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Acute promyelocytic leukemia

January 01, 1970

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]

Acute promyelocytic leukemia
Bone marrow smear from a patient with acute promyelocytic leukemia, showing characteristic abnormal promyelocytes.[1]
SpecialtyHematology 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]

Signs and symptoms edit

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 edit

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 edit

 
Acute promyelocytic leukemia may also have a hypogranular variant, which can have very scant Auer rods.[11] 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.

Treatment edit

Initial treatment edit

 
Tretinoin
 
Mitozantrone
 
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]

Maintenance therapy edit

After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy with methotrexate, mercaptopurine and ATRA.[18] 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).[19] Likewise in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance.[20]

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 edit

Arsenic trioxide (As2O3) is currently being evaluated for treatment of relapsed/refractory disease. Remission with arsenic trioxide has been reported.[21] Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein.[21] Arsenic also increases caspase activity which then induces apoptosis.[21] It does reduce the relapse rate for high risk patients.[22] In Japan a synthetic retinoid, tamibarotene, is licensed for use as a treatment for ATRA-resistant APL.[23]

Investigational agents edit

Some evidence supports the potential therapeutic utility of histone deacetylase inhibitors such as valproic acid or vorinostat in treating APL.[24][25][26] According to one study, a cinnamon extract has effect on the apoptotic process in acute myeloid leukemia HL-60 cells.[27]

Prognosis edit

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.[28] 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.[29]

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.[30]

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

Epidemiology edit

Acute promyelocytic leukemia represents 10–12% of AML cases.[16] The median age is approximately 30–40 years,[31] which is considerably younger than the other subtypes of AML (70 years), however in elderly population APL has peculiar characteristics.[32] Incidence is higher among individuals of Latin American or South European origin.[33] 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.[34][35][36] 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]

References edit

  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) 2009-03-01 at the Wayback Machine (Public Domain)
  2. ^ a b c "Acute Promyelocytic Leukemia". National Organization for Rare Disorders. Retrieved March 9, 2023.
  3. ^ a b c d e f g h i j k l m n 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. ^ a b 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. ^ a b c 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. ^ a b 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. ^ a b c 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. ^ a b c d e 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.
  18. ^ Kotiah, SD (28 October 2013). Anand, J; Braden, CD; Harris, JE (eds.). "Acute Promyelocytic Leukema Treatment Protocols". Medscape Reference. WebMD. Retrieved 14 January 2014.
  19. ^ Fenaux, P; Chastang, C; Chevret, S; Sanz, M; Dombret, H; Archimbaud, E; Fey, M; Rayon, C; Huguet, F; Sotto, JJ; Gardin, C; Makhoul, PC; Travade, P; Solary, E; Fegueux, N; Bordessoule, D; Miguel, JS; Link, H; Desablens, B; Stamatoullas, A; Deconinck, E; Maloisel, F; Castaigne, S; Preudhomme, C; Degos, L (August 1999). "A Randomized Comparison of All Transretinoic Acid (ATRA) Followed by Chemotherapy and ATRA Plus Chemotherapy and the Role of Maintenance Therapy in Newly Diagnosed Acute Promyelocytic Leukemia". Blood. 94 (4): 1192–1200. doi:10.1182/blood.V94.4.1192. PMID 10438706.
  20. ^ 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.
  21. ^ a b c 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.
  22. ^ "Arsenic Compound Improves Survival in Acute Promyelocytic Leukemia Patients". Oncology. 21 (10). 2007.
  23. ^ Miwako, I; Kagechika, H (August 2007). "Tamibarotene". Drugs of Today. 43 (8): 563–568. doi:10.1358/dot.2007.43.8.1072615. PMID 17925887.
  24. ^ Martens, JH; Brinkman, AB; Simmer, F; Francoijs, KJ; Nebbioso, A; Ferrara, F; Altucci, L; Stunnenberg, HG (February 2010). "PML-RARa/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia". Cancer Cell. 17 (2): 173–185. doi:10.1016/j.ccr.2009.12.042. hdl:2066/84175. PMID 20159609.
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ 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.
  29. ^ 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.
  30. ^ 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.
  31. ^ 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.
  32. ^ 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.
  33. ^ 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.
  34. ^ Ravandi, F (April 2011). "Therapy-related acute promyelocytic leukemia". Haematologica. 96 (4): 493–495. doi:10.3324/haematol.2011.041970. PMC 3069223. PMID 21454880.
  35. ^ 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.
  36. ^ 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.

