儿童非霍奇金淋巴瘤诊疗建议pptppt课件.ppt

儿童非霍奇金淋巴瘤诊疗建议（2004讨论稿）中华医学会儿科分会血液组中华医学会儿科分会血液组中华儿科杂志中华儿科杂志 上海儿童医学中心上海儿童医学中心 汤静燕起草汤静燕起草 背 景 l王耀平教授执笔了第一个儿童淋巴瘤诊疗建议，王耀平教授执笔了第一个儿童淋巴瘤诊疗建议，至今已至今已1010年余。年余。l国际上儿童淋巴瘤的总体的国际上儿童淋巴瘤的总体的5 5年无病生存率已年无病生存率已达达70%70%以上。以上。l我国仍相对落后，诊断和治疗水平相差较大。我国仍相对落后，诊断和治疗水平相差较大。NHL Protocol ReviewNHL-BFM90 Report(T-LBL)Blood,2000,95(2):416l0-180-18y,T-cell,F:M 24:81.y,T-cell,F:M 24:81.l106 patients,I:2,II:2,III:82,106 patients,I:2,II:2,III:82,IV:19.BM(+)15,CNS(+)3.IV:19.BM(+)15,CNS(+)3.lProtocol:Protocol:ALL-like protocol.ALL-like protocol.Induction:CTX 1g/m,d36,64.Re-in d36Induction:CTX 1g/m,d36,64.Re-in d36HDMTX 5.0g/m/24h X 4.HDMTX 5.0g/m/24h X 4.Asp X 2Asp X 2（10000/M x 810000/M x 8，x4x4）CRTCRT：1200 cGy for III/IV1200 cGy for III/IVTotal CTX 3g,Adr 240mg/m.Total CTX 3g,Adr 240mg/m.Total therapy 2 y.Total therapy 2 y.lResult5y EFS 90%No different atlSex,age,Sex,age,lLDH(500),LDH(500),lIII or IV,III or IV,limmunotyping,immunotyping,ld33 CR or not d33 CR or not POG 8704 Report-T-ALLand T-NHLLeukemia 1999;13:335Leukemia 1999;13:335lT-ALL 357caes,T-NHL(lymphoblastic)195lwhole protocol basicly like ALLlAfter CR:High dose Asp 25000/m/w x 20W from d 99 as consolidationNo high dose Asp consolidationl4 4y EFS ALL:68%vs 55%y EFS ALL:68%vs 55%NHL:78%vs 64%NHL:78%vs 64%l BFM 90 B-cell ReportBlood 1999;94:3294lObject:Object:LDH and early response LDH and early response For group III and LDH 500,MTX For group III and LDH 500,MTX from 0.5 to 5.0from 0.5 to 5.02 cycles for complete resected 2 cycles for complete resected diseasediseasesystemic chemo plus intravencular systemic chemo plus intravencular therapy for CNS positive patienstherapy for CNS positive patiensGroupinglR1:R1:CR,CR,lR2:R2:no-abdomen primary or incompletely resect,no-abdomen primary or incompletely resect,LDH 500,LDH 500 LDH500 or multiple bone,BM,CNS involvement,6 cyclesor multiple bone,BM,CNS involvement,6 cycleslNo-CR after 2 cycles:HDAra-c+Vp-16 for 2 No-CR after 2 cycles:HDAra-c+Vp-16 for 2 cycles If CR,plus another 3 cyclescycles If CR,plus another 3 cycles Protocol B-Cell-BFM-90 R1 V-A-B R2 V-AA-BB-CR-AA-BB R3 V-AA-BB-CR-AA-BB-AA-BB PR-CC-CR-AA-BB-CC PR OP-Negtive Positive-ABMTlV 1 2 3 4 5 Pred 30mg/m/d x x x x x CTX 200mg/m/1h x x x x x