兒童非霍奇金淋巴瘤診療建議培訓(xùn)課件

1、兒童非霍奇金淋巴瘤診療建議兒童非霍奇金淋巴瘤診療建議 背 景 王耀平教授執(zhí)筆了第一個(gè)兒童淋巴瘤診療建議，至今已10年余。 國際上兒童淋巴瘤的總體的5年無病生存率已達(dá)70%以上。我國仍相對(duì)落后，診斷和治療水平相差較大。 兒童非霍奇金淋巴瘤診療建議2 背 景 王耀平教授執(zhí)筆了第一個(gè)兒童淋巴瘤診療建議，至今已1NHL Protocol Review兒童非霍奇金淋巴瘤診療建議3NHL Protocol Review兒童非霍奇金淋巴瘤診療NHL-BFM90 Report (T-LBL)Blood ,2000,95(2):4160-18y, T-cell, F:M 24:81.106 patients,

2、I:2, II:2, III:82, IV:19. BM(+) 15, CNS(+) 3.Protocol:ALL-like protocol.Induction: CTX 1g/m, d36,64.Re-in d36HDMTX 5.0g/m/24h X 4.Asp X 2（10000/M x 8，x4）CRT：1200 cGy for III/IVTotal CTX 3g, Adr 240mg/m.Total therapy 2 y. 兒童非霍奇金淋巴瘤診療建議4NHL-BFM90 Report (T-LBL)Blood Result5y EFS 90%No different atSex,

3、 age,LDH(500), III or IV,immunotyping, d33 CR or not 兒童非霍奇金淋巴瘤診療建議5 兒童非霍奇金淋巴瘤診療建議5POG 8704 Report-T-ALLand T-NHLLeukemia 1999;13:335T-ALL 357caes, T-NHL(lymphoblastic) 195whole protocol basicly like ALLAfter CR:High dose Asp 25000/m/w x 20W from d 99 as consolidationNo high dose Asp consolidation兒童非

4、霍奇金淋巴瘤診療建議6POG 8704 Report-T-ALLand T-NH4y EFS ALL: 68% vs 55% NHL: 78% vs 64%兒童非霍奇金淋巴瘤診療建議74y EFS ALL: 68% vs 55%兒童非霍奇金淋BFM 90 B-cell ReportBlood 1999;94:3294Object:LDH and early response For group III and LDH 500 , MTX from 0.5 to 5.02 cycles for complete resected diseasesystemic chemo plus intrav

5、encular therapy for CNS positive patiens兒童非霍奇金淋巴瘤診療建議8BFM 90 B-cell ReportBlood 199GroupingR1: CR, R2: no-abdomen primary or incompletely resect, LDH 500 or multiple bone,BM,CNS involvement,6 cyclesNo-CR after 2 cycles: HDAra-c+Vp-16 for 2 cycles If CR, plus another 3 cycles 兒童非霍奇金淋巴瘤診療建議9GroupingR1

6、: 兒童非霍奇金淋巴瘤診療建議9Protocol 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-ABMT兒童非霍奇金淋巴瘤診療建議10Protocol B-Cell-BFM-90 R1 VV 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 兒童非霍奇金淋巴瘤診療建議11兒童非霍奇金淋巴瘤診療建議11A 1 2 3 4 5 DX 10mg/

7、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%23.5h兒童非霍奇金淋巴瘤診療建議12A B 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 x兒童非霍奇金淋巴瘤診療建議13B AA 1 2 3 4 5 Dx 10mg

8、/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 x兒童非霍奇金淋巴瘤診療建議14AA * CF 30mg 42,48h, q6h ajusted as follows: 1-2umol/L 30mg/m 2-3umol/L 45mg/m 3-4umol/L 60mg/m 4-5umol/l 75mg/m 5umol/L: CFmg=MTXumol/L/kg MTX 10%30, 90%23.5h兒童

