贫血的治疗进展课件

1、1 癌性贫血的评估与治疗进展 2 3 NCINCI分级分级 0 0（正常）（正常） 1 1（轻度）（轻度） 2 2（中度）（中度） 3 3（重度）（重度） 4 4（危及（危及 生命）生命） 11.011.0 9.5 - 10.9 9.5 - 10.9 8.0 - 9.4 8.0 - 9.4 6.5 - 7.9 6.5 - 7.9 6.5 6.5 * * WNLWNLwithin normal limitswithin normal limits 14.0-18.0g/dL 14.0-18.0g/dL 12.0-16.0g/dL 12.0-16.0g/dL （女）（女） WHOWHO Groop

2、man JE, Itri LM. J Natl Cancer Inst. 1999;91:1616-1634.Groopman JE, Itri LM. J Natl Cancer Inst. 1999;91:1616-1634. WNL WNL 10.0 - WNL10.0 - WNL 8.0 - 10.0 8.0 - 10.0 6.5 - 6.5 - 7.97.9 6.5 6.5 ECOGECOGSWOGSWOG CALGBCALGBGOGGOG WNLWNL 10.0 - WNL 10.0 - WNL 8.0 - 8.0 - 10.010.0 6.5 - 6.5 - 7.97.9 6.5

3、 6.5 WNLWNL 10.0 - WNL 10.0 - WNL 8.0 - 8.0 - 10.010.0 6.5 - 6.5 - 7.97.9 6.5 6.5 WNLWNL 10.0 - WNL 10.0 - WNL 8.0 - 9.9 8.0 - 9.9 6.5 - 7.9 6.5 - 7.9 6.5 6.5 WNLWNL 10.0 - WNL 10.0 - WNL 8.0 - 8.0 - 10.010.0 6.5 - 6.5 - 7.97.9 6.5 6.5 4 与疾病有关的贫血 v 肿瘤类型 v 疾病程度和发病病程 v 是否存在感染 与治疗有关的贫血 v 方案和强度 v 化疗 v 放

4、疗 v 外科干预 v 既往治疗史 Mercadante S, et al. Cancer Treat Rev. 1999;26:303-311Mercadante S, et al. Cancer Treat Rev. 1999;26:303-311 5 79%79% 21%21% 恶性血液肿瘤恶性血液肿瘤 实体瘤实体瘤 36%36%* *病人入组时就病人入组时就 贫血贫血 66%66%在在6 6个月的研究个月的研究 中发展为贫血中发展为贫血 36%36%病人接受贫血治病人接受贫血治 疗疗 接受贫血治疗的起接受贫血治疗的起 始始Hb = 9.6 g/dLHb = 9.6 g/dL 53%53%

5、* * 病人入组时就病人入组时就 贫血贫血 72% 72% 在在6 6个月的研究个月的研究 中发展为贫血中发展为贫血 47% 47% 病人接受贫血病人接受贫血 治疗治疗 接受贫血治疗的起接受贫血治疗的起 始始Hb = 8.8 g/dLHb = 8.8 g/dL * *Anemia defined as Hb 12 g/dLAnemia defined as Hb 12 g/dL Hb = hemoglobinHb = hemoglobin Ludwig H, et al. Proc Am Soc Hematol. 2002:abstr 884.Ludwig H, et al. Proc Am

6、Soc Hematol. 2002:abstr 884. 6 715% 病人接受输血 50 中度或重度贫血发生率（）中度或重度贫血发生率（） (Hb 10.5 g/dl) 0 0 10 20 30 40 12246810 化疗时间（月）化疗时间（月） Coiffier et al. Eur J Cancer 2001; 37: 161723 8 * *NCI, WHO Common Toxicity Criteria, Cancer and Leukemia Group B, or toxicity system not specified NCI, WHO Common Toxicity C

7、riteria, Cancer and Leukemia Group B, or toxicity system not specified Grade 1/2 and Grade 3/4 were not fully reported in all studies Grade 1/2 and Grade 3/4 were not fully reported in all studies Eloxatin prescribing information. Bedford, OH: Sanofi-Synthelabo, Inc.; 2002. Eloxatin prescribing info