I/T x lA 1 2 3 4 5 DX 10mg/m/d x x x x x Ifos 800mg/m/d/1h x x x x x MTX 500mg/m/24h*x IT x Ara-c 150mg/m/q12h/1h xx xx Vp-16 100mg/m/1h x x *CF 12mg/m 48,54h,10%MTX/30,90%23.5hlB 1 2 3 4 5 Dx 10mg/m x x x x x CTX 200mg/m/1h x x x x x MTX 500mg/m/24h x IT x Adr 25mg/m/1h xlAA 1 2 3 4 5 Dx 10mg/m x x x x x Ifos 800mg/m/1h x x x x x MTX 5g/m/24h*x IT x VcR 1.5mg/m x Ara-C 150mg/m/1h/q12h xx xx Vp-16 100mg/m/d/1h x xl*CF 30mg 42,48h,q6h ajusted as CF 30mg 42,48h,q6h ajusted as follows:follows:1-2umol/L 30mg/m 1-2umol/L 30mg/m 2-3umol/L 45mg/m 2-3umol/L 45mg/m 3-4umol/L 60mg/m 3-4umol/L 60mg/m 4-5umol/l 75mg/m 4-5umol/l 75mg/m 5umol/L:CFmg=MTXumol/L/kg 5umol/L:CFmg=MTXumol/L/kg MTX 10%30 MTX 10%30,90%23.5h,90%23.5hlBB 1 2 3 4 5 Dx 10mg/m x x x x x CTX 200mg/m/1h x x x x x MTX 5.0g/24h x IT x Adr 25mg/m/1h xlCC 1 2 3 4 5 Dx 20mg/m x x x x x VDS 3mg/m(max 5mg)x Ara-C 2.0g/m/3h xx xx Vp-16 150mg/m/1h x x x IT x CNS(+)Intraventricularly Chemol AA and BBAA and BB MTX 3mg,Pred 2.5mg d1,2,3,4 MTX 3mg,Pred 2.5mg d1,2,3,4 Ara-C 30mg d5 Ara-C 30mg d5lCCCC MTX 3mg,Pred 2.5mg d3,4,5,6 MTX 3mg,Pred 2.5mg d3,4,5,6 Ara-C 30mg d7 Ara-C 30mg d7ABMT Pre-conditioning -8 -7 -6 -5 -4 -3 -2 -1 0Busulfan 120mg/m*!VP-16 300mg/m/4h !CTX 1.5g/m/1h#!Stem cell transfusion !*Divided p.o#If CNS(+)thiotepa 300mg/m/d x 3 replace of CTXResult and ConclusionlR1:100%,R2:96%,R3 78%.R1:100%,R2:96%,R3 78%.lHDMTX effective in R2 and R3HDMTX effective in R2 and R3lStage III,LDH500u/L,PEFS 81%,Stage III,LDH500u/L,PEFS 81%,control 43%.6y EFS control 43%.6y EFS lABMT(residual after 3 cycles)ABMT(residual after 3 cycles)effective,5/6 survived,control:effective,5/6 survived,control:4/5 progress.4/5 progress.lConfirmed the objective 1,2,3,4Confirmed the objective 1,2,3,4LDH and early response LDH and early response()For group III and LDH 500,MTX For group III and LDH 500,MTX from 0.5 to 5.0 from 0.5 to 5.0()2 cycles for complete resected 2 cycles for complete resected disease disease()systemic chemo plus intravencular systemic chemo plus intravencular therapy for CNS positive patiens therapy for CNS positive patiens()Improved Cure rate on Children with B-cell ALL Improved Cure rate on Children with B-cell ALL and Stage IV B-cell NHL-Result of the