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1、成人急性淋巴细胞白血病的治疗ALL化学治疗诱导治疗诱导治疗自发缓解VCR + Pred（VP）诱导， CR 36 67%VCR + DNR + Pred （VDP）诱导，CR 70 85%VCR + DNR + L-Asp + Pred （VDLP） 缓解期延长VCR + DNR + CTX + Pred （VDCP）缓解后治疗缓解后治疗T-ALL ：大剂量CTX冲击 + Ara-C成熟B-ALL：短疗程诱导及强化治疗中枢系统白血病的预防及治疗中枢系统白血病的预防及治疗Remission Induction Regimens And Postremission Therapy for ALL
2、No. of CNS Survival Reference patients Induction Consolidation Maintenance Prophylaxis CR% Med(mo) Blood 368 V, P, D, Cy, Dex, V, Dox, Cy 6-MP, MTX MTX, XRT 74 2871:123, 1988 Ara-c, 6-MP Ara-C, TGBlood 168 V, P, Dox, Cy Ara-C, MTX, TG V, P, Dox, 6-MP MTX 68 18 73:87, 1989 V, P, A, Cy MTX, ActD, Cy B
3、CNUBlood 109 V, P, A, D V, P, A, D 6-MP, MTX MTX, XRT 88 28 78:2814, 1991 Ara-c, VM26, MTX Leukemia 541 V, P, D, A V, P, Mito; 6-MP, MTX MTX 80 NR 6:182, 1992 Cy V, Dex, MTX; VM26, Ara-CBlood 197 V, P, A, D, Cy Cy, Ara-c, 6-MP, V 6-MP, MTX MTX, XRT 85 3685:78:2814, 1995 A, Dox, Dex, TG V, P Blood 12
4、8 Cy, V, Dox, Dex MTX, Ara-C 6-MP, MTX, V, P MTX, Ara-C 91 36 86:173a, 1995 Group Year n (pts) Age* Induction Consolidation Maintenance CR LFSStudies with 500 patientsGMALL 02/84 1993 562 28 V,P,A,D,C,AC,M,MP V,DX,AD,AC,C,TG,VM MP,M 75% 39%at7yFGTALL 1993 581 33 V,P,D/R,C AD,AC AD,AC,A MP,M,V,C,P,AD
5、,AC 76% 30%at10yMRC-UKALL XA 3 1997 618 15 V,P,A,D AC,VP,D,TG MP,M,V,P 82% 28% at5yMRC/ECOG 4 1999 920 V,P,D,A,C,AC,MP HDM,A AC,VP,V,DX, MP,M,V,P 89% D, C,TG SCT GMALL 05/93 5 2001 1163 35 V,P,A,D,C,AC,M,MP V,DX,AD,AC,C,TG,VM, MP,M 83% AC, HDM, A, CHDAC,MiGIMEMA 0288 6 2002 794 28 V,P,A,D,C,HDAC,Mi
6、V,HDM,HDAC,DX,VM MP,M,V,AC,Mi,VM, 82% 29% at9y HDAC ,HDM,DXTotal 4638 82% 31% (%=weighted mean) Results of adult acute lymphoblastic leukemia (ALL) studies(1)Dieter Hoelzer,et al,Hematology,2002 164-191Results of adult acute lymphoblastic leukemia (ALL) studies(2)Group Year n (pts) Age* Induction Co
7、nsolidation Maintenance CR LFSRecent Studies with 100 patientsPethema ALL-93 7 1998 108 28 V,P,D,A,C HDM,V,D,P,A,C,VM,AC MP,M V, P, Mi, 86% 41% at4y A, C, VM,ACCALGB 8 1998 198 35 V,P,D,A,C C,MP,AC,V,A,M,AD,DX,TG,P MP,M,V,P 85% 36% at3ySweden 9 1999 120 44 HDAC,C,D,V,BX AD,HDAC,V,BX,C,D, n.r. 85% 36
8、% at3y VP SCTMDACC 10 2000 204 39 V,AD,DX,C HDM,HDAC,C,P MP,M,V,P 91% 38% at 5y Lombardia 11 2001 121 35 I,V,A,P,C I,V,C,VM,HDAC,HDM, MP,M 84% 49% at3y DX SCTNetherlands 12 2001 193 33 Standard HDAC, VP16 + allo/auto SC 82% 35% at 5yTotal 944 86% 38%(%=weighted mean)Dieter Hoelzer,et al,Hematology,2