9、非霍奇金淋巴瘤診療建議15* CF 30mg 42,48h, q6h ajusteBB 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 x兒童非霍奇金淋巴瘤診療建議16BB兒童非霍奇金淋巴瘤診療建議16CC 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 兒童非霍奇金淋巴瘤診療建議17CC兒童非霍奇金淋巴瘤診療建議

10、17CNS(+) Intraventricularly Chemo AA and BB MTX 3mg, Pred 2.5mg d1,2,3,4 Ara-C 30mg d5CC MTX 3mg, Pred 2.5mg d3,4,5,6 Ara-C 30mg d7兒童非霍奇金淋巴瘤診療建議18CNS(+) Intraventricularly ChemABMT 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

11、 transfusion !* Divided p.o# If CNS(+) thiotepa 300mg/m/d x 3 replace of CTX兒童非霍奇金淋巴瘤診療建議19ABMT Pre-conditioning Result and ConclusionR1:100%, R2: 96%, R3 78%.HDMTX effective in R2 and R3Stage III, LDH500u/L, PEFS 81%, control 43%. 6y EFS ABMT(residual after 3 cycles) effective, 5/6 survived, contro

12、l: 4/5 progress. 兒童非霍奇金淋巴瘤診療建議20Result and ConclusionR1:100%, Confirmed the objective 1,2,3,4LDH and early response ()For group III and LDH 500 , MTX from 0.5 to 5.0 ()2 cycles for complete resected disease ()systemic chemo plus intravencular therapy for CNS positive patiens ()兒童非霍奇金淋巴瘤診療建議21Confirm

13、ed the objective 1,2,3,Improved Cure rate on Children with B-cell ALL and Stage IV B-cell NHL-Result of the UKCCSG 9003 Protocol British J of cancer 1998,77(12),2281-22851990-1996B-ALL 35, 13 with CNS(+)(L325% blasts)Stage IV B-NHL 28, 22 with CNS(+)9003 based on LMB 86CNS+, 24Gy in 15 fraction兒童非霍奇

14、金淋巴瘤診療建議22Improved Cure rate on Children9003 ProtocolCOP(1)-COPADM1(2)-COPADM2(5)- CYVE*(8)-CYVE*(11)-COPADM3(14)- -CYVE#(17)- COPAD(20)-CYVE#(23)COP: CTX 300mg/m d1 VCR 1mg/m d1 Pred 60mg/m d1-7 IT d1,3,5兒童非霍奇金淋巴瘤診療建議239003 ProtocolCOP(1)-COPADM1(2COPADM1 VCR 2mg/m d1 Adr 60mg/m/6h d2 CTX 500mg/m d

15、2,3,4 HDMTX 8g/m/3h d1, CF 15mg/m Pred 60mg/m d1-5 IT d1,3,5兒童非霍奇金淋巴瘤診療建議24COPADM1兒童非霍奇金淋巴瘤診療建議24COPADM2: Same as COPADM1,but VCR d1,6 CTX1.0g/m d2,3,4CYVE*(HDAra-C): Ara-C 50/m/over 12h d1-5 Ara-C 3.0g/m/over 3h d1-4 VP-16 200mg/m/over 2h d1-4兒童非霍奇金淋巴瘤診療建議25COPADM2:兒童非霍奇金淋巴瘤診療建議25COPADM3 Same as CO

16、PADM1, but: CTX 500mg/m/d d2,3 IT d1CYVE#(low dose) Ara-C 50mg/m/q12h,d1-5 VP-16 150mg/m d2-4COPAD: Same as COPADM3, but no HDMTX兒童非霍奇金淋巴瘤診療建議26COPADM3兒童非霍奇金淋巴瘤診療建議2610 relapse(16%),CNS 2, BM 2, CNS+BM 3, Jaw 1, within 11m after Dx.2 No-CR, all of the 12 died.7(11%) died of toxicity (septic 5, septi

17、c + renal failure 2).43(69%) EFS average 3.1y.HD-Ara-C possibly play key role兒童非霍奇金淋巴瘤診療建議2710 relapse(16%),CNS 2, BM 2, CCD 30 + Anaplastic large cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the french society of pediatric Oncology Blood 1998;92(10):3591