UKCCSG and Stage IV B-cell NHL-Result of the UKCCSG 9003 Protocol 9003 Protocol British J of cancer 1998,77(12),2281-2285British J of cancer 1998,77(12),2281-2285l1990-19961990-1996lB-ALL 35,13 with CNS(+)(L325%B-ALL 35,13 with CNS(+)(L325%blasts)blasts)lStage IV B-NHL 28,22 with CNS(+)Stage IV B-NHL 28,22 with CNS(+)l9003 based on LMB 869003 based on LMB 86lCNS+,24Gy in 15 fractionCNS+,24Gy in 15 fraction9003 ProtocollCOP(1)-COPADM1(2)-COPADM2(5)-COP(1)-COPADM1(2)-COPADM2(5)-CYVE*(8)-CYVE*(11)-COPADM3(14)-CYVE*(8)-CYVE*(11)-COPADM3(14)-CYVE#(17)-COPAD(20)-CYVE#(23)-CYVE#(17)-COPAD(20)-CYVE#(23)COP:COP:CTX 300mg/m d1 CTX 300mg/m d1 VCR 1mg/m d1 VCR 1mg/m d1 Pred 60mg/m d1-7 Pred 60mg/m d1-7 IT d1,3,5 IT d1,3,5lCOPADM1COPADM1 VCR 2mg/m d1 VCR 2mg/m d1 Adr 60mg/m/6h d2 Adr 60mg/m/6h d2 CTX 500mg/m d2,3,4 CTX 500mg/m d2,3,4 HDMTX 8g/m/3h d1,CF 15mg/mHDMTX 8g/m/3h d1,CF 15mg/m Pred 60mg/m d1-5 Pred 60mg/m d1-5 IT d1,3,5 IT d1,3,5lCOPADM2:COPADM2:Same as COPADM1,but Same as COPADM1,but VCR d1,6 VCR d1,6 CTX1.0g/m d2,3,4 CTX1.0g/m d2,3,4lCYVE*(HDAra-C):CYVE*(HDAra-C):Ara-C 50/m/over 12h d1-5 Ara-C 50/m/over 12h d1-5 Ara-C 3.0g/m/over 3h d1-4Ara-C 3.0g/m/over 3h d1-4 VP-16 200mg/m/over 2h d1-4VP-16 200mg/m/over 2h d1-4lCOPADM3COPADM3 Same as COPADM1,but:Same as COPADM1,but:CTX 500mg/m/d d2,3 CTX 500mg/m/d d2,3 IT d1 IT d1lCYVE#(low dose)CYVE#(low dose)Ara-C 50mg/m/q12h,d1-5 Ara-C 50mg/m/q12h,d1-5 VP-16 150mg/m d2-4 VP-16 150mg/m d2-4lCOPAD:COPAD:Same as COPADM3,but no HDMTX Same as COPADM3,but no HDMTXl10 10 relapse(16%),CNS 2,BM 2,CNS+BM relapse(16%),CNS 2,BM 2,CNS+BM 3,Jaw 1,within 11m after Dx.3,Jaw 1,within 11m after Dx.l2 No-CR,all of the 12 died.2 No-CR,all of the 12 died.l7(11%)died of toxicity7(11%)died of toxicity(septic 5,(septic 5,septic+renal failure 2).septic+renal failure 2).l43(69%)EFS average 3.1y.43(69%)EFS average 3.1y.lHD-Ara-C possibly play key roleHD-Ara-C possibly play key roleCD 30+Anaplastic large cell lymphoma in CD 30+Anaplastic large cell lymphoma in children:analysis of 82 patients enrolled in children:analysis of 82 patients enrolled in two consecutive studies of the french society two consecutive studies of the french society of pediatric Oncology of pediatric Oncology Blood 