Acute Promyelocytic Leukemia

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Retrieved

2021-01-23

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Trials

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Genes

NPM1, RARA, NUMA1, PML, ZBTB16, STAT5B, IRF2BP2, PRKAR1A, FLT3, F3, KIT, ITGAM, CEBPA, AKT1, THBD, DNMT3A, WT1, IFNG, STAT3, ITGB2, TBL1XR1, CD44, BCOR, DAPK2, AQP9, NRAS, ITGAL, CEBPE, IDH1, IDH2

NPM1, RARA, NUMA1, PML, ZBTB16, STAT5B, IRF2BP2, PRKAR1A, FLT3, F3, KIT, ITGAM, CEBPA, AKT1, THBD, DNMT3A, WT1, IFNG, STAT3, ITGB2, TBL1XR1, CD44, BCOR, DAPK2, AQP9, NRAS, ITGAL, CEBPE, IDH1, IDH2, ITGAX, IL17A, TET2, NABP1, GLI2, GLI1, SMO, DEFA3, SMC1A, FNDC3B, MIR15A, FIP1L1, MIR16-1, BIRC5, RAP1GAP, ASXL1, CCL7, MYC, TP53, FANCB, PRAM1, CSF3, RAB40B, BCRP3, CD34, ANXA2, BCR, MPO, TNF, SMPD1, CD38, SUMO1, RUNX1, ABCB1, BCL2, ELANE, CD33, MECOM, NCAM1, SP100, CCR7, PIK3CG, PIK3CB, CTSG, BCRP2, PIK3CA, PIK3CD, IL1B, ANXA8, ANXA8L1, RUNX1T1, CDKN2A, NCOR2, TRIB3, CXCL8, RARG, ERBB2, THRA, CASP3, CEBPB, VEGFA, CDKN1A, ABL1, NFE2L2, GABPA, ANPEP, NCOR1, RNF4, SUB1, RUNX2, KMT2A, IRF8, AS3MT, ICAM1, AIDA, SET, TRBV20OR9-2, ABCC11, TERT, PTK2B, ABCC8, NXT1, HIF1A, CSF2, TBC1D9, RARB, C20orf181, CDKN2B, REG1A, CDKN2D, VAV1, HOTAIRM1, MRPL28, PTEN, MAPK14, CSF1R, G0S2, LGALS3, RXRA, PLG, MAPK3, S100A8, KRAS, H3P9, CYP26A1, HPRT1, PIN1, MAP2K1, HOXA1, SUMO2, PPARG, MAP2K7, SOAT1, KDM1A, PTPA, SMYD5, BRD4, ODC1, NUP98, IL23A, PADI4, XAB2, S100A10, IL10, JAK1, CRLF3, IL7R, IL4, IL3, PRDX4, MATN1, HTC2, MCL1, RELA, SGSM3, IRF1, PTPN11, ABCC1, PTGS2, IRF9, MFAP1, SYT1, MIR146A, FASLG, EGFR, PTF1A, ATG5, TSHR, TRAP, GSTK1, APRT, DAXX, UBA7, SLC25A10, MIRLET7C, UBE2L6, CRABP1, H3P38, TOP2B, KDM6A, RERE, ATRX, CDKN1B, BCL6, BLM, CD19, MIR221, GPRC5A, BCRP1, CXCR4, MBD2, BRCA1, TP73, NEAT1, ANXA1, FCGR1A, ST13, ABL2, GSTT1, GORASP1, GSTM1, HDAC9, WNK1, FUT4, FUT1, FLT1, H3P13, BAALC, ERG, EOMES, SLCO6A1, JAG1, THBS1, TGM2, PCGF2, TGFB1, F9, DLK1, ADAMTS13, IER3, CD84, TNFSF10, BLZF1, CDKL1, RASSF1, PRDX3, PIAS1, EHMT2, RPP14, CKAP4, TP63, TNFRSF10D, TNFRSF10C, IL18R1, TNFRSF10A, PIM2, SRA1, SQSTM1, PPIG, SLC9A3R1, CHST3, ATG7, BCAR1, NR1D1, RACK1, RIN1, KLK4, NDRG1, ISG15, ZMPSTE24, CDK2AP2, PCLAF, MVP, ATP6AP2, UBD, PDLIM7, EBP, AGPAT2, NAE1, CCNA1, TNFSF13B, CTCF, KHDRBS1, PDPN, RNF8, PRC1, AURKB, TXNIP, XPR1, DMTF1, NOG, TRIM16, MSC, WIF1, NAT1, CHEK2, CBLL2, MIR10B, MIR10A, MIR107, MIRLET7B, ASPG, NCR3LG1