18、ALCL- Malignant histocytosis80-90% T-cell, a few as B-cellt(2;5), NPM/ALK(nucleophosmine gene/tyrosine kinase gene)10-15% of all NHLSt.Jude stage I/II 28%, III/IV 72%82 cases , total therapy 7m, no I/TB-Cell like protocol兒童非霍奇金淋巴瘤診療建議28CD 30 + Anaplastic large cell Protocol: COP-COPAM x 2-(VEBBP-Seq

19、uence 1) x 4兒童非霍奇金淋巴瘤診療建議29Protocol: 兒童非霍奇金淋巴瘤診療建議29No CNS relapse first3y SR83%, EFS 66%No risk factor: 3y EFS 95%, =1 factor 47%St.Jude I/II: 3y EFS 94%, III/IV 55%21 cases relapse within 7-49m(median 10m)Risk factor; mediastinal mass,visceral involvement,LDH800兒童非霍奇金淋巴瘤診療建議30No CNS relapse first兒

20、童非霍奇金淋巴瘤兒童非霍奇金淋巴瘤診療建議31兒童非霍奇金淋巴瘤診療建議31Treatment 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 ABMT兒童非霍奇金淋巴瘤診療建議32兒童非霍奇金淋巴瘤診療建議32A CTX 800mg/m2/d1, 200mg/m2/d2,3,4 VcR 2mg/m2/d1,8,15

21、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

22、/m/d1,2,3,4,5CTX in total: 12.45g/mIfos in total : 18g/mAdr in total : 245mg/m兒童非霍奇金淋巴瘤診療建議33AM兒童非霍奇金淋巴瘤診療建議331994.6-2000.6明確診斷并決定接受治療者均列入統(tǒng)計(jì)隨訪至2000.12.30中斷聯(lián)系超過6個(gè)月列為失訪兒童非霍奇金淋巴瘤診療建議341994.6-2000.6明確診斷并決定接受治療者均列入統(tǒng)計(jì)Results4/52 gave up treatment within 30 days44/48 (91%) CR5/48 lost following-up at CR 5/

23、48 relapsed and 4 died( 85%。間變型大細(xì)胞性淋巴瘤常用標(biāo)記：CD30 +，EMA +/-，ALK +/- 淋巴母細(xì)胞型淋巴瘤（LB）常用標(biāo)記T-LB：B-LB：TdT +TdT +CD1a +/- CD10 +/-CD3 +/-CD19 +CD7 +CD79a +兒童非霍奇金淋巴瘤診療建議45免疫分型T-LB：B-LB：TdT +TdT +CD1a分子生物學(xué)檢查Burkitts淋巴瘤常見t（2；8），t（8；14）或t（8；22）。間變型大細(xì)胞性淋巴瘤常見有t（2；5），ALK/NPM融合。兒童非霍奇金淋巴瘤診療建議46分子生物學(xué)檢查兒童非霍奇金淋巴瘤診療建議46疾病

24、分期檢查 （分期標(biāo)準(zhǔn) 建議采用St.Jude分期系統(tǒng)）骨髓涂片胸腹影像學(xué)檢查（正側(cè)位胸片、腹部盆腔B型超聲或CT、MRI）腦脊液離心甩片找腫瘤細(xì)胞，必要時(shí)頭顱MRI以除外顱內(nèi)轉(zhuǎn)移。選擇性全身骨掃描兒童非霍奇金淋巴瘤診療建議47疾病分期檢查 （分期標(biāo)準(zhǔn) 建議采用St.Jude分期系統(tǒng)）治療治療手段以化療為主，手術(shù)和放療為輔放療：除中樞浸潤、脊髓腫瘤壓迫癥、化療后局部殘留病灶、姑息性治療等特殊情況外，不推薦放療。手術(shù)：手術(shù)主要用于下列情況： 兒童非霍奇金淋巴瘤診療建議48治療治療手段以化療為主，手術(shù)和放療為輔兒童非霍奇金淋巴瘤診療除手術(shù)活檢外，無其它方法可明確診斷并作免疫分型時(shí)積極考慮活檢術(shù)估計(jì)腫

