滤泡性淋巴瘤一线治疗新策略
2007中华医学会恶性淋巴瘤CME
滤泡性淋巴瘤
典型免疫表型:CD10+,CD23±,CD20+,CD43-,CD5-,周期素D1-
分子遗传学检测: 抗原受体; bcl-2重排
细胞遗传学/FISH检测: t(14:18)
惰性淋巴瘤患者的生存:
斯坦福经验, 1960–1996
Adapted from Horning. Semin Oncol. 1993;20(suppl 5):75.
患者 (%)
年
1987-1996
1976-1986
1960-1975
100
60
40
20
0
80
0
Actuarial survival curves for patients with low-grade NHL treated at Stanford University from 1960–1976, 1976–1987, and 1987–1996 are essentially indistinguishable, which shows that the widespread use
of single-agent or multi-agent chemotherapy or combined modality therapy has not had a significant impact on the natural course of
the disease.6
化疗治疗滤泡性淋巴瘤
无论怎样改变化疗
方案
气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载
,均不能改善滤泡性淋巴瘤患者的总生存, 原因:
滤泡性淋巴瘤骨髓受累较多,化疗不能彻底清除骨髓中肿瘤细胞
化疗不能使bcl-2/IgH+细胞转阴,即不能获得分子学缓解
80-90年代,滤泡性淋巴瘤的治疗策略:观望等待(watch&wait),直至疾病进展
免疫化疗治疗滤泡性淋巴瘤
是否可以提高临床疗效?
# 缓解率, 尤其是完全缓解率
# 无进展生存/无事件生存, 总生存
是否可以获得分子学缓解?
是否有治愈的可能?
2007版NCCN推荐的FL治疗策略
一线治疗
环磷酰胺
CHOP+利妥昔单抗
CVP+利妥昔单抗
F/FND+利妥昔单抗
利妥昔单抗维持治疗
2005ASH会议首次发表
免疫化疗可以显著延长初治FL患者的总生存
M39021研究: R-CVP vs.CVP
GLSG(德国低度淋巴瘤研究组)2000研究:
R-CHOP vs. CHOP
M39023研究R-MCP vs. MCP
M39021研究:CVP±利妥昔单抗治疗初治滤泡性淋巴瘤 :研究设计
321位滤泡性 NHL (IWF B, C, D)
III–IV期
平均53岁
未接受过治疗
可测量病灶
组织学回顾
随
机
CVP x 4 周期
(每3周)
利妥昔单抗+ CVP
x 4周期
(每3周)
再
分
期
CVP x 4 周期
(每3周)
利妥昔单抗+ CVP
x 4 周期
(每3周)
SD, PD退出
CR, PR
利妥昔单抗 375mg/m2 i.v. day 1
环磷酰胺 750mg/m2 i.v. day 1
长春新碱 1.4mg/m2 i.v. day 1
强的松40mg/m2 p.o. days 1–5
Marcus R, et al. Blood 2005;105:1417
目前并无所谓治疗晚期惰性淋巴瘤的一线方案,CVP和CHOP是较为常用的方案.
从 2000年4月至2002年3月, 322位患者入组了这个3期试验.
患者随机进入R+CVP组或CVP组
90%为滤泡小细胞或混合型,9%为滤泡大细胞型
先予各4周期治疗,SD和PD患者退出,缓解的患者继续各4周期治疗
CVP±利妥昔单抗治疗
初治滤泡性淋巴瘤:患者分析
Marcus R, et al. Blood 2005;105:1417
两组患者的基本情况,临床和病理特征无明显差异
CVP±利妥昔单抗治疗初治滤泡性淋巴瘤 :缓解率
Solal-Celigny, et al. Blood 2005;106:Abs.350
缓解率 CVP, % (n=159) R-CVP, % (n=162)
p value
CR 8 30 –
CRu 3 11 –
(CR/CRu ) 10 41 p<0.0001
PR 47 40 –
OR (CR + CRu + PR) 57 81 p<0.0001
CR quadruple
probability
R-CVP: 中位 27 月
CVP: 中位 6.6 月
p<0.0001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 6 12 18 24 30 36 42 48 54 60
月
CVP±利妥昔单抗治疗初治滤泡性淋巴瘤
:治疗失败时间(TTF)(随访42月)
Solal-Celigny, et al. Blood 2005;106:Abs.350
延长20月
The relatively short TTF (7 months) observed with CVP is a result of SD at cycle 4 being considered a treatment failure
The TTP seen with CVP (15 months) is similar to that observed in other recent phase III trials of CVP
probability
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 6 12 18 24 30 36 42 48 54 60
月
CVP±利妥昔单抗治疗初治滤泡性淋巴瘤:总生存率 (OS) (随访42月)
Solal-Celigny, et al. Blood 2005;106:Abs.350
p=0.03
CVP: 71%
R-CVP: 83%
A trend towards significance for an improvement in OS.
