儿童非霍奇金淋巴瘤诊疗建议.pptx

儿童非霍奇金淋巴瘤诊疗建议（儿童非霍奇金淋巴瘤诊疗建议（20042004讨论稿）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 背背 景景 n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。n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。n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 Protocol ReviewNHL-BFM90 Report(T-LBL)NHL-BFM90 Report(T-LBL)Blood,2000,95(2):416Blood,2000,95(2):416n0-180-18y,T-cell,F:M 24:81.y,T-cell,F:M 24:81.n106 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.nProtocol:Protocol:nALL-like protocol.ALL-like protocol.nInduction:CTX 1g/m,d36,64.Re-in d36Induction:CTX 1g/m,d36,64.Re-in d36nHDMTX 5.0g/m/24h X 4.HDMTX 5.0g/m/24h X 4.nAsp X 2Asp X 2（10000/M x 810000/M x 8，x4x4）nCRTCRT：1200 cGy for III/IV1200 cGy for III/IVnTotal CTX 3g,Adr 240mg/m.Total CTX 3g,Adr 240mg/m.nTotal therapy 2 y.Total therapy 2 y.nResultn5y EFS 90%nNo different atnSex,age,Sex,age,nLDH(500),LDH(500),nIII or IV,III or IV,nimmunotyping,immunotyping,nd33 CR or not d33 CR or not POG 8704 Report-T-ALLand T-NHLPOG 8704 Report-T-ALLand T-NHLLeukemia 1999;13:335Leukemia 1999;13:335nT-ALL 357caes,T-NHL(lymphoblastic)195nwhole protocol basicly like ALLnAfter CR:nHigh dose Asp 25000/m/w x 20W from d 99 as consolidationnNo high dose Asp consolidationn4 4y EFS ALL:68%vs 55%y EFS ALL:68%vs 55%NHL:78%vs 64%NHL:78%vs 64%n BFM 90 B-cell ReportBFM 90 B-cell ReportBlood 1999;94:3294Blood 1999;94:3294nObject:Object:nLDH and early response LDH and early response nFor group III and LDH 500,MTX For group III and LDH 500,MTX from 0.5 to 5.0from 0.5 to 5.0n2 cycles for complete resected 2 cycles for complete resected diseasediseasensystemic chemo plus intravencular systemic chemo plus intravencular therapy for CNS positive patienstherapy for CNS positive patiensGroupingGroupingnR1:R1:nCR,CR,nR2:R2:nno-abdomen primary or incompletely resect,no-abdomen primary or incompletely resect,nLDH 500,LDH 500 LDH500 nor multiple bone,BM,CNS involvement,6 cyclesor multiple bone,BM,CNS involvement,6 cyclesnNo-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-90Protocol 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-ABMTnV 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 nA 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%23.5hnB 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 xnAA 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 xn*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%23.5hnBB 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 xnCC 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 ChemoCNS(+)Intraventricularly Chemon 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 d5nCCCC 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-conditioningABMT 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 ConclusionResult and ConclusionnR1:100%,R2:96%,R3 78%.R1:100%,R2:96%,R3 78%.nHDMTX effective in R2 and R3HDMTX effective in R2 and R3nStage III,LDH500u/L,PEFS 81%,Stage III,LDH500u/L,PEFS 81%,control 43%.6y EFS control 43%.6y EFS nABMT(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.nConfirmed the objective 1,2,3,4Confirmed the objective 1,2,3,4nLDH and early response LDH and early response()nFor 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()n2 cycles for complete resected 2 cycles for complete resected disease disease()nsystemic 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),2281-2285n1990-19961990-1996nB-ALL 35,13 with CNS(+)(L325%B-ALL 35,13 with CNS(+)(L325%blasts)blasts)nStage IV B-NHL 28,22 with CNS(+)Stage IV B-NHL 28,22 with CNS(+)n9003 based on LMB 869003 based on LMB 86nCNS+,24Gy in 15 fractionCNS+,24Gy in 15 fraction9003 9003 ProtocolProtocolnCOP(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 d1,3,5nCOPADM1COPADM1 