External links edit

  • Sanz, Miguel A.; Grimwade, David; Tallman, Martin S.; Lowenberg, Bob; Fenaux, Pierre; Estey, Elihu H.; Naoe, Tomoki; Lengfelder, Eva; Büchner, Thomas; Döhner, Hartmut; Burnett, Alan K.; Lo-Coco, Francesco (2009). "Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European Leukemia Net". Blood. 113 (9): 1875–1891. doi:10.1182/blood-2008-04-150250. hdl:1765/18239. PMID 18812465.
  • PDQ Adult Treatment Editorial Board (2002–2020). "Adult Acute Myeloid Leukemia Treatment (PDQ®): Patient Version". Adult Acute Myeloid Leukemia Treatment (PDQ®). National Cancer Institute (US). PMID 26389377.

January 01, 1970
acute, promyelocytic, leukemia, this, article, needs, updated, please, help, update, this, article, reflect, recent, events, newly, available, information, 2015, apml, subtype, acute, myeloid, leukemia, cancer, white, blood, cells, there, abnormal, accumulatio. This article needs to be updated Please help update this article to reflect recent events or newly available information May 2015 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 Acute promyelocytic leukemiaBone marrow smear from a patient with acute promyelocytic leukemia showing characteristic abnormal promyelocytes 1 SpecialtyHematology and oncologyUsual onset 40 years old 2 CausesUncontrolled proliferation of promyelocytes 2 FrequencyDevelops in about 600 to 800 people per year United States 2 Contents 1 Signs and symptoms 2 Pathogenesis 3 Diagnosis 4 Treatment 4 1 Initial treatment 4 2 Maintenance therapy 4 3 Relapsed or refractory disease 4 4 Investigational agents 5 Prognosis 6 Epidemiology 7 References 8 External linksSigns and symptoms editThe symptoms tend to be similar to AML in general with the following being possible symptoms 9 Anemia Fatigue Weakness Chills Depression Difficulty breathing dyspnea Low platelets thrombocytopenia leading to easy bleeding Fever Infection as a result of low neutrophils neutropenia Elevated white blood cells leukocytosis Coagulopathy including disseminated intravascular coagulation Bicytopenia Easy bleeding from low platelets may include Bruising ecchymosis Gingival bleeding Nose bleeds epistaxis Bleeding from the gums Increased menstrual bleeding menorrhagia Brain bleed intracerebral hemorrhage Pathogenesis editAcute 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 1a 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 edit nbsp Acute promyelocytic leukemia may also have a hypogranular variant which can have very scant Auer rods 11 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 nbsp Hypogranular variant of APL Giemsa stain 1000x Treatment editInitial treatment edit nbsp Tretinoin nbsp Mitozantrone nbsp 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 Maintenance therapy edit After stable remission was induced the standard of care previously was to undergo 2 years of maintenance chemotherapy with methotrexate mercaptopurine and ATRA 18 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 lt 0 01 19 Likewise in the 2000 US APL study the survival rates in those receiving ATRA maintenance was 61 compared to just 36 without ATRA maintenance 20 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 edit Arsenic trioxide As2O3 is currently being evaluated for treatment of relapsed refractory disease Remission with arsenic trioxide has been reported 21 Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML RAR fusion protein 21 Arsenic also increases caspase activity which then induces apoptosis 21 It does reduce the relapse rate for high risk patients 22 In Japan a synthetic retinoid tamibarotene is licensed for use as a treatment for ATRA resistant APL 23 Investigational agents edit Some evidence supports the potential therapeutic utility of histone deacetylase inhibitors such as valproic acid or vorinostat in treating APL 24 25 26 According to one study a cinnamon extract has effect on the apoptotic process in acute myeloid leukemia HL 60 cells 27 Prognosis editPrognosis 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 28 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 29 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 30 In another study 10 year survival rate was estimated to be approximately 77 7 Epidemiology editAcute promyelocytic leukemia represents 10 12 of AML cases 16 The median age is approximately 30 40 years 31 which is considerably younger than the other subtypes of AML 70 years however in elderly population APL has peculiar characteristics 32 Incidence is higher among individuals of Latin American or South European origin 33 