9、002 164-191Cancer and Leukemia Group B (CALGB) Study 8811 (1)Course I: Induction (4 wk)CTXIV1200 mg/m2Day 1DNRIV45 mg/m2Days 1, 2, 3VCRIV2 mgDays 1, 8, 15, 22PredPO60 mg/m2Days 1-21L-AspSC6000 IU/m2Days 5, 8, 11, 15, 18, 22For patients 60 yr oldCTX800mg/m2Days 1DNR30mg/m2Days 1, 2, 3Pred60mg/m2Days
10、1-7Larson RA, et al, Blood, 85:2025-2037CALGB 8811 （2）Course II: Early intensification (4 wk, repeat once)MTXIT15 mgDay 1CTXIV1000 mg/m2Day 16-MPPO60 mg/m2/dDays 1-14Ara-CSC75 mg/m2/dDays 1-4, 8-11VCRIV2 mgDays 15, 22L-AspSC6000 IU/m2Days 15, 18, 22, 25Course III: CNS prophylaxis and interim mainten
11、ance (12 wk)Cranial irradiation2400 cGyDays 1-12MTXIT15 mgDays 1, 8, 15, 22, 296-MPPO60 mg/m2/dDays 1-70MTXPO20 mg/m2Days 36, 43, 50, 57, 64 CALGB 8811 (3)Course IV: Late intensification (8 wk)ADRIV30 mg/m2Days 1, 8, 15VCRIV2 mgDays 1, 8, 15DEXPO10 mg/m2/dDays 1-14CTXIV1000 mg/m2/dDay 296-TGPO60 mg/
12、m2/dDays 29-42Ara-CSC75 mg/m2/dDays 29-32, 36-39Course V: Prolonged maintenance (until 24 mo from diagnosis)VCRIV2 mgDay 1 of every 4 wkPredPO60 mg/m2/dDays 1-5 of every 4 wkMTXPO20 mg/m2Days 1, 8, 15, 226-MPPO60 mg/m2/dDays 1-28CALGB 8811 (4)Results of TherapyPatients214Patients eligible197Inductio
13、n death17 (9%)Refractory disease13 (7%)CR167 (85%) Died in remission10 (6%) Censored for BMT in 1st CR5 (3%) Relapsed77 (46%) CCR75 (45%) CALGB 8811 (5) Results of therapy Remission Duration Survival CR Median Probability of CCR Median Probability of Survival Variable n (%) n (%) p (mo) at 3 yr (95%
14、 CI) p (mo) at 3 yr (95%) p Total 197 165 (85) 29 0.46 (0.37-0.55) 36 0.50 (0.42-0.50)CR 167 45Age (yr)30 87 (44) 82 (94) 0.01 36 0.51 (0.38-0.63) 0.21 42 0.69 (0.57-0.68) 0.0130-59 92 (47) 78 (85) 25 0.43 (0.39-0.57) 25 0.39 (0.28-0.51)60 18 (9) 7 (39) 12 0.43 (0.16-0.75) 1 0.17 (0.06-0.39)Leucocyt
15、es30,000 130 (66) 115 (88) 0.06 37 0.51 (0.40-0.62) 0.05 44 0.59 (0.49-0.68) 0.001 30,000 66 (34) 51 (77) 19 0.36 (0.22-0.53) 19 0.34 (0.23-0.47)FABL1 71 (37) 64 (90) 0.35 38 0.54 (0.39-0.68) 0.16 44 0.63 (0.50-0.74) 0.03L2 87 (46) 73 (84) 26 0.46 (0.33-0.59) 25 0.45 (0.34-0.57)L3 8 (4) 6 (75) 3 0.1