, NUP43, RAB7B, CLEC4D, NCR3, CENPV, PTCRA, GPR180, RMDN2, PTGDR2, DRAM2, OVCA2, PRRT2, CGB8, CGB5, LGALS12, HAVCR2, LMNB2, TCHP, USP48, ARHGAP24, RNF34, WLS, MIR125B1, MIR142, MIR143, MIR15B, H3P30, H3P8, LOC110013312, RN7SL263P, PGR-AS1, PCAT1, KLRC4-KLRK1, MIR766, SNORD112, PSG10P, NCF1, MIR382, MIR342, MIR340, XRCC6P5, ZFAS1, PSG8, MIR17HG, MIR34B, MIR34A, MIR29B2, MIR29B1, MIR223, MIR222, MIR192, MIR182, MIR181A2, DHDDS, LIN28A, MUL1, HIPK2, LAMTOR2, IGHV1-12, EML4, HPGDS, PDCD4, DISC1, ZBTB32, GNL3, PHGDH, SENP3, WIPI2, ZNF451, PRDX5, SH3BP4, NUP62, CDK20, PRAME, SUZ12, PHF8, PEG10, MYCBP2, WDFY3, DKK1, KLRK1, GABARAPL2, USP18, SP140, RGCC, KLF15, MARCKSL1, DERL2, GPSM3, BCORL1, USP37, ARID1B, PNPLA2, CHPT1, ENAH, SYBU, KRBOX4, QRSL1, RMDN3, MSTO1, PIWIL2, WIPI1, SWT1, RHOF, MBD3, BCL11A, KDM3B, ASB2, GINS2, SF3B6, IKBKG, WT1-AS, LEF1, DCTN4, RMDN1, PIR, CCL5, CNTNAP1, IGFBP3, GATA2, FOS, FLG, FOXO3, FOXO1, FOXC1, FH, FGFR1, FGF13, FEN1, F13B, F13A1, F10, F2RL1, F2, EZH2, EYA2, ETV6, ERBB4, EPS15, EPHB2, EP300, ELAVL1, EIF4G2, EIF4EBP1, EGR1, EGF, KAT2A, GCY, GDNF, HLA-DRB1, ID1, HTR3A, HSPG2, HSP90AB1, HSP90AA1, HES1, HOXD3, HOXB2, HOXA9, HNMT, HMGN2, HMGN1, HK3, GFRA1, HIC1, HHEX, HGF, HFE, HDAC1, HCK, GTF2I, GTF2H1, GSTP1, GSK3B, GLB1, GHR, EFNA4, E2F1, DTNA, AIRE, CAMP, CAD, BRAF, BMP6, BMP4, BMP2, BIK, BAX, ARSD, AR, AQP7, FAS, APAF1, CASP10, ANXA5, ANXA3, ALOX5, ALK, ALB, AGTR2, AGL, ADCY9, ADCY7, ACTL6A, ACTB, ABO, CASP8, CBR1, ATN1, CGB3, ARID3A, DNMT1, DIO3, DAPK1, DAP, CYP2B6, CUX1, CRYBA1, CREB1, KLF6, CEACAM7, CEACAM3, CGA, CCNA2, CEACAM5, CD52, CDKN2C, CDC25C, CDK1, CD68, CD47, CD14, CD6, CD2, CCNE1, CCNB1, ID2, IL1A, PPM1D, IL6, TGM1, TGFA, TFRC, TERC, TACR1, STAT5A, STAT2, STAT1, SPI1, SOD1, SUMO3, SMARCA4, SLC1A2, SHB, SFRP1, SDHD, SCT, ATXN1, S100A9, RPE65, RNPEP, RNASE3, RET, PLAAT4, RAF1, RAD21, PVT1, TIMP1, TNFAIP2, TPMT, ZFP36, NR0B2, FZD9, ARID1A, TAM, NCOA3, CDR3, WT4, TFEB, DEK, ZMYM2, RNF112, MZF1, XRCC1, TWIST1, XPO1, XBP1, WNT5A, VIM, VHL, VDR, UVRAG, UCN, UBE2I, UBE2E2, TYMS, TXNRD1, PTPRC, PTPN6, PTGS1, MCM2, MRE11, MPST, MPL, MMP9, AFF1, MLLT1, MAP3K10, MLF1, MGMT, RAB8A, MEIS1, MDM4, SMAD4, COX1, LPA, LMO2, LMNB1, LMNA, LGALS1, LBR, STMN1, LAMP1, KLRD1, KLRB1, IL18, IL15, MSH3, MYB, PTGDS, PLSCR1, PSMC6, PSG5, PSG2, PROS2P, MAPK8, MAPK1, PRKCB, PRKCA, SRGN, PRF1, POLD1, PMAIP1, PLAT, NEDD8, PHB, PGR, PFAS, PECAM1, PDGFRB, PBX1, PAX5, PRKN, NOTCH1, NME1, NGFR, NFIL3, H3P10

