Acute Lymphoblastic Leukemia

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Retrieved

2021-01-23

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Trials

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Genes

NOTCH1, IKZF1, CDKN2A, SH2B3, FBXW7, BLM, LIG4, KMT2A, PTEN, LMO2, EZH2, NOTCH3, FLT3, ETV6, NBN, NUDT15, CD6, TRBV20OR9-2, CD19, MS4A1, TCF3, CD33, TAL1, CD22, H3P10, SPG7, GNB1, KRT20, NR3C1, CRLF2

NOTCH1, IKZF1, CDKN2A, SH2B3, FBXW7, BLM, LIG4, KMT2A, PTEN, LMO2, EZH2, NOTCH3, FLT3, ETV6, NBN, NUDT15, CD6, TRBV20OR9-2, CD19, MS4A1, TCF3, CD33, TAL1, CD22, H3P10, SPG7, GNB1, KRT20, NR3C1, CRLF2, CSF2, RUNX1, PTPN11, GSTP1, GSTT1, CASR, PSMB6, PRKAR1A, ASRGL1, CD34, TNF, TRG, CD38, CSF3, MRPL28, CXADR, TBC1D9, CYP1A1, TRIM13, DHFR, NQO1, NR1I3, ATN1, ABCG2, HPGDS, CEBPE, DLL1, KIT, CNTNAP1, CDR3, CDKN2B, NXT1, CXCR4, YY1, ERG, EVPL, TYMS, TPMT, TP53, PIK3CG, FANCB, TRGC1, PMS2, GSTM1, PIK3CD, IL7, OPN1SW, BCL2, GSTK1, ASPG, MTTP, MTHFR, IGH, MPO, ARR3, MME, AFF1, MYC, ANPEP, MDM2, TARP, CXADRP1, ITPA, JAK1, ALL1, JAK2, ABL1, H3P9, BCR, ABCC1, SUB1, NRAS, HTC2, ABCB1, PIK3CA, PIK3CB, TMEM132D, ARID5B, PBX1, SLCO6A1, PAX5, HLF, IL3, FAS, IL2, GGH, AKT1, IL7R, WT1, CD44, NT5C2, CCND1, IFNG, RFC1, IL6, VEGFA, ASNS, ARHGAP24, CDK2, SLC19A1, IL3RA, CREBBP, CYP3A5, CCN2, IL10, CYP3A4, WLS, IL18R1, EBI3, IFNA1, CDKN1C, TP73, IFNA13, ZNF384, BCL6, FHIT, SAI1, S100A4, ATM, MSH3, MLLT10, HLA-DRB1, AICDA, MEF2D, RAG1, STAT5A, HRX, CTNNB1, STAT5B, MTX1, JAK3, GATA3, MTRR, ATG5, GEM, MLLT1, NRP1, IL15, PICALM, TLX1, HOXA9, EBF1, MCL1, KIR3DL1, ROPN1L, RBM45, ASPM, C3, CES1, ASPA, ASIP, MARCKSL1, CRYZ, DUX4, A1CF, MIR196B, LINC02605, MTOR, BTG1, HERPUD1, CALCA, HLA-A, BLNK, CD86, NUP214, CASP3, CDK4, RUNX1T1, SCT, SNAP25, EP300, ROR1, LEF1, MIR155, IGF2BP1, BCL2L11, MERTK, CYP2D6, IL2RA, MSH2, MTAP, MDM4, CCR7, MTR, KRAS, FOXO3, MLLT3, TGFB1, TG, SOAT1, TNFRSF9, CD40, FGFR1, FUT4, ADA, SPP1, TRD, CEP72, CD27, LRP1, FPGS, IDH1, CXCL12, BCRP2, NCAM1, HPRT1, IDH2, PDGFRB, P2RY8, HOXA@, BAX, TLX3, CALM1, GLS, CALM2, CALM3, PML, HLA-B, COL18A1, MIR146A, PTPRC, RB1, CSF1R, NAT2, ABCC3, CD52, CDKN1A, EPOR, CDKN1B, MVP, SNAP91, CYP2E1, FOXP1, PROM1, CDK6, EIF4E, HFE, PRKAA2, TRDJ1, NME1, MSI2, NPM1, PTPN6, TNFRSF13C, DERL1, SERPINE1, TSLP, CASP8, HDAC9, MAPK3, HDAC1, F2, ADIPOQ, HSP90AA1, PIP4K2A, HLA-DPB1, PRKAB1, PRKAA1, TCF7L1, BMI1, RALGAPB, A2ML1, KDR, AFF3, LAMC2, RPSA, LEP, CTCF, ISG20, BCRP3, COX8A, MEIS1, IL18, EIF2AK4, MLH1, MIR34B, MIR221, APAF1, CYP2B6, BIRC5, EFS, IL1B, SIRT1, MIRLET7B, IGFBP7, LINC01194, DCK, IGF1R, RMDN2, MYB, ZNF521, PTPRA, B3GAT1, PAG1, FANCL, WEE1, NLRP2, RTEL1, CD79A, CDKN2C, CD40LG, SHMT1, WNT5A, TRDC, ERCC2, ZAP70, GATA1, OPN1LW, ACKR3, CD7, PCBP4, RARA, TRDD3, SYK, FLT1, TAC1, PRAME, MIR203A, MIR181A2, SMUG1, SYNE1, ZNF197, MIR150, UHRF1, XPO1, UGT1A1, LAMTOR1, PPP1R13B, MMP9, TCF7L2, NSD2, MIR142, ABCC4, MIR126, TNFSF10, CIB1, MIR223, TERT, NUDC, KRT7, IGK, VDR, UBE2I, RMDN1, LCK, VWF, WT1-AS, H3P12, MIR1290, CXCR6, IL24, LMNA, LMO1, RASSF10, ATRAID, LPA, PTP4A3, SCLY, MDK, PACSIN2, MIR335, TLR4, MAP3K7, CD99, TFRC, RMDN3