16、7 (0.03-0.56) 6 0.38 (0.11-0.74) CALGB 8811 (6)Results of therapy Remission Duration Survival CR Median Probability of CCR Median Probability of Survival Variable n (%) n (%) p (mo) at 3 yr (95% CI) p (mo) at 3 yr (95%) p Immunophenotypes B 67 (48) 55 (82) 0.02 25 0.42 (0.27-0.58) 0.14 19 0.36 (0.25
17、-0.49) 0.004T 31 (22) 31 (100) 28 0.57 (0.37-0.76) 40 0.67 (0.47-0.82) BMy 19 (14) 14 (74) 27 0.38 (0.18-0.64) 27 0.47 (0.26-0.69)TMy 8 (6) 7 (88) 40 0.86 (0.49-0.97) 40 0.75 (0.41-0.93)Other 15 (11) 13 (87) 31 0.53 (0.28-0.76) 43 0.60 (0.36-0.80)B+BMy 86 (61) 69 (80) 0.01 25 0.41 (0.28-0.55) 21 0.3
18、8 (0.28-0.50) 0.001T+TMy 39 (28) 38 (97) 32 0.63 (0.44-0.78) 40 0.69 (0.51-0.82)Cytogenetics and MolecularPh+ or BCR-ABL+ 30 21 (70) 0.11 7 0.11 (0.04-0.28) 11 0.16 (0.07-0.32) 0.001Negative by 1 test 83 70 (84) 33 0.56 (0.43-0.69) 44 0.45 (0.45-0.67)Negative by both test 29 25 (86) 40 0.72 (0.51-0.
19、86) 40 0.62 (0.44-0.78) Treatment Results in Adult Burkitt-type L3 ALLReference N Induction Continuation CR (%) LFS (%)SFOP 17 C, V, P, Dox V, P 76 58Baillieres Clin Oncol MTX 3-8g MTX 8g 7:339, 1994 CTX 0.5-1g Ara-C 3gMDACC 13 V, Dox, Dex MTX 1g 85 46Proc ASCO,14:339,1995 Ara-C 1.8g Ara-C 3g GMALL
20、24 C, Ara-C, VM, P C, Ara-C, P 63 50 Blood, 87:495, 1996 MTX 0.5g MTX 0.5g 35 V, Ifo, VM, Ara-C V, C, Ara-C, Dex 74 71 Dex, MTX 1.5g MTX 1.5gCALGB 24 V, Ifo, VP, Ara-C C, V, Dox, Ara-C 75 66Proc ASCO,16:24a,1997 Dex, MTX 1.5g MTX 1.5g ABAABBPCNS Irrd204681012141618weeksB-NHL-86 protocol for B-cell A
21、LLTreatment of B-cell ALLB-NHL 86 protocolPretreatment WBC 25,000 /l, or large tumor mass Pred 60 mg/m2, PO 5 days CTX 200 mg/m2, IV To avoid tumor lysis syndrome and correct possible metabolic disturbanceCycle A Given at week 1, 7, 13 MTX 15 mg, Ara-C 40 mg, Dex 4 mg, IT, day 1 VCR 2 mg , IV, day 1
22、 MTX 1500 mg/m2, 24h INF, day 1 IFO 800 mg/m2, IV, days 1 5, VM26 100 mg/m2, days 4, 5 Ara-C 150 mg/m2/q12h, IV, days 4, 5 Dex 10 mg/m2, PO, days 1 - 5 Hoelzer D, et al, Blood, 87:495, 1996Cycle BGiven at week 4, 10, 16 MTX 15 mg, Ara-C 40 mg, Dex 4 mg, IT, day 1 VCR 2 mg , IV, day 1 MTX 1500 mg/m2,
23、 24h INF, day 1 CTX 200 mg/m2, IV, days 1 5, ADR 25 mg/m2, days 4, 5 Dex 10 mg/m2, PO, days 1 5CNS Prophylaxis and Treatment MTX, Ara-C, Dex triple intrathecal therapy Irradiation 24 Gy, given weeks 5 - 7 without CNS involvement, cranial irradiation with CNS involvement, cranial and spinal irradiati