Drugs

(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl) amino)methyl)tetrahydrofuran-3,4-diol, (S)-5-(1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethylamino-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile, 1,2-bis(methylsulphonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine, 1-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-3-(3-fluorophenyl)urea, 1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea, 1-[2-(Benzo[1,2,5]thiadiazol-5-ylamino)-6-(2,6-dichloro-phenyl)-pyrido[2,3-d]pyrimidin-7-yl]-3- tert-butyl-urea, 2-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-N-((5S,5aS,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)acetamide, tetrahydrochloride, 2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thienol[3,2,-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)-acetamide dihydrate, 2-[[3-({4-[(5-{2-[(3-Fluorophenyl)amino]-2-oxoethyl}- 1H-pyrazol-3-yl)amino]- quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl dihydrogen phosphate trihydrate, 2-hydroxymethyl-2-methoxymethyl-1-azabicyclo[2,2,2]octan-3-one, 225Ac-lintuzumab, 26 base single stranded phosphodiester DNA oligonucleotide, 5'-O-(trans-9"-octadecenoyl)-1-ß-D-arabinofuranosyl cytosine, 6-{[(1R,2S)-2-aminocyclohexyl]amino}-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one monocitrate, Alitretinoin ( PANRETIN ), Allogeneic T cells encoding an exogenous TK gene, Allogeneic bone marrow stem cells treated ex vivo with 16,16-dimethyl prostaglandin E2, Allogeneic ex vivo expanded umbilical cord blood cells, Allogeneic ex vivo-generated natural killer cells from CD34+ umbilical cord blood progenitor cells, Allogeneic human dendritic cells derived from a CD34+ progenitor cell line, Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, Allogeneic umbilical cord blood cells treated ex vivo with 16,16-dimethyl prostaglandin E2, Allogeneic, umbilical cord blood-derived, ex vivo-expanded, haematopoietic CD133+ cells / allogeneic, umbilical cord blood-derived, non-expanded, haematopoietic CD133- cells, Alvocidib, Amonafide L-malate, Antisense oligonucleotide 5'-d[P-Thio} (CCCTG CTCCC CCCTG GCTCC)-3', Arsenic trioxide ( Arsenic Trioxide Accord, Arsenic trioxide Mylan, Arsenic trioxide medac, TRISENOX ), Azacitidine ( AZACITIDINE ACCORD, AZACITIDINE BETAPHARM, AZACITIDINE CELGENE, AZACITIDINE MYLAN, VIDAZA ), Bisantrene hydrochloride, Clofarabine ( CLOLAR, EVOLTRA, IVOZALL ), Combretastatin A1 diphosphate-, Crenolanib besylate, Daunorubicin (liposomal), Decitabine ( DACOGEN ), Devimistat, Donor lymphocyte preparation depleted of functional alloreactive T-cells, Enasidenib ( IDHIFA ), Eryaspase ( GRASPA ), Fully human IgG1 antibody specific for CD33, Gemtuzumab Ozogamicin ( MYLOTARG ), Gilteritinib ( XOSPATA ), Guadecitabine, Histamine dihydrochloride ( CEPLENE ), Homoharringtonine ( CEFLATONIN ), Human monoclonal antibody against inhibitory killer cell lg-like receptors (1-7 F9), Idasanutlin, Inecalcitol, Isocitrate dehydrogenase 2-mutant inhibitor, Ivosidenib ( TIBSOVO ), L-Asparaginase ( KIDROLASE, SPECTRILA ), Laromustine ( CLORETATZNE ), Lestaurtinib, Lintuzumab, Liposomal combination of cytarabine and daunorubicin ( VYXEOS ), Liposomal daunorubicin, Midostaurin ( RYDAPT ), Mitoxantrone ( NOVANTRONE ), N-(2-amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl] benzamide, N-(5-tert-Butylisoxazol-3-yl)-N'-{4-[7-(2-(morpholin-4-yl)ethoxy)imidazo[2,1- b][1,3]benzothiazol-2-yl]phenyl}urea di-hydrochloride salt, N-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide hydrochloride, NEDD8-activating enzyme (NAE) inhibitor, Onvansertib, P-ethoxy growth factor receptor-bound protein 2 (Grb2) antisense oligonucleotide, Plerixafor ( MOZOBIL ), Pracinostat, Recombinant human histone H1.3 and recombinant human N-bis-met-histone H1.3, Recombinant human interleukin-3 truncated diphtheria toxin fusion protein ( ELZONRIS ), Ribonucleotide reductase R2 specific phosphorothioate oligonucleotide, Sapacitabine, Selinexor ( XPOVIO ), Tamibarotene, Tipifarnib ( ZARNESTRA ), Tosedostat, Troxacitabine, Ulocuplumab, Vadastuximab talirine, Val-Leu-Gln-Glu-Leu-Asn-Val-Thr-Val (Pr1 nanopeptide, sequence 169-177, of proteinase 3), Venetoclax ( VENCLEXTA, VENCLYXTO ), Volasertib, Vosaroxin, Wilms' tumour 1 (WT1) vaccine, Zosuquidar trihydrochloride, cenisertib, cusatuzumab, haematopoietic stem cells and blood progenitors umbilical cord-derived expanded with (1R, 4R)-N1-(2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl)cyclohexane-1,4-diamine dihydrobromide dihydrate, humanised monoclonal antibody of the IgG4 kappa isotype targeting CD47, lysine-specific histone demethylase (LSD1, also known as KDM1A) inhibitor