1998;92(10):3591Blood 1998;92(10):3591lALCL-Malignant histocytosisALCL-Malignant histocytosisl80-90%T-cell,a few as B-cell80-90%T-cell,a few as B-celllt(2;5),NPM/ALK(nucleophosmine t(2;5),NPM/ALK(nucleophosmine gene/tyrosine kinase gene)gene/tyrosine kinase gene)l10-15%of all NHL10-15%of all NHLlSt.Jude stage I/II 28%,III/IV 72%St.Jude stage I/II 28%,III/IV 72%l82 cases,total therapy 7m,no I/T82 cases,total therapy 7m,no I/TlB-Cell like protocolB-Cell like protocollProtocol:Protocol:COP-COPAM x 2-(VEBBP-Sequence 1)x 4 COP-COPAM x 2-(VEBBP-Sequence 1)x 4lNo CNS relapse firstl3y SR83%,EFS 66%lNo risk factor:3y EFS 95%,=1 factor 47%lSt.Jude I/II:3y EFS 94%,III/IV 55%l21 cases relapse within 7-49m(median 10m)lRisk factor;mediastinal mass,visceral involvement,LDH800TreatmentStrategy(B-NHL,LargeCell)GroupA(I,II)ABCRABM2GroupB(III,IV)PABCRABABM12PRCCRABCMResidualCNS+SL-OPTumornegativeTumorpositiveABMTA CTX 800mg/m2/d1,200mg/m2/d2,3,4 VcR 2mg/m2/d1,8,15 Adr 20mg/m2/d1,2 Ara-C 500(1000,1500)mg/m2/12h/d1 I/T MTX,Ara-C,Dx d1,8,15B Ifos 1200mg/m2/d1,2,3,4,5 Vp-16 60mg/m2/d1,2,3 MTX 15mg/m2/d1,2,3 VcR 2mg/m2/d8 I/T d1,8,15MC:CTX 1000mg/m/d1 MTX 300mg/m/d15 VcR 2mg/m/d1,8,15 Pred 60mg/m/d1,2,3,4,5H:CTX 750mg/m/d1 Adr 25mg/m/d1,2 VcR 2mg/m/d1 Pred 100mg/m/d1,2,3,4,5CTX in total:12.45g/mIfos in total:18g/mAdr in total:245mg/m1994.6-2000.6明确诊断并决定接受治疗者均列入统计随访至2000.12.30中断联系超过6个月列为失访Resultsn4/52gaveuptreatmentwithin30daysn44/48(91%)CRn5/48lostfollowing-upatCRn5/48relapsedand4died(85%Ki-67+85%。间间变变型型大大细细胞胞性性淋淋巴巴瘤瘤常常用用标标记记：CD30 CD30+，EMA EMA+/-+/-，ALK+/-ALK+/-淋巴母细胞型淋巴瘤（淋巴母细胞型淋巴瘤（LBLB）常用标记常用标记T-LB：B-LB：TdT+TdT+CD1a+/-CD10+/-CD3+/-CD19+CD7+CD79a+l分子生物学检查分子生物学检查BurkittBurkitts s淋淋巴巴瘤瘤常常见见t t（2 2；8 8），t t（8 8；1414）或或t t（8 8；2222）。）。间间变变型型大大细细胞胞性性淋淋巴巴瘤瘤常常见见有有t t（2 2；5 5），ALK/NPMALK/NPM融合。融合。疾病分期检查（分期标准（分期标准 建议采用建议采用St.JudeSt.Jude分期系统）分期系统）骨髓涂片骨髓涂片胸胸腹腹影影像像学学检检查查（正正侧侧位位胸胸片片、腹腹部部盆盆腔腔B B型超声或型超声或CTCT、MRIMRI）脑脑脊脊液液离离心心甩甩片片找找肿肿瘤瘤细细胞胞，必必要要时时头头颅颅MRIMRI以除外颅内转移。以除外颅内转移。选择性全身骨扫描选择性全身骨扫描治疗l治疗手段以化疗为主，手术和放疗为辅治疗手段以化疗为主，手术和放疗为辅l放放疗疗：除除中中枢枢浸浸润润、脊脊髓髓肿肿瘤瘤压压迫迫症症、化化疗疗后后局局部部残残留留病病灶灶、姑姑息息性性治治疗疗等等特特殊情况外，不推荐放疗。殊情况外，不推荐放疗。l手术：手术主要用于下列情况：手术：手术主要用于下列情况：l除除手手术术活活检检外外，无无其其它它方方法法可可明明确确诊诊断断并并作作免免疫分型时积极考虑活检术疫分型时积极考虑活检术l估估计计肿肿块块不不能能完完全全切切除除时时应应仅仅做做小小切切口口活活检检术术，不推荐肿瘤部分或大部分切除术。