CVP±利妥昔单抗治疗初治滤泡性淋巴瘤:安全性
Marcus R, et al. Blood 2003;102:28a (Abs.t 87)
两组治疗的耐受性均良好,虽然R+CVP组的粒细胞减少略增加,但感染的发生率无差异,也未发生与治疗有关的死亡
CVP±利妥昔单抗治疗初治滤泡性淋巴瘤:小 结
显著提高缓解率
显示生存益处
美罗华+CVP方案毒性低,且出现的时间短
Marcus R, et al. Blood 2005;105:1417
Solal-Celigny, et al. Blood 2005;106:Abs.350
与CVP相比,R+CVP治疗晚期滤泡性NHL,显著改善患者的ORR, CR, TTF.
这些结果在随访18月时获得,并由随访25月所证实
GLSG2000研究: CHOP±利妥昔单抗
治疗初治滤泡性淋巴瘤:研究设计
随机
4-6 x CHOP
4-6 x 利妥昔单抗 + CHOP
CR, PR
CR, PR
随
机
干细胞移植
2xCHOP(+美罗华) +标准干扰素维持治疗
2xCHOP(+美罗华)+ 强化干扰素维持治疗
2xCHOP(+美罗华)+ 标准干扰素维持治疗
<60 岁
60 岁
Hiddemann W, et al.Blood 2005;106:Abs.3725-32
德国低度淋巴瘤研究组( GLSG )牵头的随机临床,从2000年5月起, 超过800位初治的滤泡和套细胞淋巴瘤患者入组这个随机试验,疗程根据缓解出现的早或晚从6至8个,缓解患者再根据年龄二次分组分别接受移植或不同剂量干扰素维持治疗
CHOP ±利妥昔单抗治疗初治滤泡性淋巴瘤 :缓解率
Hiddemann W, et al.Blood 2005;106:Abs.3725-32
CHOP
(n=272) (%)
(n=28
4
) (%)
p
value
CR
完全缓解
17
20
PR
部分缓解
74
77
MR
微小缓解
3
1
SD
疾病稳定
2
1
PD
疾病进展
3
1
O
R
总缓解
91
97
0.005
总缓解率美罗华联合CHOP从90%提高到96%, 有显著差异.
CHOP ±利妥昔单抗治疗初治滤泡性淋巴瘤
:治疗失败时间(TTF) (随访2年)
R-CHOP: 中位 - 未达到
CHOP: 中位 - 29月
p<0.0001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Probability
0 1 2 3
年
Hiddemann W, et al.Blood 2005;106:Abs.3725-32
2年随访,无失败生存率比较,美罗华联合CHOP超过80%,而CHOP仅70%
CHOP ±利妥昔单抗治疗初治滤泡性淋巴瘤 : 生存率(OS)(随访2年)
1.0
0.8
0.6
0.4
0.2
年
R-CHOP (272/285): 95%
CHOP (249/272): 90%
0 1 2 3 4 5
p=0.016
Hiddemann W, et al. Blood 2005;106:3725–32
Probability
随
机
化
CHOP
MCP
GLSG 1996研究
GLSG 2000研究
381
148
272
284
初治FL患者数
GLSG两个连续研究的比较
随
机
化
6-8 CHOP
6-8 CHOP +利妥昔单抗
Hiddemann W, et al. ASH2006;Abstract483
G
L
S
G
1
9
9
6
2
0
0
0
缓解率对比
GLSG两个连续研究的比较
Hiddemann W, et al. ASH2006;Abstract483
初治FL 患者数 CR + PR
% MR + SD
%
MCP 148 84 5
CHOP 381 89 7
CHOP 272 91 6
R-CHOP 284 96 3
治疗无失败时间对比
GLSG两个连续研究的比较
Hiddemann W, et al. ASH2006;Abstract483
总生存时间对比
GLSG两个连续研究的比较
Hiddemann W, et al. ASH2006;Abstract483
CHOP ±利妥昔单抗治疗初治滤泡性淋巴瘤 :小结
Hiddemann W, et al.Blood 2005;106:Abs.3725-32
利妥昔单抗+CHOP获得显著生存优势
德国的低度淋巴瘤研究组(GLSG)推荐利妥昔单抗+CHOP
是一线治疗FL的首选方案