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An aggressive form of acute myeloid leukemia (AML), characterized by arrest of leukocyte differentiation at the promyelocyte stage, due to a specific chromosomal translocation t(15;17) in myeloid cells, and manifests with easy bruising, hemorrhagic diathesis and fatigue.

Epidemiology

Acute promyelocytic leukemia (APL) accounts for 10% of AML cases and its incidence is estimated to be 1/1,000,000 people in Europe.

Clinical description

APL onset usually occurs in middle-aged adults and very rarely in pediatric patients. Manifestions include fever, fatigue, dizziness, mild cough with expectoration, exercise-induced dyspnea, weight loss or loss of appetite. Easy bruising or hemorrhagic diathesis (epistaxis, gums bleeding, hematuria, petechiae, metrorrhagia) are frequently observed.

Etiology

The vast majority (93-95%) of APL cases are caused by de novo translocation t(15;17)(q22;q21) that results in the fusion of RARA (retinoic acid receptor-alpha (RARalpha); 17q21.1) with the PML (promyelocytic leukemia (PML); 15q24.1) gene. PML and RARalpha are both implicated in normal hematopoiesis. PML possesses growth suppressor and proapoptotic activity and RARalpha is a transcription factor that mediates effect of retinoic acid (RA) at specific response elements and is believed to be important in proliferation and differentiation of promyelocytes into neutrophils. In a minority of cases (<1%), APL may arise from variant translocations including t(11;17)(q23;q21), t(5;17)(q35;q21), t(11;17)(q13;q21), t(3;17)(q26;q21)der(17), del(17)(q21), t(4;17)(q12;q21), der (2)t(2;17)(q32;q21) whereby RARalpha is fused to ZBTB16, NPM1, NUMA1, TBL1XR1, STAT5b, PRKAR1A, FIP1L1 and NABP1 genes respectively. 35% of APL cases express additional chromosomal abnormalities (trisomy 8, the most frequent, and other abnormalities involving chromosomes 1, 3, 9, 7, 11, 20 and 17, as well as mutations in FLT3 (13q12)). 5-7% of APL cases are related to previous chemotherapy and/or radiotherapy.

Diagnostic methods

Diagnosis relies on laboratory findings showing pancytopenia (hyperleukocytosis in around 20%) and on bone marrow examination which shows highly granulated promyelocytic cells (scarce granulation if macrogranular), all positive on myeloperoxidase staining. Immunophenotyping of promyelocytic cells shows positivity for CD33, CD13, CD64, CD117, and CD123 and MPO, and negativity for DR, CD34, CD15 and CD65. The diagnosis is confirmed by molecular screening (RT-PCR), anti-PML antibody and cytogenetic or FISH (fluorescence in situ hybridization) analysis of PML/RARA fusion genes.

Differential diagnosis

Differential diagnosis includes the other subtypes of AML.

Management and treatment

The mainstay treatment for APL consists of a combination of either all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy or ATRA and arsenic trioxide (ATO). This latter combination may also be used for relapsed APL and is equally effective as an alternative therapy for elderly APL patients, especially for those considered unfit for chemotherapy. Surveillance for any hemorrhagic signs is necessary, due to the high risk of disseminated intravascular coagulation.

Prognosis

Prognosis of APL after treatment is favorable with complete remission rates of around 90% with 2-year overall survival > 90%. The Sanz score (based on peripheral leukocyte and platelet counts), forms the mainstay for risk stratification in many APL clinical trials; patients with a white blood cell count of > 10 x 109 /L are deemed high risk, with an approximately 15-25% chance of relapse following ATRA + anthracycline chemotherapy. Other factors identified to be associated with an adverse outcome include CD56 expression and advanced age.