24、onRisk Groups in precursor-B and T-lineage ALLGood Risk: both B and T-lineage ALL with all of the following features No adverse cytogenetic abnormalities Age 30 years WBC count at presentation 30, 000/L Achieve CR in 4 6 weeksIntermediate Risk: ALL with prognosis features of neither good nor poor ri
25、sk groupPoor Risk: ALL with any of the following prognosis features: Age 60 years Precursor-B with WBC count 30, 000 /l Adverse Cytogenetics - t (9;22), t (4:11), or trisomy 8 Achievment of late CR, 4 - 6 weeks post induction 高危成人高危成人ALL的治疗的治疗t (4; 11) ALL 发生率：儿童ALL 2 5%，婴儿42- 66%，成人 3 6%； 免疫表型：主要为早
26、期B前体细胞（前前B），HLA-DR, CD19, CD22, CD79a 阳性，CD10阴性。59%患者共表达髓系抗原CD15和 CDw65。 临床特点：女性多见（60%），高白细胞，预后差，儿童LES仅为9-19%， 成人缓解期小于1年。 治疗要点：早期强化，Ara-C 3 g/m2, days 1 4, Mito 10 mg/m2, days 2 6； CR1期异基因骨髓移植，两者LFS分别为48%、60%。 t (9; 22) ALL 化疗CR率不低，但缓解期短，应尽早行Allo-BMT Schoch C, et al, Ann hematol, 70:195, 1995 CNS白血病
27、白血病 初诊时CNS白血病发生率 (%) 成人ALL 6 T-cell ALL 8 成熟B-cell ALL 13 CNS白血病复发率 （%） 无预防治疗 30 （29 32） 鞘注化疗 13 （8 19） 颅脑照射 24 Gy 9 （3 19） 大剂量化疗 14 （10 16） 大剂量化疗 + 鞘注 7 （2 16） 大剂量化疗 + 鞘注 + 颅脑照射 6 （1 13）Salvage regimens in relapsed or refractory adult ALL MedianStudy Therapy N CR(%) CR / Survival (mos)A. Vincristin
28、e-steroid-anthracyclinesCancer Treat Rep, 63:1413,1979 V, Dox, Pred 10 40 7 / -J Clin Oncol, 8:994, 1990 V, Dox, Dex 64 39 6.5 / 5.3Leukemia, 11:2039, 1997 V, Dox, Dex, CTX 66 44 12 / 8Br J Hematol, 97:86, 1997 V, IDA, Pred, BMT 61 56 2 / -B. MTX-ASPCancer, 43:1089, 1979 Asp, MTX 12 33 7 / -Blood, 5
29、9:334, 1982 MTX, V, Asp, Dex 14 79 7.5 / 11.2Am J Hematol, 4:173, 1978 V, P, Dox, Asp 23 69 4 / 7Cancer Treat Rep, 65:83, 1981 Asp, MTX 26 58 4 / - Asp, MTX, Ifo 11 55 3.3 / -Salvage Regimens in Relapsed or Refractory adult ALL MedianStudy Therapy N CR(%) CR / Survival (mos) C. High-dose Ara-C (HDAC
30、)Am J Med, 81:387, 1986 HDAC 21 38 2 / 3.5Leukemia, 4:637, 1990 Mito + HDAC 24 50 3.5 / -Cancer, 65:5, 1990 Mito + HDAC 21 38 2 / 3.5Blood, 72:433, 1988 Amsa + HDAC 40 72 4 / -Cancer, 72:2155, 1993 Flud + HDAC 30 30 5.5 / 3Leuk Lymph, 25:579, 1997 Flud + Ara-C + G-CSF 12 83 - / -Proc ASCO, 6:147, 19
31、87 HDAC 16 50 6 / - 成 人 ALL HSCT 治疗 在过去的10年里，成人ALL的治疗取得了显著的进步，较大的多中心研 究中CR率75%-89%,LFS28%-39%。在ALL预后良好亚型的治疗上取得了较 大的进步，如T-ALL或成熟B-ALL,LFS50%。而Ph/BCR-ABL阳性ALL的 LFS20%。预后因素用于危险分层，并根据其亚组分型和复发危险进行 个体化治疗至关重要。HSCT可以使高危或复发或未缓解的病人获得延长的LDF。51.1 ALL in First remission通过衡量移植相关死亡率与单独标准化疗的治愈率，通过衡量移植相关死亡率与单独标准化疗的治