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 34 35 36 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 References edit Image by Mikael Haggstrom MD Reference for findings Syed Zaidi M D APL with PML RARA APL with PML RARA Last author update 1 February 2013Source 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 a b c Acute Promyelocytic Leukemia National Organization for Rare Disorders Retrieved March 9 2023 a b c d e f g h i j k l m n 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 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 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 a b 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 a b c Ades 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 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 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 Chen Z Brand NJ et al March 1993 Fusion between a novel Kruppel 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 Image by Mikael Haggstrom 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 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 a b 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 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 a b c Kotiah SD Besa EC 3 June 2013 Sarkodee Adoo C Talavera F Sacher RA McKenna R Besa EC eds Acute Promyelocytic Leukemia Treatment amp Management Medscape Reference WebMD Retrieved 14 January 2014 a b c d e 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 Martindale The Complete Drug Reference Pharmaceutical Press 23 September 2011 Kotiah SD 28 October 2013 Anand J Braden CD Harris JE eds Acute Promyelocytic Leukema Treatment Protocols Medscape Reference WebMD Retrieved 14 January 2014 Fenaux P Chastang C Chevret S Sanz M Dombret H Archimbaud E Fey M Rayon C Huguet F Sotto JJ Gardin C Makhoul PC Travade P Solary E Fegueux N Bordessoule D Miguel JS Link H Desablens B Stamatoullas A Deconinck E Maloisel F Castaigne S Preudhomme C Degos L August 1999 A Randomized Comparison of All Transretinoic Acid ATRA Followed by Chemotherapy and ATRA Plus Chemotherapy and the Role of Maintenance Therapy in Newly Diagnosed Acute Promyelocytic Leukemia Blood 94 4 1192 1200 doi 10 1182 blood V94 4 1192 PMID 10438706 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 a b c 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 Arsenic Compound Improves Survival in Acute Promyelocytic Leukemia Patients Oncology 21 10 2007 Miwako I Kagechika H August 2007 Tamibarotene Drugs of Today 43 8 563 568 doi 10 1358 dot 2007 43 8 1072615 PMID 17925887 Martens JH Brinkman AB Simmer F Francoijs KJ Nebbioso A Ferrara F Altucci L Stunnenberg HG February 2010 PML RARa RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia Cancer Cell 17 2 173 185 doi 10 1016 j ccr 2009 12 042 hdl 2066 84175 PMID 20159609 Leiva M Moretti S Soilihi H Pallavicini I Peres L Mercurio C Dal Zuffo R Minucci S de The 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 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 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 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 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 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 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 Rosati Serena Gurnari Carmelo Breccia Massimo Carmosino Ida Scalzulli Emilia Montefusco Enrico Perrone Salvatore Annibali Ombretta Martini Vincenza Trape 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 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 Ravandi F April 2011 Therapy related acute promyelocytic leukemia Haematologica 96 4 493 495 doi 10 3324 haematol 2011 041970 PMC 3069223 PMID 21454880 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 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 External links editSanz Miguel A Grimwade David Tallman Martin S Lowenberg Bob Fenaux Pierre Estey Elihu H Naoe Tomoki Lengfelder Eva Buchner Thomas Dohner Hartmut Burnett Alan K Lo Coco Francesco 2009 Management of acute promyelocytic leukemia Recommendations from an expert panel on behalf of the European Leukemia Net Blood 113 9 1875 1891 doi 10 1182 blood 2008 04 150250 hdl 1765 18239 PMID 18812465 PDQ Adult Treatment Editorial Board 2002 2020 Adult Acute Myeloid Leukemia Treatment PDQ Patient Version Adult Acute Myeloid Leukemia Treatment PDQ National Cancer Institute US PMID 26389377 Retrieved from https en wikipedia org w index php title Acute promyelocytic leukemia amp oldid 1210378893, wikipedia, wiki, book, books, library,

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