25、塊不能完全切除時(shí)應(yīng)僅做小切口活檢術(shù)，不推薦腫瘤部分或大部分切除術(shù)。急腹癥二次活檢在落后地區(qū)如無條件化療，對(duì)于局限性疾病可采用手術(shù)治療，但復(fù)發(fā)進(jìn)展率很高。兒童非霍奇金淋巴瘤診療建議49除手術(shù)活檢外，無其它方法可明確診斷并作免疫分型時(shí)積極考慮活檢急診處理： 氣道及上腔靜脈壓迫癥狀氣道及上腔靜脈壓迫癥狀 胸膜腔積液或心包積液時(shí)可引流改善癥狀 腫瘤細(xì)胞溶解綜合癥 兒童非霍奇金淋巴瘤診療建議50急診處理： 氣道及上腔靜脈壓迫癥狀氣道及上腔靜脈壓迫癥狀 兒B-NHL（成熟B-ALL）適應(yīng)癥:未治B細(xì)胞性NHL（無條件作免疫分型時(shí)病理形態(tài)為Burkitts型NHL）、或病理形態(tài)為大細(xì)胞型。未治成熟B-ALL

26、（即骨髓中大于30%腫瘤細(xì)胞表達(dá)SIgM或/和輕鏈，或腫瘤細(xì)胞有t（8；14）、t（8；22），t（8；2）各臟器功能基本正常。無先天性免疫缺陷病，無器官移植史，非第二腫瘤。 兒童非霍奇金淋巴瘤診療建議51B-NHL（成熟B-ALL）適應(yīng)癥:兒童非霍奇金淋巴瘤診療建分組及治療計(jì)劃分組R1組 化療前已完全緩解，LDH正常。R2組 LDH小于正常2倍的I, II期，包括孤立 性骨病灶。R3組 III,IV期，或LDH大于正常2倍。R4組 2個(gè)療程未獲完全緩解者。兒童非霍奇金淋巴瘤診療建議52分組及治療計(jì)劃分組兒童非霍奇金淋巴瘤診療建議52R4兒童非霍奇金淋巴瘤診療建議53R4兒童非霍奇金淋巴瘤診療

27、建議53兒童非霍奇金淋巴瘤診療建議54兒童非霍奇金淋巴瘤診療建議54T-NHL（淋巴母細(xì)胞型）適應(yīng)癥:未治T-細(xì)胞性NHL（或病理形態(tài)為淋巴母細(xì)胞型NHL）.各臟器功能基本正常。無先天性免疫缺陷病，無器官移植史，非第二腫瘤.分組R1組 完全緩解（即手術(shù)已完全切除腫塊）、I期，LDH小于正常值2倍。R2組 I期，LDH大于正常值2倍。II期及孤立性骨病灶。R3組 III, IV期。兒童非霍奇金淋巴瘤診療建議55T-NHL（淋巴母細(xì)胞型）適應(yīng)癥:兒童非霍奇金淋巴瘤診療建議圖2-T-NHL治療計(jì)劃兒童非霍奇金淋巴瘤診療建議56兒童非霍奇金淋巴瘤診療建議56 T-NHL化療方案及劑量表R1R2R3日期

28、DrugDoseDayNONONONOYesYesCourse IPVA+LCATPredVcRDoxL-Asp（美國）CTX6-TGAra-C45mg/m2/d1.5mg/m2/iv30mg/m2/2h10000u/m2（日本X 0.7）750mg/m2/2h75mg/m22000mg/m2/2h/q12h1-28, taper 3+31,8,15,225,12,19,265,7,9,11,13,15,17,1929,43,5729-35,43-49,57-6329-30,43-44,57-58YesYesYesYesNONOCourse IIPVA+LCATPredVcRDoxL-Asp（美國）CTX6-TGAra-C45mg/m2/d1.5mg/m2/iv30mg/m2/2h10000u/m2（日本X 0.7）