成人急性淋巴细胞白血病的治疗课件

成人急性淋巴细胞白血病的治疗 ALL化学治疗 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 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 Remission Induction Regimens And Postremission Therapy for ALL 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 28 71:123, 1988 Ara-c, 6-MP Ara-C, TG Blood 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 BCNU Blood 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-C Blood 197 V, P, A, D, Cy Cy, Ara-c, 6-MP, V 6-MP, MTX MTX, XRT 85 36 85:78:2814, 1995 A, Dox, Dex, TG V, P Blood 128 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 LFS Studies with 500 patients GMALL 02/84 1993 562 28 V,P,A,D,C,AC,M,MP V,DX,AD,AC,C,TG,VM MP,M 75% 39%at7y FGTALL 1993 581 33 V,P,D/R,C AD,AC AD,AC,A MP,M,V,C,P,AD,AC 76% 30%at10y MRC-UKALL XA 3 1997 618 15 V,P,A,D AC,VP,D,TG MP,M,V,P 82% 28% at5y MRC/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,Mi GIMEMA 0288 6 2002 794 28 V,P,A,D,C,HDAC,Mi V,HDM,HDAC,DX,VM MP,M,V,AC,Mi,VM, 82% 29% at9y HDAC ,HDM,DX Total 4638 82% 31% (%=weighted mean) Results of adult acute lymphoblastic leukemia (ALL) studies(1) Dieter Hoelzer,et al,Hematology,2002 164-191 Results of adult acute lymphoblastic leukemia (ALL) studies(2) Group Year n (pts) Age* Induction Consolidation Maintenance CR LFS Recent Studies with 100 patients Pethema 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,AC CALGB 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% at3y Sweden 9 1999 120 44 HDAC,C,D,V,BX AD,HDAC,V,BX,C,D, n.r. 85% 36% at3y VP SCT MDACC 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 SCT Netherlands 12 2001 193 33 Standard HDAC, VP16 + allo/auto SC 82% 35% at 5y Total 944 86% 38% (%=weighted mean) Dieter Hoelzer,et al,Hematology,2002 164-191 Cancer and Leukemia Group B (CALGB) Study 8811 (1) Course I: Induction (4 wk) CTXIV1200 mg/m2Day 1 DNRIV45 mg/m2Days 1, 2, 3 VCRIV2 mgDays 1, 8, 15, 22 PredPO60 mg/m2Days 1-21 L-AspSC6000 IU/m2Days 5, 8, 11, 15, 18, 22 For patients 60 yr old CTX800mg/m2Days 1 DNR30mg/m2Days 1, 2, 3 Pred60mg/m2Days 1-7 Larson RA, et al, Blood, 85:2025-2037 CALGB 8811 （2） Course II: Early intensification (4 wk, repeat once) MTXIT15 mgDay 1 CTXIV1000 mg/m2Day 1 6-MPPO60 mg/m2/dDays 1-14 Ara-CSC75 mg/m2/dDays 1-4, 8-11 VCRIV2 mgDays 15, 22 L-AspSC6000 IU/m2Days 15, 18, 22, 25 Course III: CNS prophylaxis and interim maintenance (12 wk) Cranial irradiation2400 cGyDays 1-12 MTXIT15 mgDays 1, 8, 15, 22, 29 6-MPPO60 mg/m2/dDays 1-70 MTXPO20 mg/m2Days 36, 43, 50, 57, 64 CALGB 8811 (3) Course IV: Late intensification (8 wk) ADRIV30 mg/m2Days 1, 8, 15 VCRIV2 mgDays 1, 8, 15 DEXPO10 mg/m2/dDays 1-14 CTXIV1000 mg/m2/dDay 29 6-TGPO60 mg/m2/dDays 29-42 Ara-CSC75 mg/m2/dDays 29-32, 36-39 Course V: Prolonged maintenance (until 24 mo from diagnosis) VCRIV2 mgDay 1 of every 4 wk PredPO60 mg/m2/dDays 1-5 of every 4 wk MTXPO20 mg/m2Days 1, 8, 15, 22 6-MPPO60 mg/m2/dDays 1-28 CALGB 8811 (4) Results of Therapy Patients214 Patients eligible197 Induction 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% 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 45 Age (yr) 30 87 (44) 82 (94) 0.01 36 0.51 (0.38-0.63) 0.21 42 0.69 (0.57-0.68) 0.01 30-59 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) Leucocytes 30,000 130 (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) FAB L1 71 (37) 64 (90) 0.35 38 0.54 (0.39-0.68) 0.16 44 0.63 (0.50-0.74) 0.03 L2 87 (46) 73 (84) 26 0.46 (0.33-0.59) 25 0.45 (0.34-0.57) L3 8 (4) 6 (75) 3 0.17 (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 (0.25-0.49) 0.004 T 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 0.38 (0.28-0.50) 0.001 T+TMy 39 (28) 38 (97) 32 0.63 (0.44-0.78) 40 0.69 (0.51-0.82) Cytogenetics and Molecular Ph+ or BCR-ABL+ 30 21 (70) 0.11 7 0.11 (0.04-0.28) 11 0.16 (0.07-0.32) 0.001 Negative 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 (0.51-0.86) 40 0.62 (0.44-0.78) Treatment Results in Adult Burkitt-type L3 ALL Reference N Induction Continuation CR (%) LFS (%) SFOP 17 C, V, P, Dox V, P 76 58 Baillieres Clin Oncol MTX 3-8g MTX 8g 7:339, 1994 CTX 0.5-1g Ara-C 3g MDACC 13 V, Dox, Dex MTX 1g 85 46 Proc ASCO,14:339,1995 Ara-C 1.8g Ara-C 3g GMALL 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 1.5g CALGB 24 V, Ifo, VP, Ara-C C, V, Dox, Ara-C 75 66 Proc ASCO,16:24a,1997 Dex, MTX 1.5g MTX 1.5g ABAABBP CNS Irrd 204681012141618weeks B-NHL-86 protocol for B-cell ALL Treatment of B-cell ALL B-NHL 86 protocol Pretreatment 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 disturbance Cycle 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 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, 1996 Cycle B Given 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, 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 5 CNS 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 irradiation Risk Groups in precursor-B and T-lineage ALL Good 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 weeks Intermediate Risk: ALL with prognosis features of neither good nor poor risk group Poor 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ALL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 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 Median Study Therapy N CR(%) CR / Survival (mos) A. Vincristine-steroid-anthracyclines Cancer Treat Rep, 63:1413,1979 V, Dox, Pred 10 40 7 / - J Clin Oncol, 8:994, 1990 V, Dox, Dex 64 39 6.5 / 5.3 Leukemia, 11:2039, 1997 V, Dox, Dex, CTX 66 44 12 / 8 Br J Hematol, 97:86, 1997 V, IDA, Pred, BMT 61 56 2 / - B. MTX-ASP Cancer, 43:1089, 1979 Asp, MTX 12 33 7 / - Blood, 59:334, 1982 MTX, V, Asp, Dex 14 79 7.5 / 11.2 Am J Hematol, 4:173, 1978 V, P, Dox, Asp 23 69 4 / 7 Cancer 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 Median Study Therapy N CR(%) CR / Survival (mos) C. High-dose Ara-C (HDAC) Am J Med, 81:387, 1986 HDAC 21 38 2 / 3.5 Leukemia, 4:637, 1990 Mito + HDAC 24 50 3.5 / - Cancer, 65:5, 1990 Mito + HDAC 21 38 2 / 3.5 Blood, 72:433, 1988 Amsa + HDAC 40 72 4 / - Cancer, 72:2155, 1993 Flud + HDAC 30 30 5.5 / 3 Leuk Lymph, 25:579, 1997 Flud + Ara-C + G-CSF 12 83 - / - Proc ASCO, 6:147, 1987 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。 5 1.1 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，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 Study N DFS with allogeneic HSCT (%) DFS with autograft or chemo (%) P Value Hovon18(56) 124 53 36 0.05 UKALL (Ph-)(57) 434 54 34 0.04 UKALL (Ph+)(58) 148 41 a 27 a 0.5 LALA87(9) 257 46 a 31 a 0.04 IBMTR(59) 719 34 32 NS Japanese Study(60) 290 53 b 30 b 0.02 BGMT 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 remission IBMTR19911997资料显示CR2移植病人的DFS 是 42%。 K. Wheeler等研究表明 Allo- HSCT 5年DFS增加了14% (from 26.4% to 40.7%) K. Wheeler, etal, Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia. Br. J. Haematol. 101 (1998), pp. 94103. 1.3 ALL in primary induction failure or second relapse 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 AL