8、rmation. Bedford, OH: Sanofi-Synthelabo, Inc.; 2002. Groopman JE, Itril LM. J Natl Cancer Inst. 1999;91:1616-1634.Groopman JE, Itril LM. J Natl Cancer Inst. 1999;91:1616-1634. 9 * *NCI, WHO, ECOG, GOG, or unspecified NCI, WHO, ECOG, GOG, or unspecified toxicity grading systems toxicity grading syste

9、ms Grade 1/2 and Grade 3/4 were not fully Grade 1/2 and Grade 3/4 were not fully reported in this study reported in this study Groopman JE, Itri LM. J Natl Cancer Inst. 1999;91:1616-1634.Groopman JE, Itri LM. J Natl Cancer Inst. 1999;91:1616-1634. Chau I, et al. Br J Cancer. 2001;85:1258-1264.Chau I

10、, et al. Br J Cancer. 2001;85:1258-1264. Urakami S, et al. J Urol. 2002;168:2444-2450.Urakami S, et al. J Urol. 2002;168:2444-2450. CAF = CTX + ADM + 5-Fu CHOP =CTX + ADM + 5-Fu+ PDN 10 Eur. J. Cancer, 2004Eur. J. Cancer, 2004 11 癌症残余癌症残余/ /复发复发 癌症新诊断癌症新诊断 缓解期缓解期 0102030405060 全部病人全部病人 贫血病人贫血病人 (%)

11、欧洲15367癌症病人贫血调查 贫血： Hb 12 g/dl 67.0%患者至少发生1次贫血 Ludwig et al. European Journal of Cancer 2004; 40: 2293-2306 31% 35% 48.5% 39% 12 43.5% 贫血病人贫血病人 (%)(%) 放疗放疗 新诊断新诊断 尚未接受治疗尚未接受治疗 化疗放疗化疗放疗 化疗化疗 01020304050607080 28.7% 50.5% 31.7% Ludwig et al. European Journal of Cancer 2004; 40: 2293-2306 欧洲15367癌症病人贫血

12、调查 贫血： Hb 12 g/dl 13 肿瘤细胞肿瘤细胞 免疫系统免疫系统 被激活被激活 贫血贫血 细胞因子细胞因子(TNF, IL-1(TNF, IL-1a a/ /b b, IFN-, IFN-g g) ) 减少减少 减少减少 抑制抑制 EPOEPO生成生成 铁利用铁利用 BFU-EBFU-E（红系爆式集落形成单位）（红系爆式集落形成单位） CFU-E CFU-E（红系集落形成单位）（红系集落形成单位） TNFTNF 巨噬细胞巨噬细胞 吞噬红细胞作用 异常红细胞生成 溶血素、发热、血管损伤 等因素造成红细胞系损伤 红细胞红细胞 寿命缩短寿命缩短 Nowrousian. Med Oncol

13、 1998; 15 (Suppl 1): S19Nowrousian. Med Oncol 1998; 15 (Suppl 1): S1928 14 贫血对癌症病人的不利影响 降低癌症病人生活质量 降低抗癌治疗效果 降低癌症病人生存率 15 贫血贫血 认知功能减退 情绪低落 乏力 性功能障碍 注意力下降 活动能力减退 1.Ludwig et al. Semin Oncol 2001; 28 (Suppl 8): 714. 3.Curt et al. Oncologist 2000; 5: 353360.1.Ludwig et al. Semin Oncol 2001; 28 (Suppl 8)

14、: 714. 3.Curt et al. Oncologist 2000; 5: 353360. 2.Portenoy et al. Oncologist 1999; 4: 110. 4.Stone et al. Ann Oncol 2000; 11: 2.Portenoy et al. Oncologist 1999; 4: 110. 4.Stone et al. Ann Oncol 2000; 11: 561567.561567. 眩晕 16 问卷调查： 消除乏力更重要？ 还是缓解疼痛更重要？ Vogelzang et al. Semin Hematol Semin Hematol 199

15、7; 34 (Suppl 2): 412; 34 (Suppl 2): 412 乏力严重影响患者生活质量 17 QoL (LASA, mm) Hb (g/dl)Hb (g/dl) 6.7 mm 3.7 mm Crawford et al. Cancer 2002; 95: 88895 18 中位组织中位组织 pO2 (mm Hg) 正常正常 Hb轻度贫血轻度贫血重度贫血重度贫血 70 50 20 0 60 40 10 30 肿瘤组织肿瘤组织 正常组织正常组织 p=0.0001 Hb 1112.9 g/dl (男) 1111.9 g/dl (女) Becker et al. Becker et