, AUTS2, LRPPRC, PGF, ABCB4, PHF2, PMEL, AFF4, GLS2, SET, DHX32, NR0B2, LPAR2, HAP1, CCNA1, S100A8, S100A6, SMYD2, PRDM9, IGHV1-12, EIF3A, PRKCB, MAPK1, MAP2K1, PSG2, BAALC, PTK7, TBL1XR1, PVT1, EEF1E1, HAVCR2, TOM1, TAM, MUC1, BTLA, PTPRG, STAT1, SSTR4, TES, CASP8AP2, NFKB1, NM, SYBU, NNMT, MAFK, DAZAP1, TPPP2, SOX4, SNX2, NT5E, OPRK1, PAEP, PRKN, WNT3A, PDGFRA, STIL, ZEB2, PECAM1, VPREB1, NAT1, GATA2, EPHA3, ETFA, BRAF, ERBB2, EPO, BMP4, HLA-C, CEACAM5, EPHX1, HLA-DQB1, CEACAM1, CFL1, HMMR, CEACAM3, HOXA5, CCN1, CEACAM8, ENO2, ENG, CHEK1, HOXB7, SERPINC1, HSPB1, ABCC2, EGF, ICAM1, IFNB1, IGF1, IGFBP2, MECOM, EXT1, BRS3, F3, FOLH1, FN1, FUS, G6PD, CCK, CBL, FLT3LG, CBFB, FOXO1, CD28, FGF2, CD80, FAT1, GFI1, CAT, CASP10, FANCC, CAMP, CXCR3, GPR42, GPT, CD58, DDR1, GSK3B, GSTM2, MSH6, BTK, IGFBP3, CEACAM7, FOS, CSF3R, CTLA4, AHR, EDNRA, E2F1, IRS1, CXCL8, DPYD, CTSG, ACTB, DCC, INPP5D, IL4, ADRA2B, ADRA1A, IL6ST, ABO, KIR2DS1, DPP4, TCFL5, DDX41, CD70, CD47, ERVW-1, IL23A, HDAC7, CST3, TRIM33, EMCN, CD72, WWOX, IGF2BP2, ZMYND11, ISYNA1, KDM5B, WNT16, WAC, TMED7, CD69, CD48, CD59, CSN2, MAP3K20, THEG, DCTN6, TNFSF13B, ZBTB7A, PLK4, DACT1, EBP, CD37, BCL11A, IGF2BP3, SEPTIN11, CD2, CD1D, PRDX4, CCND3, ATF7IP, ANP32B, CNDP2, ZNRD2, CCND2, CXCL13, CCNC, CYBB, ACSS2, CIB2, ZC4H2, MYDGF, CYLD, PRMT5, IMPACT, CD5, KDM3B, COLEC10, ARPP21, IL17D, TLR9, H2BS1, RIN2, PDLIM5, CD36, ADAMTSL4, TNFSF8, QRSL1, FBLIM1, GIPC2, WBP1L, TNFRSF8, MOCOS, MSTO1, ELP2, CD14, CD79B, RASSF1, GPR132, CKS1B, COBL, ATP11A, ARHGEF12, CCR5, DICER1, CKS2, SPIDR, CLCF1, CISH, CHI3L1, SSBP2, LY96, PLA2G15, TFIP11, FBXL2, LETMD1, CHRNA4, RIPK3, MLC1, CYFIP1, MPRIP, CNTFR, CREB1, CASC3, WDHD1, CILK1, CARD8, SACM1L, KLRK1, CRHR1, CORO1A, MAPRE1, CR1, CD160, ADAMTS13, USP33, WWP1, PIM2, SEPTIN6, CHRM3, NAT9, CDH11, TRBV7-9, CEL, CEBPA, HCST, CDX2, HPSE, PPP1R13L, CDKN2D, TRBV16, TRBC1, STAP1, TRAC, TRIB2, SETD2, CDK9, POLG2, CD274, CCR9, CDH13, IGHV3-69-1, NMU, IGHV3OR16-7, SMR3B, FBXL5, FBXO8, TSPAN16, CRKL, STEAP1, SLC27A4, CEACAM4, SLC27A5, DKK3, DKK2, PCDHA@, AGO2, NAAA, RAB40B, IL17C, CSF1, PCDH17, NEU3, KIR3DL2, RNF20, AREG, BIRC2, MIR15A, MIR16-1, MIR17, ANXA5, MIR185, MIR187, MIR192, MIR196A1, ANXA2, MIR206, MIR210, MIR181A1, MIR214, MIR22, ALPP, ALPI, MIR29B1, MIR29B2, MIR29C, MIR31, APRT, MIR144, ALK, MIR143, BCRP4, PGP, HOXA-AS2, BCL9, DDX51, CLEC4D, ADAMTSL5, ABCB5, H3P44, TICAM2, BAK1, B2M, ATRX, ATR, ATIC, MIR100, MIR125B1, MIR125B2, MIR128-2, MIR137, ASS1, MIR34A, MIR9-2, PCSK9, CDKN2B-AS1, SYCE1L, MFT2, ADM, ACTN4, TMED7-TICAM2, ACTG1, MIR3117, MIR2909, SNHG16, PPR1, KLRC4-KLRK1, COMMD3-BMI1, LOC102723407, LOC102724334, CBSL, LOC102724971, MTCO2P12, ABCA3, H3P13, H3P23, H3P47, MIR665, GGTLC4P, MIR9-3, GGT2, MIR99A, MIR17HG, BLID, AKR1B1, ALB, MIR339, AFM, MIR424, MIR425, H4C15, MIR499A, POU5F1P3, ADRB2, POU5F1P4, GGTLC5P, SNORD116@, MIR595, MIR625, MIR652, GGTLC3, POTEF, GCSAM, ZDHHC23, METTL3, SLC28A3, TNMD, CBFA2T3, FBRS, IKZF5, GORASP1, PLEKHG2, RANBP17, BCL11B, RUNX2, WNK1, CAV3, ZMAT4, CASP2, CAPG, TRABD, PNPLA3, TSGA10, PBX4, LBH, AMN, DOCK8, ELSPBP1, PRDM16, MXD3, HPSE2, FMN2, SPHK2, TCIM, CBS, SLC12A9, CBLB, KNL1, AVEN, ZNF695, GOPC, SALL4, RUNX3, SCYL1, BIRC6, DLEU1, PCDH10, KLHL1, METTL14, CCAR2, KMT2C, BACH2, CALR, CALCR, CERS6, EXOSC6, BRCA1, BMP6, UHMK1, SLX4IP, CMPK2, BLVRB, PRRC1, PACRG, CTCFL, CXCR5, PDIK1L, BHMT, CREBRF, CLEC12A, ZNF296, RASSF6, CFB, DLEU7, ZEB1-AS1, JMJD1C, IL27, H4-16, TWIST2, CHST9, TADA1, AIF1L, PARP9, SETDB2, MAGT1, BUB1, ZCCHC7, MAML2, ACCS, ATAD1, ZNF382, UBASH3B, ABCC11, ZFP36L2, LHX4, RCSD1, DNER, UBE2Q2, PRRT2, NLRP3, FCRL1, ZFP36L1, CYP1B1, DNMT1, LILRB2, PMAIP1, PNN, SEPTIN5, SEPTIN4, POLD1, POMC, POU5F1, PPARA, PTPA, PRF1, HIF1A, HIC1, HDC, HDAC2, PRKCA, HAL, H2AZ1, GZMB, MAPK8, GZMA, MAP2K2, MAP2K7, HK1, PLK1, CYP2C19, PLCG2, HOXB5, HOXB4, PAM, HOXB3, PARN, HOXB2, HOXB1, PCNA, PDE1A, PDGFB, HOXB@, HOXA10, SLC29A2, HNF4A, HMOX1, HMGB1, HLX, PIM1, HLA-DRA, HLA-DQA1, PLAT, EIF2AK2, PRPS1, PRSS1, GYPE, RPL22, GLI3, GLI2, GH1, S100A9, S100A10, GGT1, SCD, SRL, CCL2, CCL3, CCL4, CCL21, CCL22, XCL1, GFER, SELE, SELPLG, GDF10, SRSF2, SFTPD, BRD2, RMRP, RIT1, PVR, GYPB, PSMD9, PSMD12, GYPA, PTGS2, GSTM3, GRIK2, GRIA1, PTPRO, RAG2, GML, RAP1GDS1, GPER1, PLAAT4, KDM5A, RBBP4, GNG11, REG1A, GNA15, REN, P4HB, OTC, SIX6, MAP3K10, LYL1, LYN, MARCKS, SMAD7, MAOA, MAPT, MBL2, MBP, IRF3, MCM2, CD46, SMCP, IRF1, INSR, MEF2C, CXCL10, MEFV, ING2, MFAP1, KITLG, IL16, CYP4F3, LTB, LTA, LEPR, KIR2DL1, KCNH2, CD82, JUND, STMN1, LBR, JUNB, LCN2, JUN, LGALS1, LSS, LGALS3, ITPR1, LIPA, FADS1, ITGB1, ITGAM, ITGA4, LPL, IRF4, IL12B, IL12A, OPRM1, IL11, NELL1, NFATC2, NFIL3, NFKB2, NGFR, NKX3-1, HSPA5, HSPA4, PRMT1, NOS3, HRAS, NOTCH2, HPR, PNP, HOXD4, HOXB9, YBX1, HOXB8, NTRK1, NUP88, HOXB6, NEDD9, NEDD8, HSPB2, IGL, MMP1, IL1RN, MOS, CD200, MPL, IL1A, MPP1, MPST, MRE11, RBPJ, IAPP, MSR1, IGFBP4, COX2, MTHFD1, IGFBP1, IGF2, IFI27, MYH11, CEACAM6, KAT2A, SIAH2, GATA4, HSPB3, ELK3, AKR1C3, SOCS1, ELK1, BECN1, ELF3, TNFSF13, ELANE, FADD, TRIM24, EIF5A, EGR1, EGFR, CFLAR, HDAC3, NR1I2, PER3, SQSTM1, EFNB1, ENDOU, BCL10, PIK3R3, IRS4, ELN, GFI1B, EPHA1, KMT2D, HMGA2, TCL1A, TAF15, COIL, MLRL, H4C9, CTTN, H4C1, H4C14, H4C4, H4C6, H4C12, H4C11, H4C3, H4C8, H4C2, H4C5, H4C13, MBD2, NOL3, EPHB2, PHC1, DNM2, SARDH, DLX3, HDAC6, HDAC5, TIMM8A, DEFB1, DHX15, ABCC5, ABCB6, PPIF, RASGRP1, DDC, NAMPT, BRINP1, DAP, TRIB1, MSLN, SPRY1, CD55, NET1, P2RY14, DNMT3A, HDAC4, CD83, PKD2L1, SPAG9, PIAS2, ARHGEF1, EDNRB, IL1RL1, AURKB, MSC, PDLIM7, KLF4, KMT2B, SLIT2, NRXN1, DUSP7, PIGL, BAG4, CLOCK, NCOR1, TCL1B, DNTT, KAT6A, EPHB4, SLA, THY1, FLT4, TACR1, FLII, TAT, TCF4, FLI1, TCF7, ZEB1, TCF12, TCOF1, TRB, FOXM1, FH, FER, TERC, TERF1, FDXR, TFR2, FCGRT, FCGR2B, THBD, SYT1, AFF2, ABCC8, GAD1, SLC6A8, GAS6, SLC25A1, SLCO1A2, SMARCA1, SMARCB1, GART, FSCN1, GAPDH, SOD2, AURKA, SORL1, SOS1, SOX11, SPI1, FRAXE, SST, FOSB, STAT3, STC1, THPO, TIMP2, DEK, TLE1, F2R, VEGFC, VIS1, TRPV1, EWSR1, LAT2, ETS1, WNT7A, WNT10B, WNT2B, ESR1, ERCC1, XRCC1, XRCC3, XRCC5, ZBTB16, ZBTB17, MAP3K12, PRDM2, MOGS, USP7, VCP, NR1H2, UNG, TTC4, FAP, TMSB4X, PTK2B, TNFRSF1A, TOP2A, FABP3, TPM3, F10, NR2C2, TNFSF4, UCK2, TNFRSF4, TXN, TYK2, F9, TYRO3, F8, UCHL1, UCN, UMOD, RELA