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 d1,3,5nCOPADM2:COPADM2:Same as COPADM1,but Same as COPADM1,but VCR d1,6 VCR d1,6 CTX1.0g/m d2,3,4 CTX1.0g/m d2,3,4nCYVE*(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 d1-4nCOPADM3COPADM3 Same as COPADM1,but:Same as COPADM1,but:CTX 500mg/m/d d2,3 CTX 500mg/m/d d2,3 IT d1 IT d1nCYVE#(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 d2-4nCOPAD:COPAD:Same as COPADM3,but no HDMTX Same as COPADM3,but no HDMTXn10 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.n2 No-CR,all of the 12 died.2 No-CR,all of the 12 died.n7(11%)died of toxicity7(11%)died of toxicity(septic 5,(septic 5,septic+renal failure 2).septic+renal failure 2).n43(69%)EFS average 3.1y.43(69%)EFS average 3.1y.nHD-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):3591nALCL-Malignant histocytosisALCL-Malignant histocytosisn80-90%T-cell,a few as B-cell80-90%T-cell,a few as B-cellnt(2;5),NPM/ALK(nucleophosmine t(2;5),NPM/ALK(nucleophosmine gene/tyrosine kinase gene)gene/tyrosine kinase gene)n10-15%of all NHL10-15%of all NHLnSt.Jude stage I/II 28%,III/IV 72%St.Jude stage I/II 28%,III/IV 72%n82 cases,total therapy 7m,no I/T82 cases,total therapy 7m,no I/TnB-Cell like protocolB-Cell like protocolnProtocol:Protocol:COP-COPAM x 2-(VEBBP-Sequence 1)x 4 COP-COPAM x 2-(VEBBP-Sequence 1)x 4nNo CNS relapse firstn3y SR83%,EFS 66%nNo risk factor:3y EFS 95%,=1 factor 47%nSt.Jude I/II:3y EFS 94%,III/IV 55%n21 cases relapse within 7-49m(median 10m)nRisk factor;mediastinal mass,visceral involvement,LDH800Treatment Strategy(B-NHL,Large Cell)Group A(I,II)A B CR A B M2 Group B(III,IV)P A B CR A B A B M12 PR C CR A B C M Residual CNS+SL-OP Tumor negative Tumor positive ABMTA 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/m1994.6-2000.61994.6-2000.6明确诊断并决定接受治疗者均明确诊断并决定接受治疗者均列入统计列入统计随访至随访至2000.12.302000.12.30中断联系超过中断联系超过6 6个月列为失访个月列为失访Resultsn4/52 gave up treatment within 30 daysn44/48(91%)CRn5/48 lost following-up at CR n5/48 relapsed and 4 died(85%Ki-67+85%。n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+/-n 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+n分子生物学检查分子生物学检查nBurkittBurkitts 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）。）。n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）n骨髓涂片骨髓涂片n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型型超声或超声或CTCT、MRIMRI）n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。n选择性全身骨扫描选择性全身骨扫描治疗治疗n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n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。n手术：手术主要用于下列情况：手术：手术主要用于下列情况：n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疫分型时积极考虑活检术分型时积极考虑活检术n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。n急腹症急腹症n二次活检二次活检n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采用手术治疗，但复发进展率很高。用手术治疗，但复发进展率很高。急诊处理：急诊处理：n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 n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 n肿瘤细胞溶解综合症肿瘤细胞溶解综合症 B-NHLB-NHL（成熟成熟B-ALLB-ALL）n适应症适应症:n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。n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）n各脏器功能基本正常。各脏器功能基本正常。n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。分组及治疗计划分组及治疗计划n分组分组nR1R1组组 化疗前已完全缓解，化疗前已完全缓解，LDHLDH正常。正常。nR2R2组组 LDHLDH小于正常小于正常2 2倍的倍的I,III,II期，包括孤立期，包括孤立 性骨病灶。性骨病灶。nR3R3组组 III,IVIII,IV期，或期，或LDHLDH大于正常大于正常2 2倍。倍。nR4R4组组 2 2个疗程未获完全缓解者。个疗程未获完全缓解者。R4R4T-NHLT-NHL（淋巴母细胞型）淋巴母细胞型）n适应症适应症:n未治未治T-T-细胞性细胞性NHLNHL（或病理形态为淋巴母细胞型或病理形态为淋巴母细胞型NHLNHL）.n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，无无器器官官移植史，非第二肿瘤移植史，非第二肿瘤.n分组分组nR1R1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。nR2R2组组 I I期，期，LDHLDH大于正常值大于正常值2 2倍。倍。IIII期及孤立性骨病灶。期及孤立性骨病灶。nR3R3组组 III,IVIII,IV期。期。图图2-2-T-NHLT-NHL治疗计划治疗计划T-NHL化疗方案及剂量表化疗方案及剂量表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)