M39023研究 MCP±利妥昔单抗治疗
初治滤泡性/套细胞淋巴瘤 :研究设计
利妥昔单抗 375mg/m2 IV d1
米托蒽醌 8 mg/m² IV d1 + 2
氮芥 3 x 3mg/m² PO d1–5
强的松 25 mg/m² PO d1–5
晚期FL, IC 和MCL
18–75 岁
初治患者
随
机
MCP x 6 周期
(每 4 周 1次)
利妥昔单抗+ MCPx 6 周期 (每 4 周 1 次)
再
分
期
MCP x 2 周期
(每 4 周 1次)
利妥昔单抗+ MCPx 2 周期 (每 4 周 1次)
SD, PD 退出
CR, PR
FL予以干扰素维持治疗
Herold M, et al.Ann Oncol 2005; 16(Suppl.5):V51-21(Abs.60)
Inclusion criteria
CD20+ follicular NHL; Ann Arbor stage III or IV (classes B, C and D)
No previous systemic antilymphoma treatment
WBC <25 x 109/L
No CNS involvement
Additional standard inclusion criteria
MCP±利妥昔单抗治疗初治滤泡性/套细胞淋巴瘤 :患者分析
Herold M, et al.Ann Oncol 2005; 16(Suppl.5):V51-21(Abs.60)
MCP±利妥昔单抗治疗初治
滤泡性淋巴瘤 :缓解率
R-MCP MCP p值
FL患者 n=105 n=96
ORR (%) 92.4 75 <0.0001
CR (%) 49.5 25 <0.0001
Herold M, et al.Ann Oncol 2005; 16(Suppl.5):V51-21(Abs.60)
MCP±利妥昔单抗治疗初治 滤泡性淋巴瘤
:无进展生存率 (PFS)(随访48月)
1.0
0.75
0.5
0.25
0
0 10 20 30 40 50 60
(月)
R-MCP
3年 77.4%
MCP
3年 44%
p<0.0001
probability
Herold M, et al.Ann Oncol 2005; 16(Suppl.5):V51-21(Abs.60)
R-MCP
4年 71%
MCP
4年 40%
MCP±利妥昔单抗治疗初治 滤泡性淋巴瘤
:总生存率 (OS)(随访37月)
1.0
0.75
0.5
0.25
0
0 10 20 30 40 50 60
(月)
P=0.014
R-MCP
3年88%
MCP
3年74%
probability
Herold M, et al.Ann Oncol 2005; 16(Suppl.5):V51-21(Abs.60)
R-MCP
3年87%
MCP
3年74%
MCP±美罗华治疗初治滤泡性淋巴瘤
:小结
M39023(利妥昔单抗+MCP)试验再度证实了利妥昔单抗+化疗一线治疗滤泡性淋巴瘤的研究结果 M 39021- 利妥昔单抗+CVP, Marcus et al GLSG2000 – 利妥昔单抗+CHOP ,Hiddemann et al
利妥昔单抗+ MCP作为滤泡性淋巴瘤的一线标准方案 可使老年患者更加受益(以米托恩醌替代阿霉素)
Herold M, et al.Ann Oncol 2005; 16(Suppl.5):V51-21(Abs.60)
3个显示免疫化疗改善滤泡性淋巴瘤的
长期生存 的随机对照临床试验
Herold M, et al.Ann Oncol 2005; 16(Suppl.5):V51-21(Abs.60)
Hiddemann W, et al.Blood 2005;106:Abs.3725-32
Solal-Celigny, et al. Blood 2005;106:Abs.350
FL无标准话疗方案,但利妥昔单抗联合各种化疗方案都显示长期生存益处
历史数据显示化疗不能延长总生存,利妥昔单抗联合CVP/CHOP/MCP 首次显示免疫化疗能够突破化疗的局限
利妥昔单抗联合各种化疗方案是FL一线治疗的首选
一线免疫化疗治疗滤泡性淋巴瘤
: 总 结
分子学缓解
患者若要获得治愈,必须获得真正的完全缓解
既往20年,发展了更为敏感的技术以检测少量的残余肿瘤细胞
是否现在需要改变CR的定义,将分子学缓解包含在内?
是否治疗目的是获得“分子学CR”,最终通过实现临床与分子学
的双重缓解以达到最终治愈?