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, 6-thioguanine (oral liquid), Allogeneic CD34+ cells expanded ex vivo with an aryl hydrocarbon receptor antagonist, Allogeneic T cells encoding an exogenous TK gene, Allogeneic ex vivo expanded umbilical cord blood cells, 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, Aplidine, Autologous CD3+ T cells transduced with retroviral vector containing a chimeric antigen receptor directed against CD19 (Autologous CD3+ T cells containing CD19 chimeric antigen receptor), Autologous engineered anti -CD19 Chimeric Antigen Receptor (CAR +) T -cells ( KYMRIAH ), Axicabtagene ciloleucel ( YESCARTA ), Blinatumomab ( BLINCYTO ), Clofarabine ( CLOLAR, EVOLTRA, IVOZALL ), Crisantaspase, Dasatinib ( SPRYCEL ), Epratuzumab, Eryaspase ( GRASPA ), Forodesine hydrochloride, Hematopoietic stem and progenitor cells expanded ex-vivo with a low molecular weight aryl hydrocarbon receptor (AHR) antagonist, Imatinib mesilate ( GLEEVEC, GLIVEC, IMATINIB TEVA, IMATINIB TEVA B.V. ), Inotuzumab ozogamicin ( BESPONSA ), Iodine (131I) tositumomab, L-Asparaginase ( KIDROLASE, SPECTRILA ), Mercaptopurine (oral liquid), Mercaptopurine (oral suspension) ( PURIXAN, XALUPRINE ), Methotrexate (oral liquid) ( JYLAMVO ), Moxetumomab pasudotox ( LUMOXITI ), Nelarabine ( ARRANON, ATRIANCE ), Pegaspargase ( ONCASPAR, PEGASPAR ), Pegylated L-asparaginase, Pegylated recombinant Erwinia chrysanthemi L-asparaginase, Plitidepsin, Ponatinib ( ICLUSIG ), Recombinant human histone H1.3 and recombinant human N-bis-met-histone H1.3, Siplizumab, Stem/progenitor cells derived from ex vivo expanded allogeneic umbilical cord blood cells, Vincristine sulfate liposomes ( MARQIBO ), 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