16、al. Int J Radiat Oncol Biol PhysInt J Radiat Oncol Biol Phys 2000; 46: 459 2000; 46: 4596666 Hb 13 g/dl (男) 12 g/dl (女) Hb 11 g/dl 5 15 13 133例头颈癌 19 预后差预后差 贫血贫血 作为强烈的选择压力作为强烈的选择压力 新的变异体凋亡潜力下降新的变异体凋亡潜力下降 ，血管增生潜力上升，血管增生潜力上升 对治疗抵抗对治疗抵抗 化疗化疗/ /放疗放疗 促进基因组不稳定性促进基因组不稳定性 （通过点突变、基因扩增、 和染色体重排） 增加基因变异的数目增加基因变

17、异的数目 （被配对基因抑制的隐含基 因变异） 肿瘤乏氧肿瘤乏氧 加速肿瘤进展加速肿瘤进展 增加远距离转移增加远距离转移 Hckel Semin Oncol 2001; 28 (Suppl 8): 3641.Hckel Semin Oncol 2001; 28 (Suppl 8): 3641. 20 Nature Review Cancer VOL 4:437, 2004Nature Review Cancer VOL 4:437, 2004 21 Nature Review Cancer VOL 4:437, 2004Nature Review Cancer VOL 4:437, 2004 2

18、2 150 100 50 0 增加中位死亡危险比例增加中位死亡危险比例 (%) 肺癌肺癌 125 75 25 前列腺癌前列腺癌淋巴瘤淋巴瘤头颈癌头颈癌全部全部 19% 47% 67% 75% 65% Caro et al.Caro et al. Cancer Cancer 2001; 91: 2214212001; 91: 221421 23 24 25 术后局控率术后局控率 (%) 无贫血组无贫血组 (n=231) 手术后手术后 (年年) 0 20 40 60 80 100 051234 贫血组贫血组* * (n=27) *Hb 13 g/dl (men), 12 g/dl (women)

19、Lutterbach. et al. Int J Radiat Oncol Biol Phys 2000; 48: 134550Lutterbach. et al. Int J Radiat Oncol Biol Phys 2000; 48: 134550 回顾性研究 258名喉癌 5年生存率年生存率: p=0.003 26 月月 生存率（）生存率（） 1.0 0.6 0.4 0.2 0 0204080 p=0.004 60 0.8 中位中位pO2 10 mmHg n=41 中位中位pO2 10 mmHg n=48 Hckel 28 (Suppl 8): 362001; 28 (Suppl 8

20、): 364141 52%的患者PO2 10 mmHg 其中68%的患者PO25mmHg 27 28 29 ECAS data *With or without With or without iron *With or without iron or transfusions No treatment 61.1% Iron alone 6.5% Epoetin* 17.4% Transfusion* 14.9% Ludwig et al. Eur J Cancer 2004;40:2293306 欧洲15367癌症病人 贫血： Hb 12 g/dl 30 0 0303060609090120

21、120150150180180210210 sterborg. Med Oncol 1998; 15 (Suppl 1): S479sterborg. Med Oncol 1998; 15 (Suppl 1): S479 Ludwig et al. N Engl J Med 1990; 322: 16939Ludwig et al. N Engl J Med 1990; 322: 16939 Hb (g/dl)Hb (g/dl) 治疗天数治疗天数 8 8 1212 1414 1010 4 4 6 6 EpoetinEpoetin TransfusionsTransfusions = 输血 31

22、 1. Ludwig et al. Hematol J 2002; 3: 12130 3. Ludwig et al. N Engl J Med N Engl J Med 1990; 322: 169391990; 322: 16939 2. Rizzo et al. J Clin Oncol 2002; 20: 4083107 4. 4. Semin Oncol Vol 25(suppl 7):2, 1998Semin Oncol Vol 25(suppl 7):2, 1998 32 * Hb 1011 g/dL, 建议 EPO治疗； Hb 10 g/dL, 强烈推荐EPO治疗 贫血无症状

