MDS诊断与治疗

MDS的诊断与治疗,陈峰,江苏省血液病研究所苏州大学附属第一医院血液科,MDS本质是起源于造血干细胞的恶性克隆性疾病。 血细胞减少 无效造血 高风险向AML转化MDS细胞起源于尚未有系列分化的早期干细胞，部分MDS患者兼有髓系和淋系克隆。 Mufti GJ , Haematologica 2008;93:1712-7,MDS诊断及分型历史,MDS的诊断流程,Criteria of Vienna 必要标准,1 持续（6月）一系或多系血细胞减少：红细胞（Hb110g/L）；中性粒细胞（ANC1.5109/L）；巨核细胞（BPC15% （包括骨髓活检+免疫组化）2 原始细胞：骨髓涂片中达5-19% 3 典型染色体异常：常规核型分析或FISH,MDS维也纳标准辅助标准（用于符合必要标准，但未达到确定标准，但临床呈典型MDS表现者，如输血依赖的大细胞贫血）,1 流式细胞术：显示骨髓细胞表型异常，提示红细胞系或/和髓系存在单克隆细胞群 2 单克隆细胞群存在明确的分子学标志： HUMARA分析，基因芯片谱型或点突变（如RAS突变） 3骨髓或/和循环中祖细胞： CFU集落（集簇）形成显著和持久减少,MDS维也纳标准,符合两个必要标准和一个（至少）确定标准可诊断MDS符合两个必要标准，而不符合确定标准，参考辅助标准，诊断为“高度疑似MDS”，定期随访染色体核型和骨髓活检+免疫组化为确定标准，应列入MDS诊断必须测定项目辅助检测项目对技术设备要求较高，可以集中区域诊疗中心进行,MDS Classifications,French-American-British (FAB)World Health Organization (WHO)International Prognostic Scoring Systems (IPSS)WHO based Prognostic Scoring Systems (WPSS)RARS with marked thrombocytosis (RARS-T),WHO-2008,MDS Classifications(2008),MDS Classifications(2008),MDS Classifications(2008),MDS Classifications,*Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U#If the marrow myeloblast percentage is 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classification is RAEB-1.# If the marrow myeloblast percentage is 5% and there are 1% myeloblasts in the blood, the case should be classified as MDS-U.Cases with Auer rods and 5% myeloblasts in the blood and 10% in the marrow should be classified as RAEB-2.,MDS/MPN Classifications(2008),MDS/MPN Classifications(2008),MDS/MPN Classifications(2008),If myelodysplasia is minimal or absent, CMML can still be diagnosed if the other requirements are met and there is an acquired clonal cytogenetic or molecular genetic abnormality present in the hematopoietic cells, or the monocytosis has persisted for at least 3 months and all other causes of monocytosis have been excluded.#Provisional entity. In WHO classification from 2002 the cut-off for platelet count was 600 x 109/L. In the WHO 2008 classification the cut-off value is 450 x 109/L, to be in line with the classification of essential thrombocythemia. Around 50% of cases with RARS-T carry the JAK2 mutation, but this is not a diagnostic criterion.,MDS治疗总体原则the annual congress of the European Hematology Association 2009;3:172-176,A risk-adapted treatment strategy 是必须的危险因素分组是以WPSS为基础,A: very low WPSS risk: RA,RAS,5q-综合征(无输血依赖) watch-waiting strategyB: low WPSS risk： 多系病态造血，5q-综合征（输血依赖），中等预后核型 1、如无明显血细胞减少引发症状： watch-waiting strategy 2、如输血依赖：EPO,EPO无效进入移植，按需去铁治疗 3、60岁以下低增生MDS可采取ATG/CSAC: intermediate high and very high risk: 1、 小于65岁中危、高危及极高危、有合适供体患者、一般情况允许推 荐、 异基因造血干细胞移植 2、无合适供体者，采取5-AZA或Decitabine。如无效，进入临床实验或支持治疗。,A risk-adapted treatment strategy the annual congress of the European Hematology Association 2009;3:172-176,NCCN治疗指南（低危、中危-1组）,NCCN 治疗指南（高危组）,General Approach to MDS,1. 