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A rare disease characterized by malignant proliferation of lymphoid cells blocked at an early stage of differentiation and accounts for 75% of all cases of childhood leukaemia.

Epidemiology

About 3,000 children in the United States and 5,000 children in Europe are diagnosed with ALL per year.

Clinical description

The peak incidence occurs between 2 and 5 years of age. ALL may be either asymptomatic or acute with a life-threatening haemorrhage, infection, or episode of respiratory distress. Although ALL primarily affects the bone marrow and peripheral blood, any organ or tissue may be infiltrated by the abnormal cells. The most frequent signs are lymphadenopathies, hepatosplenomegaly, fever, signs of haemorrhage, and bone pain.

Etiology

Most cases show chromosomal and genetic abnormalities, occurring spontaneously in genes playing important regulatory roles in controlling the lymphoid cell population. The most common ALL translocation, the t(12;21), appears to have good prognostic implications.

Diagnostic methods

ALL is biologically heterogeneous and morphologic, immunologic, cytogenetic, biochemical, and molecular genetic characterisation of leukaemia lymphoblasts is needed to establish the diagnosis or to exclude other possible causes of bone marrow failure and, finally, to classify ALL subtypes. Biological findings include hyperleukocytosis due to circulating lymphoblasts, anaemia and thrombocytopaenia. Diagnosis is established by bone marrow biopsy revealing leukaemic cell infiltration.

Management and treatment

The chemotherapy protocols adopted by international cooperative groups have four main objectives: induction with the aim of complete remission, preventative therapy to avoid central nervous system involvement, consolidation/re-induction, and maintenance therapy. Although management of relapse remains largely controversial, high dose chemotherapy blocks and stem cell transplantation are approaches increasingly adopted in most cases. In 2006, clofarabine obtained EU marketing authorisation as an Orphan drug for second line treatment of paediatric ALL patients. A novel tyrosine-kinase inhibitor, dasatinib, has been shown to be a safe and effective treatment option for adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia and resistance or intolerance to imatinib. Clinical trials with this inhibitor are ongoing in the paediatric population. With the need to stratify patients into risk groups and to provide risk-adapted therapy, treatment requires high levels of organisation, expertise and knowledge.

Prognosis

The increase in the survival rate for children younger than 15 years of age has been dramatic, moving from less than 10% in the early 60's to about 75% in the late 90's. Unfortunately, however, results are still rather poor in countries with limited resources, which are home to around 80% of the child population.