23、无危险因素 贫血无症状贫血无症状 有危险因素有危险因素 有症状的贫血有症状的贫血 观察 周期重新评估 Hb Hb 11g/dL11g/dL* * 输血（根据指征）输血（根据指征） 和和/ /或或EPOEPO治疗治疗 铁的相关指标 (血清铁, 总铁结合力, 血清铁蛋白) Epoetin alfaDarbepoetin alfa 考虑考虑 EPOEPO治疗治疗 Practice Guidelines in Oncology: Cancer and Treatment-Related Anemia. Practice Guidelines in Oncology: Cancer and Treatm

24、ent-Related Anemia. Version 2.2007. Available at: . Version 2.2007. Available at: . 33 - 10,000 U TIW 或 40,000 U QW - 补铁：根据需要（当铁蛋白100ng/mL, 转铁 蛋白饱和度20%时） - 4w无反应者增加剂量 10000 U 增加到 20000 U TIW 40000 U 增加到 60000 U QW - 最佳 Hb = 12 g/dL -2.25 mcg/kg QW 或 3 mcg/kg Q2W 或 200 mcg Q2W - 补铁：根据需要（当铁蛋白 100 ng/m

25、L, 转铁蛋白饱和度 20%时） - 6w无反应者增加剂量 - 最佳 Hb = 12 g/dL Epoetin alfaEpoetin alfa 34 EPOEPO O O2 2 RBCsRBCs 红骨髓红骨髓 循环循环 RBCsRBCs 肾脏肾脏 化疗的肾毒性化疗的肾毒性钝化钝化 EPO 生成生成 35 红细胞生成的模型 （The Koury and Bondurant model of erythropoiesis） C) Increased EPO production Pre-EPO-dependent cell EPO-dependent cells (with decreasing

26、 EPO-sensitivity or increasing EPO requirement) Mature red cell B) Blunted EPO productionA) Normal EPO production Koury et al. Transfusion 1990; 30: 673674. Cazzola et al. Blood 1997; 89: 42484267. 36 Beutler E. In: Williams Hematology. 6th ed. 2000:355-368.Beutler E. In: Williams Hematology. 6th ed

27、. 2000:355-368. EPOEPO刺激刺激 5 Days5 Days Stem cellsStem cells Hemoglobin synthesisHemoglobin synthesis Progenitor cellsProgenitor cells (BFU-E, CFU-E)(BFU-E, CFU-E) ReticulocytesReticulocytes Red blood cellsRed blood cells 37 EPO与EPOR结合，使EPOR 形成双链 EPOR双链发生结构改变，双 链的酪氨酸蛋白酶2彼此靠近 活化，进而磷酸化 STAT5系统启动，PI3激酶

28、及 EPR/MAP激酶信号通路启动 抗凋亡基因BCL-2高表达， RBCRBC生存时间延长生存时间延长 Lung Cancer (2003) 41, S133-S145Lung Cancer (2003) 41, S133-S145 38 巨噬细胞巨噬细胞 +EPO+EPO -EPO-EPO CFU-ECFU-E 红细胞红细胞 GATA-1 39 40 Glaspy研究：美国4298例2项研究分析 Oncologist Vol 7:126, 2002Oncologist Vol 7:126, 2002 41 Glaspy研究：美国4298例2项研究分析 Hb (g/dl) * * 所有组与基线

29、相比,P0.007,差异明显 # # 所有组与前一个月相比,P0.007,差异明显 *# *# *# *# Oncologist Vol 7:126, 2002Oncologist Vol 7:126, 2002 42 A. 无铂化疗组无铂化疗组 能级能级 水平水平 卧床时间减少卧床时间减少 日常活动日常活动 能力能力 工作能力工作能力 * p0.001 # p0.05 * * * * # Glaspy研究：美国4298例2项研究分析 生活质量改善评分生活质量改善评分 Oncologist Vol 7:126, 2002Oncologist Vol 7:126, 2002 43 B 铂剂化疗组

30、铂剂化疗组 * p0.001 # p0.05 能级能级 水平水平 卧床时间卧床时间 减少减少 日常活动日常活动 能力能力 工作能力工作能力 * * * * # Glaspy研究：美国4298例2项研究分析 生活质量改善评分生活质量改善评分 Oncologist Vol 7:126, 2002Oncologist Vol 7:126, 2002 44 JCO Vol 19:2865, 2001JCO Vol 19:2865, 2001 375例恶性肿瘤病人 A.Hb10.5 B.Hb1.5g 随机分组（2:1) EPO组：251例 EPO150-300 IU/Kg 每周3次 共用12-24周 安