B细胞淋巴瘤中PCR可检测的标志物
B细胞淋巴瘤常见的染色体易位
t(14;18) 滤泡性淋巴瘤-bcl-2+
t(11;14) 套细胞淋巴瘤
通过PCR扩增,进行检测
滤泡性淋巴瘤PCR可检测的分子靶
bcl-2/IgH: 65–80%
无标志: 10–15%
VDJ+: 10–20%
14/18染色体易位-产生融合基因-导致bcl-2+
染色体18q21
(bcl-2基因)
染色体14q32
(IgH基因)
MBR
t(14;18)
bcl-2
JH
mcr
VH DH JH
PCR阴性患者可获得长期生存
Freedman A et al. Blood 1999;94:3325–33
1.0
0.8
0.6
0.4
0.2
0
Probability
0 2 4 6 8 10 12 14
年
PCR –
PCR +
分别在诊断,CHOP治疗后,
利妥昔单抗治疗后的bcl-2/IgH+细胞的数量
BM
PB
76
At
diagnosis
66
After
CHOP
Bcl-2/IgH + cells
per million normal cells
N
67
At
diagnosis
65
After
CHOP
37
After
rituximab
37
After
rituximab
p<0.0001
106
105
104
103
102
101
100
10–1
106
105
104
103
102
101
100
10–1
p<0.0001
p<0.0001
p<0.0001
利妥昔单抗与分子学缓解
定量检测bcl-2/IgH+ 细胞是评估疗效与判断是否可以达到治愈的预测因素
利妥昔单抗对于BM中bcl-2/IgH+ 较高的患者可能尤其有效。定量评估可帮助
明确是否患者适合以大剂量化疗作为起始治疗
获得临床和分子学缓解,是滤泡性淋巴瘤治疗的主要目的
滤泡性淋巴瘤为什么要开展维持治疗概念
滤泡性淋巴瘤的自然病程
反复复发或长期不缓解
治疗后缓解时间随复发次数增多而缩短
维持治疗的目的
随时间的延长提高疗效(PR CR)
保持并延长缓解状态,提高总生存时间(OS) 13
彻底清除微小病灶(MRD),延长无病生存时间(DFS)
1Gallagher C, et al. J Clin Oncol 1986;4:147080
2Weisdorf D, et al. J Clin Oncol 1992;10:9427
3Montoto S, et al. Ann Oncol 2002;13:52330
为什么只有利妥昔单抗适合开展维持治疗
防止复发,显著延长无病生存时间
长期使用安全性良好
单药治疗,使用便利
The objective of rituximab maintenance therapy is to control remaining malignant cells after initial therapy and improve survival
although cure is currently not possible in indolent NHL, it is important to delay the next therapy for as long as possible.
Importantly, rituximab maintenance causes only minimal disruption of daily life
long half-life allows infrequent therapy while maintaining long-term exposure (in contrast to chemotherapy)
rituximab has minimal acute toxicity and there is no known cumulative toxicity
rituximab maintenance therapy can be delivered in the out-patient setting, causing minimal disruption to daily life.
利妥昔单抗维持治疗可以保持B细胞清除水平
B细胞计数 x 106/L
120
100
80
60
40
20
(月)
0 2–3 5 9 12
A = 标准治疗
B = 维持治疗
Ghielmini M, et al. Blood 2004;103:4416–23
In this study, all patients received four infusions of rituximab 375mg/m2 as induction.
Patients in arm A received no further rituximab while in arm B further rituximab infusions were given at week 12 and months 5, 7 and 9.
Circulating B-cells were rapidly depleted on induction treatment with rituximab in both arms
levels of T-helper, T-suppressor and NK cells remained approximately stable.
When no further rituximab treatment was given, B-cell recovery started 2–3 months after treatment and continued.
Rituximab maintenance therapy caused B-cells to remain depleted
at further follow-up, B-cell recovery appeared to commence once maintenance therapy was stopped.
利妥昔单抗维持治疗滤泡性淋巴瘤:
显著延长无病生存时间
1Ghielmini M, et al. Blood 2004;103:4416–23
2Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
3van Oers MHJ, et al. Blood 2006
研究组 患者 诱导治疗 维持治疗 维持vs观察 无病生存时间
SAKK 35/982 初治/复发 利妥昔单抗 R-2月1次 EFS ↑ 1223 月
ECOG 14964 初治 CVP R-6月4次 PFS ↑ 1561 月
EORTC 209815 复发 CHOP ± R R-3月1次 PFS ↑ 1552 月
There is now a considerable body of evidence demonstrating a significant clinical benefit with rituximab maintenance therapy in follicular lymphoma (FL).