32、愈率，allo-HSCT作为诱导后治疗对标准化疗后的高危复发病人是有利的作为诱导后治疗对标准化疗后的高危复发病人是有利的 Study N DFS with allogeneic HSCT (%) DFS with autograft or chemo (%) P ValueHovon18(56) 124 53 36 0.05UKALL (Ph-)(57) 434 54 34 0.04UKALL (Ph+)(58) 148 41 a 27 a 0.5LALA87(9) 257 46 a 31 a 0.04IBMTR(59) 719 34 32 NSJapanese Study(60) 290 5
33、3 b 30 b 0.02BGMT 120 68 26 0.01 Comparative studies of Allogeneic HSCT in adults (15 yrs.) with ALL in first CR a Overall survival. ， b Age30.1.2 ALL in Second remissionIBMTR19911997资料显示资料显示CR2移植病人的移植病人的DFS 是是 42%。K. WheelerK. Wheeler等研究表明等研究表明 Allo- HSCT 5Allo- HSCT 5年年DFSDFS增加了增加了14% (14% (from 2
34、6.4% from 26.4% to 40.7%)to 40.7%) K. Wheeler, K. Wheeler, etaletal, Comparison of bone marrow transplant and chemotherapy for relapsed , Comparison of bone marrow transplant and chemotherapy for relapsed childhood acutechildhood acute lymphoblastic leukaemia lymphoblastic leukaemia: the MRC UKALL X
35、 experience. Medical Research : the MRC UKALL X experience. Medical Research Council Working Party on ChildhoodCouncil Working Party on Childhood Leukaemia Leukaemia. . Br. J.Br. J. Haematol Haematol. . 101 (1998), pp. 94103. 101 (1998), pp. 94103. 1.3 ALL in primary induction failure or second rela
36、pse初次诱导失败的病人很少被随后的化疗所治愈。HSCT能够治愈其中的10-20% Hoelzer D, et al. Follow-up of the firsttwo successive German multicentre trials for adult ALL (01/81 and 02/84). German Adult ALL Study Group. Leukemia. 1993;7(Suppl 2):S130-4.2. Thiebaut A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study
37、 testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am.2000;14:1353-66第二次复发的成人ALL，Allo-HSCT治疗LFS虽然1015。但是唯一可治愈的方法Durrant IJ, et al. Intensification oftreatment for adults with acute lymphoblastic leukaemia:
38、resultsof U.K. Medical Research council randomized trial UKALLXA. Br J Haematol. 1997;99:84-92.Rowe JM, et al. Allogeneic bone marrow transplantation (BMT) for adults with acute lymphoblasticleukemia (ALL) in first complete remission (CR): Early results from the international ALL trial (MRC UKALL/EC
39、OGE2993). abstract Blood. 1999;94:732a.Gkbuget N, et al. Intensification of induction and consolidation improves only subgroups of adultALL: Analysis of 1200 patients in GMALL study 05/93. abstract Blood. 2001;98:802a.4. Annino L, et al. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of theGIMEMA ALL 0288 randomized study. Blood. 2002;99:863- 871
