; Pierce, Sherry (2014-12-06). "Survivorship in APL- Outcomes of Acute Promyelocytic Leukemia (APL) Patients (pts) after Maintaining Complete Remission (CR) for at Least 3 Years". Blood. 124 (21): 954. doi:10.1182/blood.V124.21.954.954. ISSN   0006-4971.
  33. ↑ Schiffer, CA; Stone, RM (2000). "Chapter 124: Acute Myeloid Leukemia in Adults". In Bast, RC; Kufe, DW; Pollock, RE (eds.). Holland-Frei Cancer Medicine (5th ed.). Hamilton, ON: BC Decker. Retrieved 15 January 2014.
  34. ↑ Rosati, Serena; Gurnari, Carmelo; Breccia, Massimo; Carmosino, Ida; Scalzulli, Emilia; Montefusco, Enrico; Perrone, Salvatore; Annibali, Ombretta; Martini, Vincenza; Trapè, Giulio; Colafigli, Gioia (2021-11-02). "Acute promyelocytic leukemia (APL) in very old patients: real-life behind protocols". Acta Oncologica. 60 (11): 1520–1526. doi:10.1080/0284186X.2021.1971291. hdl: 2108/278430 . ISSN   0284-186X. PMID   34461798. S2CID   238748395.
  35. ↑ Douer, D; Santillana, S; Ramezani, L; Samanez, C; Slovak, ML; Lee, MS; Watkins, K; Williams, T; Vallejos, C (August 2003). "Acute promyelocytic leukaemia in patients originating in Latin America and is associated with an increased frequency of the bcr1 subtype of the PML/RARalpha fusion gene". British Journal of Haematology. 122 (4): 563–70. doi: 10.1046/j.1365-2141.2003.04480.x . PMID   12899711. S2CID   20065990.
  36. ↑ Ravandi, F (April 2011). "Therapy-related acute promyelocytic leukemia". Haematologica. 96 (4): 493–495. doi:10.3324/haematol.2011.041970. PMC   3069223 . PMID   21454880.
  37. ↑ Elliott, MA; Letendre, L; Tefferi, A; Hogan, WJ; Hook, C; Kaufmann, SH; Pruthi, RK; Pardanani, A; Begna, KH; Ashrani, AA; Wolanskyj, AP; Al-Kali, A; Litzow, MR (March 2012). "Therapy-related acute promyelocytic leukemia: observations relating to APL pathogenesis and therapy". European Journal of Haematology. 88 (3): 237–243. doi:10.1111/j.1600-0609.2011.01727.x. PMID   22023492. S2CID   42345682.
  38. ↑ Rashidi, A; Fisher, SI (2013). "Therapy-related acute promyelocytic leukemia: a systematic review". Medical Oncology. 30 (3): 625. doi:10.1007/s12032-013-0625-5. PMID   23771799. S2CID   5454988.
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