31、慰剂组：124例 用法同上 45 375例患者: 31% 乳腺癌、16% NHL、15% MM 主要终点： - 治疗4周后需要输血的患者比例 次要终点 ： - Hb从基线到末次测量结果之间的差值 - 反应率（血红蛋白上升2g/dl且与输血无关， 即测定前的28天未输血） - QOL的变化和生存率 安全性：通过病人自主报告或对研究者提问的回答来监测 Littlewood 期临床期临床 : Epoetin alfa 治疗接受无铂化疗的癌性贫血治疗接受无铂化疗的癌性贫血 JCO Vol 19:2865, 2001JCO Vol 19:2865, 2001 46 Littlewood 期临床期临床 :

32、 Epoetin alfa Epoetin alfa 治疗接受无铂化疗的癌性治疗接受无铂化疗的癌性 贫血贫血 JCO Vol 19:2865, 2001JCO Vol 19:2865, 2001 47 JCO Vol 19:2865, 2001JCO Vol 19:2865, 2001 Littlewood 期临床期临床 : Epoetin alfa Epoetin alfa 治疗接受无铂化疗的癌治疗接受无铂化疗的癌 性贫血性贫血 48 JCO Vol 19:2875, 2001JCO Vol 19:2875, 2001 Janice研究：美国社区3012例40000IU/周 化疗+EPO E

33、PO说明书方案 40000IU*QW 49 JCO Vol 19:2875, 2001JCO Vol 19:2875, 2001 输血率输血率 H b （ （g/dl） n=2964 n=2763 n=2474 n=2071 n=1715 Janice研究：美国社区3012例40000IU/周 化疗+EPO EPO说明书方案 40000IU*QW 50 JCO Vol 23:2606, 2005 JCO Vol 23:2606, 2005 EPO说明书方案 40000IU*QW 51 JCO Vol 23:2606, 2005 JCO Vol 23:2606, 2005 EPO说明书方案 40

34、000IU*QW 52 53 ASCO 2003 Ab 3160ASCO 2003 Ab 3160 EPO新剂量方案： 8天 100,000IU Pappalardo研究 54 Hb改变： Hb 增加0.5-6.2g/dl 全组平均Hb增加2.4g/dl 输血的需求：仅1例（共28例）病人需要输血 生活质量：功能状态有改善 ASCO 2003 Ab 3160ASCO 2003 Ab 3160 Pappalardo研究 EPO新剂量方案： 8天 100,000IU 55 38例恶性肿 瘤病人 Hb1g/dl Hb2g/dl Oncologist Vol 9:459, Oncologist Vol

35、 9:459, 20042004 59 Oncologist Vol 9:459, Oncologist Vol 9:459, 20042004 60 Patton J, et al. Oncologist. 2004;9:90-96.Patton J, et al. Oncologist. 2004;9:90-96. 61 * *For patients who did not receive transfusionsFor patients who did not receive transfusions Week 4 and Week 8 values represent mean Hb

36、 during initial once-weekly dosing phase Week 4 and Week 8 values represent mean Hb during initial once-weekly dosing phase By Week 12, 10 patients had commenced Q3W maintenance dosing By Week 12, 10 patients had commenced Q3W maintenance dosing Hb values are rounded to nearest 0.1 g/dL; QW epoetin

37、alfa was reduced to 40,000 Units in 7 patients;Hb values are rounded to nearest 0.1 g/dL; QW epoetin alfa was reduced to 40,000 Units in 7 patients; Q3W epoetin alfa was reduced to 100,000 Units in 2 patientsQ3W epoetin alfa was reduced to 100,000 Units in 2 patients BaselineBaselineWeek 4Week 4 Wee

38、k 8Week 8 Week 12Week 12 Last ValueLast Value 10.110.1 11.111.1 13.013.012.912.913.013.0 20201818151514141818n =n = Patton J, et al. Oncologist. 2004;9:90-96.Patton J, et al. Oncologist. 2004;9:90-96. 62 Baseline = Hb at entry into maintenance phaseBaseline = Hb at entry into maintenance phase * *n

39、= number of patients with an Hb value recorded for a given week; this may not be the same n = number of patients with an Hb value recorded for a given week; this may not be the same as the number of patients still on study or the number of patients receiving study drug that week;as the number of patients still on study or the number of patients receiving study drug that week; Hb values are