祛铁治疗与MDS预后,170 pts with MDS：76 pts received CT 6 mos; median time to CT 30 mos; median CT 35 mos,Rose. Blood 110:abst 249, 2007,2. EPO + G-CSF,大剂量Epo (3万-6万U/w) 可联合 G/GM-CSF （不推荐常规、单独应用 ）,低危和中危-1 : 有效率46%,疗效维持时间27 个月中危-2 和高危: 有效率27%，疗效维持时间7 个月,Low WPSS risk 效果好EPO 水平500mU/ml 二者均具备:有效率61% 每周输血量2 单位 仅具备一项:有效率14%,造血生长因子并不增加转白危险,3. Immunosuppressive treatment (ATG+CSA+steroids),有效人群：年龄较轻(60y)处于发病早期骨髓呈低增生型多低危组 表达HLA-DR15(DR2)细胞遗传学正常HUMARA多态性提示多克隆常有PNH克隆（CD59 / CD55缺失）,Questions:MDS？PNH?AA?IRP?,中危组及高危组疗效不佳20% 在1年内进展为急性白血病,+8异常的MDS对ATG/CSA等强化免疫抑制治疗效果相对较好： 强化免疫抑制了异常增高的CD8+细胞受体亚家族水平，使MDS患者血细胞减少改善。但同时也抑制了+8细胞所具有的分化成熟能力，导致MDS更倾向AML转化。N.Galili, the Annual Congress of the European Hematology Association 2009;3:172-176,3. Immunosuppressive treatment (ATG+CSA+steroids),4. MDS-003 Lenalidomide,List AF.Clin Adv Hematol Oncol. 2005 ,23.,148 例低危和中危-1 及 5q-MDS Lenalidomide10mg/d,10mg/d*21d休息一周，持续2年67%脱离输血，平均 Hb 升高 5.4g/dl5q-患者完全细胞遗传学缓解和部分缓解分别为 45%和 28%6 个月疗程后36%患者病态造血完全消失 中位起效时间4.4周 随访 26个月未达到中位有效维持时间,Protocol defined ( 26 weeks),IWG( 8 weeks),*P 0.001 vs placeboBars represent 95% CI,6,8,MDS-004 Lenalidomide 5mg vs 10 mg vs placebo: RBC-TI,Fenaux et al. Blood 2009 Abstract,FDA(2005/12): 1、推荐用于低危、中危-1组输血依赖5q-综合症（伴有、不伴有其他核型异常 2、用于不存在5q缺失的低危组，有输血依赖的MDS患者。 EMEA Committee(2008/01 and 2008/03): refusal of the marketing authorization for lemalidomide 用于MDS的贫血治疗，尤其是输血依赖的5q-综合症及低危、中危-1组MDS。 原因： Lemalidomide安全性无法进行评估,可能会增加转白风险。 lemalidomide改善贫血效益并不超过其带来的潜在的危险性。,欧美对Lenalidomide的不同意见,5. Azacitidine Lower-Risk MDS: Efficacy and Safety,Musto et al. ASH 2008, Abstract 2680,* Response rate was not influenced by age, previous treatment, and transfusion dependence,5. Azacitidine 国际多中心III期随机研究AZA-001,AZA 75 mg/m2/d x 7 d q28 d,CCR,Randomization,BSC was included with each armTx continued until unacceptable toxicity or AML transformation or disease progression,Best Supportive Care (BSC) onlyLow Dose Ara-C (LDAC, 20 mg/m2/d x 14 d q28-42 d)Std Chemo (7 + 3),Screening/CentralPathology Review,Investigator CCRTx Selection,Fenaux et al Lancet Oncology 2009,国际多中心III期随机研究AZA-001,Fenaux et al Lancet Oncol 2009 10:223-232,AZA-001 : OS(2y) Vidaza versus CCR,Time (months) from Randomization,Proportion Surviving,CCR,AZA,Fenaux et al Lancet Oncology 2009,AZA-001 : RBC Transfusion Independence Vidaza versus CCR,Baseline-Dependent Patients,Baseline-Independent Patients,% of Patients,28% DifferenceP=0.0005,34% DifferenceP0.0001,Santini. ASCO. 2008 (abstr 7028).,6. MDACC II：Decitabine vs CCR,回顾性研究：Decitabine治疗组124例年龄、细胞遗传学及IPSS积分相同的强化疗组115例,试验2,Kantarjian et al. Cancer 2007;109:1133,Kantarjian et al. Blood 2007;109:52,3种剂量地西他滨治疗MDS的结果分析,12,20 mg/m2 IV x 5 days 疗效最佳20 mg/m2 SQ x 5 days10 mg/m2 IV x 10 days,Demethylating agent -Decitabine,至少治疗3个疗程(出现SAE时剂量减低25%-30%),EORTC(06011) 期研究,INT-2和High-risk老年患者233例Low Dose Decitabine Vs Best Supportive Care overall RR：34% vs 2,(months),0,6,12,18,24,30,36,42,0,10,20,30,40,50,60,70,80,90,100,O,N,Number of patients at risk :,99,114,58,33,16,8,4,2,103,119,72,47,21,14,3,3,Time to AML or death was not significant.,Median (months): 8.8 vs 6.1HR = 0.85 , 95% CI (0.64, 1.12)Logrank test: p=0.24,Decitabine,Supportive care,Supportive care,Decitabine,Wijermans et al. ASH 2008, Abstract 226,(months),0,6,12,18,24,30,36,42,0,10,20,30,40,50,60,70,80,90,100,O,N,Number of patients at risk :,96,114,71,38,22,10,6,3,99,119,83,53,24,15,4,4,Overall survival was not significant,Median (months): 10.1 vs 8.5HR = 0.88 , 95% CI (0.66, 1.17)Logrank test: p=0.38,Supportive care,Decitabine,Decitabine,Supportive care,Wijermans et al. ASH 2008, Abstract 226,NCCN2010年第1版，并将AZA升级为中危-2和高危骨髓增生异常综合征(MDS)的I类推荐治疗,Haemopoietic Stem Cell Transplantation for MDS,MDS干细胞移植的适应症,IPSS评分为中危-1、中危-2、高危MDS、骨髓原始细胞 5% ，但伴高危细胞遗传学或严重多系细胞减少输血依赖者(即使IPSS积分较低） Deeg HJ, et al. Int J Hematol, 2002; 76 (Supp l2): 29-34.,MDS干细胞移植的时机及方案选择,IBMTR回顾性研究对比三组人群，分别为非移植组MDS移植组由MDS转化为AML的移植组结果表明：IPSS中危-2或高危组，患者可从即刻移植治疗中获益IPSS低危或中危-1组，患者能从延迟移植治疗中获益首选同胞相合供者,如无可以考虑其他来源的供者，如HLA相合的非血缘供者，甚至是不合的亲缘供者患者中位年龄40-50岁，一般条件好尽可能常规清髓造血干细胞移植，预处理BUCY 年龄偏大的或一般状态差的可以尝试RIC Cutler CS, et al. Blood, 2004; 104: 579585.,Improve the outcome of allogeneic SCT in MDS,Reduce TRM (treatment-related mortality ) Reduce risk of relapse,General Options to Reduce TRM,Improvement of supportive care (e.g new antifungal and antiviral drugs, growth factors,etc.)Donor selection: Syngenetic donor HLA-identical sibling Matched unrelated donorModify conditioning regimen,Cause of death of cumulative mortality at 1 y (14,403 MDS pts after HLA-identity sib HSCT in Europe),Improvement of supportive care,General Options to Reduce TRM,Improvement of supportive care (e.g new antifungal and antiviral drugs, growths factors,etc.)Donor selection: Syngeneic donor (twin) HLA-identical sibling Matched unrelated donorModify conditioning regimen,Syngenetic donor / HLA-identical sibling,Syngenetic donor / HLA-identical sibling,Survival rate,HLA-identical sibling/ Matched unrelated donor,EBMT data :de witte et al.BJH2000,P0.001 p0.05 NS,Matched unrelated donor HSCT,Unpublished results of the EBMT data,Matched unrelated donor HSCT,Unpublished results of the EBMT data,Survival rate,EBMT data(2008 ash ),HLA-identical sibling/ Matched unrelated donor,General Options to Reduce TRM,Improvement of supportive care (e.g new antifungal and antiviral drugs, growths factors,etc.)Donor selection: Syngenetic donor HLA-identical sibling Matched unrelated donorModify conditioning regimen,Modify conditioning regimen,Reduced intensity or non- myeloablative regimensStandard conditioning,预处理方案CIBMTR对RIC的定义：TBI5Gy，马利兰总剂量9mg/kg，马法兰总剂量140mg/m2，噻替哌总剂量10mg/kg，预处理方案常包括氟达拉滨要兼顾有效性（清除肿瘤）和毒性（减少NRM），常在方案中加入新药物以减少移植副作用新药：CD52单抗；ATGGVHD的预防常用CsA、FK-506,RIC-HSCT治疗MDS,RIC / Standard conditioning in MDS (HLA-identical),Martino et al. Blood 2006,P=0.04 p0.001 p=0.1 p=0.1,621,EBMT,Luger et al.for CIBMTR ASH 200