不推荐肿瘤部分或大部分切除术。l急腹症急腹症l二次活检二次活检l在在落落后后地地区区如如无无条条件件化化疗疗，对对于于局局限限性性疾疾病病可可采用手术治疗，但复发进展率很高。采用手术治疗，但复发进展率很高。急诊处理：l气道及上腔静脉压迫症状气道及上腔静脉气道及上腔静脉压迫症状气道及上腔静脉压迫症状压迫症状 l胸膜腔积液或心包积液时可引流改善症状胸膜腔积液或心包积液时可引流改善症状 l肿瘤细胞溶解综合症肿瘤细胞溶解综合症 B-NHL（成熟B-ALL）l适应症适应症:未未治治B B细细胞胞性性NHLNHL（无无条条件件作作免免疫疫分分型型时时病病理理形形态态为为BurkittBurkitts s型型NHLNHL）、）、或病理形态为大细胞型。或病理形态为大细胞型。未未治治成成熟熟B-ALLB-ALL（即即骨骨髓髓中中大大于于30%30%肿肿瘤瘤细细胞胞表表达达SIgMSIgM或或/和和轻轻链链，或或肿肿瘤瘤细细胞胞有有t t（8 8；1414）、t t（8 8；2222），），t t（8 8；2 2）各脏器功能基本正常。各脏器功能基本正常。无先天性免疫缺陷病，无器官移植史，非第二肿瘤。无先天性免疫缺陷病，无器官移植史，非第二肿瘤。分组及治疗计划l分组分组R1R1组组 化疗前已完全缓解，化疗前已完全缓解，LDHLDH正常。正常。R2R2组组 LDHLDH小小于于正正常常2 2倍倍的的I,I,IIII期期，包包括括孤孤立立 性骨病灶。性骨病灶。R3R3组组 III,IVIII,IV期，或期，或LDHLDH大于正常大于正常2 2倍。倍。R4R4组组 2 2个疗程未获完全缓解者。个疗程未获完全缓解者。R4T-NHL（淋巴母细胞型）l适应症适应症:未未治治T-T-细细胞胞性性NHLNHL（或或病病理理形形态态为为淋淋巴巴母母细细胞胞型型NHLNHL）.各各脏脏器器功功能能基基本本正正常常。无无先先天天性性免免疫疫缺缺陷陷病病，无无器器官移植史，非第二肿瘤官移植史，非第二肿瘤.l分组分组R1R1组组 完完全全缓缓解解（即即手手术术已已完完全全切切除除肿肿块块）、I I期期，LDHLDH小于正常值小于正常值2 2倍。倍。R2R2组组 I I期期，LDHLDH大大于于正正常常值值2 2倍倍。IIII期期及及孤孤立立性性骨骨病病灶。灶。R3R3组组 III,IVIII,IV期。期。图2-T-NHL治疗计划T-NHL化疗方案及剂量表R1R2R3日期DrugDoseDayNONONONOYesYesCourseIPVA+LCATPredVcRDoxL-Asp（美国）CTX6-TGAra-C45mg/m2/d1.5mg/m2/iv30mg/m2/2h10000u/m2（日本X0.7）750mg/m2/2h75mg/m22000mg/m2/2h/q12h1-28,taper3+31,8,15,225,12,19,265,7,9,11,13,15,17,1929,43,5729-35,43-49,57-6329-30,43-44,57-58YesYesYesYesNONOCourseIIPVA+LCATPredVcRDoxL-Asp（美国）CTX6-TGAra-C45mg/m2/d1.5mg/m2/iv30mg/m2/2h10000u/m2（日本X0.7）1000mg/m2/2h75mg/m275mg/m2/sc/q12h1-28,taper3+31,8,151,8,151,3,5,7,9,11,2929-3529-35YesYesYesCourseMMTX*CFMTX/ITAra-C/ITDX/IT6-TG3000mg/m2/12h12mg/m/36h,q6hx4iv12.5mg/m2(Max12,5mg)30mg/m2(Max50mg)2.5mg,5mg(3y)75mg/m21,151,151,151,151-7,15-21NONOYesYesYesYesCourseII*PVA+LCATDXVcRDoxL-Asp（美国）CTX6-TGAra-C10mg/m2/d1.5mg/m2/iv30mg/m2/2h10000u/m2（日本X0.7）1000mg/m2/2h75mg/m275mg/m2/sc/q12h1-14,taper3+31,8,151,8,151,3,5,7,9,11,2929-3529-35NOYesYesCourseMMTX*CFMTX/ITAra-C/ITDX/IT6-TG3000mg/m2/12h12mg/m/36h,q6hx4iv12.5mg/m2(Max12,5mg)30mg/m2(Max50mg)2.5mg,5mg(3y)75mg/m21,151,151,151,151-7,15-212-NONOYesCourseCAra-CVP-16300mg/m2/2h200mg/m2/2h1,4,71,4,7Yes104WYes112WYes112WMaintenanceMTX*6-TG*VcRPred20mg/m2/w/po50mg/m2/d1.5mg/m2/q4w45mg/m2/7d/q4wIT*MTXAra-CDX12.5mg/m2(Max12,5mg)30mg/m2(Max50mg)2.5mg,5mg(3y)Qwx4(R1)Qwx6(R2)Qwx8(R3)