These studies have demonstrated a benefit for rituximab maintenance in previously untreated, relapsed and refractory FL and after induction with rituximab monotherapy and rituximab-containing immunochemotherapy.
免疫化疗治疗滤泡性淋巴瘤
是否可以提高临床疗效?
# 提高缓解率, 尤其是完全缓解率
# 延长无进展生存/无失败生存, 总生存时间
是否可以获得分子学缓解?
# 清除bcl-2+细胞
是否有治愈的可能?
# 利妥昔单抗维持治疗,清除微小残余病灶,防止复发,延长无病生存时间
患者 (%)
1987–1996
1976–1986
1960–1975
年
100
80
60
40
20
0
0 5 10 15 20 25 30
2000 – 2010
滤泡性淋巴瘤治疗前瞻?
Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use
of single-agent or multiagent chemotherapy or combined modality
therapy has not had a significant impact on the natural course of
the disease.54
谢 谢
Actuarial survival curves for patients with low-grade NHL treated at Stanford University from 1960–1976, 1976–1987, and 1987–1996 are essentially indistinguishable, which shows that the widespread use
of single-agent or multi-agent chemotherapy or combined modality therapy has not had a significant impact on the natural course of
the disease.6
目前并无所谓治疗晚期惰性淋巴瘤的一线方案,CVP和CHOP是较为常用的方案.
从 2000年4月至2002年3月, 322位患者入组了这个3期试验.
患者随机进入R+CVP组或CVP组
90%为滤泡小细胞或混合型,9%为滤泡大细胞型
先予各4周期治疗,SD和PD患者退出,缓解的患者继续各4周期治疗
两组患者的基本情况,临床和病理特征无明显差异
CR quadruple
The relatively short TTF (7 months) observed with CVP is a result of SD at cycle 4 being considered a treatment failure
The TTP seen with CVP (15 months) is similar to that observed in other recent phase III trials of CVP
A trend towards significance for an improvement in OS.
两组治疗的耐受性均良好,虽然R+CVP组的粒细胞减少略增加,但感染的发生率无差异,也未发生与治疗有关的死亡
与CVP相比,R+CVP治疗晚期滤泡性NHL,显著改善患者的ORR, CR, TTF.
这些结果在随访18月时获得,并由随访25月所证实
德国低度淋巴瘤研究组( GLSG )牵头的随机临床,从2000年5月起, 超过800位初治的滤泡和套细胞淋巴瘤患者入组这个随机试验,疗程根据缓解出现的早或晚从6至8个,缓解患者再根据年龄二次分组分别接受移植或不同剂量干扰素维持治疗
总缓解率美罗华联合CHOP从90%提高到96%, 有显著差异.
2年随访,无失败生存率比较,美罗华联合CHOP超过80%,而CHOP仅70%
Inclusion criteria
CD20+ follicular NHL; Ann Arbor stage III or IV (classes B, C and D)
No previous systemic antilymphoma treatment
WBC <25 x 109/L
No CNS involvement
Additional standard inclusion criteria
The objective of rituximab maintenance therapy is to control remaining malignant cells after initial therapy and improve survival
although cure is currently not possible in indolent NHL, it is important to delay the next therapy for as long as possible.
Importantly, rituximab maintenance causes only minimal disruption of daily life
long half-life allows infrequent therapy while maintaining long-term exposure (in contrast to chemotherapy)
rituximab has minimal acute toxicity and there is no known cumulative toxicity
rituximab maintenance therapy can be delivered in the out-patient setting, causing minimal disruption to daily life.
In this study, all patients received four infusions of rituximab 375mg/m2 as induction.
Patients in arm A received no further rituximab while in arm B further rituximab infusions were given at week 12 and months 5, 7 and 9.
Circulating B-cells were rapidly depleted on induction treatment with rituximab in both arms
levels of T-helper, T-suppressor and NK cells remained approximately stable.
When no further rituximab treatment was given, B-cell recovery started 2–3 months after treatment and continued.
Rituximab maintenance therapy caused B-cells to remain depleted
at further follow-up, B-cell recovery appeared to commence once maintenance therapy was stopped.
There is now a considerable body of evidence demonstrating a significant clinical benefit with rituximab maintenance therapy in follicular lymphoma (FL).
These studies have demonstrated a benefit for rituximab maintenance in previously untreated, relapsed and refractory FL and after induction with rituximab monotherapy and rituximab-containing immunochemotherapy.
Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use
of single-agent or multiagent chemotherapy or combined modality
therapy has not had a significant impact on the natural course of
the disease.54