ash2008—cml 郑宇. stephen o’brien, francois guilhot, brian druker, john goldman, andreas...

ASH2008—CML

郑宇

Stephen O’Brien, Francois Guilhot, Brian Druker, John Goldman, Andreas Hochhaus, Timothy Hughes, Jerald Radich, Marc Rudoltz, Jei

ry Filian, Insa Gathmann, Richard Larson

代表 IRIS 研究者们

伊马替尼用于初诊的 CML

慢性期长期疗效观察：

IRIS 研究 7 年随访数据

3

贡献者研究管理委员会• Brian Druker• Richard Larson• Steve O’Brien• Francois Guilhot

诺华临床试验小组• Manisha Mone• Jeiry Filian• Insa Gathmann• Tillmann Krahnke• Marc Rudoltz• Alan Hatfield• Elisabeth Wehrle

16 个国家 117 个中心• 澳大利亚 (11) • 新西兰 (1)• 奥地利 (1) • 比利时 (5) • 加拿大 (11) • 瑞典 (8) • 挪威 (3)• 丹麦 (3) • 法国 (10) • 德国 (17) • 荷兰 (2) • 意大利 (15) • 西班牙 (9) • 瑞士 (3) • 英国 (13) • 美国 (65)

PCR 委员会• Tim Hughes• Andreas Hochhaus• Letizia Foroni• Jerry Radich• John Goldman• Susan Branford

IRIS 7 年随访数据更新

4

IRIS 7 年数据更新 : 主要内容

• 对于所有的患者发生了什么 ?- 中断治疗- 存活

• 晚期进展事件• 完全细胞遗传学反应 (CCR) 的持久性

- 达到 CCR 就安全了吗？• PCR 数据• 不良事件• 结论

5





6

• IRIS 研究确立了伊马替尼作为 CML 慢性期初始治疗的标准用药的地位1

• 本报告是 IRIS 研究 7 年更新数据- 开始有 1106 名患者入组，每组 553 例- 1106 名患者中 554 例 (50%) 继续进行研究

• 554 名患者中 545 例 (98.4%) 接受伊马替尼治疗- 332 例接受伊马替尼一线治疗 (60% 的患者随机分配至一线

伊马替尼组， 400mg/ 日）- 213 例是从 IFN/Ara-C 交叉换药至伊马替尼组 (39% 的患者

随机分配接受 IFN/Ara-C 治疗 )

• 9 例 (1.6%) 仍接受 IFN/Ara-C 治疗• 由于仅 1.6% 的患者仍接受 IFN/Ara-C 治疗，因此本报告主要关注那些

随机分配至伊马替尼治疗组患者的长期疗效和安全性

IRIS 研究 7 年数据更新

IFN 干扰素 ; Ara-C, 阿糖胞苷。1Hochhaus A, et al. Blood. 2007; 110. Abstract 25. ASH 2007 Oral Presentation.

7

7 年后患者发生了什么？

随机分配接受伊马替尼治疗随机分配接受伊马替尼治疗的所有患者的所有患者 (n= 553; 100%)(n= 553; 100%)随机分配接受伊马替尼治疗随机分配接受伊马替尼治疗的所有患者的所有患者 (n= 553; 100%)(n= 553; 100%)

中断研究用伊马替尼治疗中断研究用伊马替尼治疗 ** (n = 221; 40%) (n = 221; 40%)

中断研究用伊马替尼治疗中断研究用伊马替尼治疗 ** (n = 221; 40%) (n = 221; 40%)

仍接受研究用伊马替尼治疗仍接受研究用伊马替尼治疗 (n = 332; 60%)(n = 332; 60%)

仍接受研究用伊马替尼治疗仍接受研究用伊马替尼治疗 (n = 332; 60%)(n = 332; 60%)

获得获得 CCR CCR (n = 317; 57%(n = 317; 57%

))

获得获得 CCR CCR (n = 317; 57%(n = 317; 57%

))

未获得未获得 CCR CCR (n = 15; (n = 15;

3%)3%)

未获得未获得 CCR CCR (n = 15; (n = 15;

3%)3%) 安全性安全性(n = 43; 8%(n = 43; 8%

))

安全性安全性(n = 43; 8%(n = 43; 8%

))

疗效疗效 (n = 82; 15(n = 82; 15

%)%)

疗效疗效 (n = 82; 15(n = 82; 15

%)%)

其他其他 (n = 96; 17(n = 96; 17

%)%)

其他其他 (n = 96; 17(n = 96; 17

%)%)

存活存活(n = 17; (n = 17;

40%)40%)

存活存活(n = 17; (n = 17;

40%)40%)

死亡死亡 ****(n = 26; (n = 26;

60%)60%)

死亡死亡 ****(n = 26; (n = 26;

60%)60%)

存活存活(n = 52; (n = 52;

63%)63%)

存活存活(n = 52; (n = 52;

63%)63%)

死亡死亡(n = 30; (n = 30;

37%)37%)

死亡死亡(n = 30; (n = 30;

37%)37%)

存活存活(n = 81; (n = 81;

84%)84%)

存活存活(n = 81; (n = 81;

84%)84%)

死亡死亡(n = 15; (n = 15;

16%)16%)

死亡死亡(n = 15; (n = 15;

16%)16%)

** 包括主要中断治疗的原因“死亡” (n=13)

* 研究中不能继续伊马替尼治疗的患者。IRIS 7 年数据更新

8

生存

百分

比（

所有

死亡

事件

）%

0

10

20

30

40

50

60

70

80

90

100

停止伊马替尼治疗后的时间（月）

0 12 24 36 48 60 72 84 96

安全性 (n=30)疗效 (n=82)骨髓干细胞移植 (n=16)其他原因 (n=80)

中断研究后 5 年约 85% 患者生存

停止伊马替尼治疗后 5 年约 50% 患者生存

IRIS 7 年数据更新

研究中中断伊马替尼治疗患者的生存

9

总生存（ ITT 原则） : 伊马替尼组

第 7 年时估计的总生存率为 86%

(94% 仅考虑 CML 相关死亡)

生存 : 与 CML 相关的死亡总生存

无事

件百

分比

%

0

10

20

30

40

50

60

70

80

90

100

从随机分组开始的时间（月）0 12 24 36 48 60 72 84 96


10





11

年事件率：伊马替尼组

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7年

事件

百分

比%

事件丧失 CHR,丧失 MCR,AP/BC,治疗期间死亡

AP/BC

3.3

7.5

4.8

1.71.5

2.8

1.6

0.9 0.80.30.5

0

2.0

0.4

• 7 年时 KM 估计的 EFS = 81%

• 7 年时 KM 估计的无 AP/BC 率 = 93%

* 总事件 (n=5) 包括 MCR 的丧失 (n=3) 和死亡 (n=2 ，其中之一包括在死亡前 6 个月获得 CMR 的 1 名患者视作进展至 AP/BC) 。* 总事件 (n=5) 包括 MCR 的丧失 (n=3) 和死亡 (n=2 ，其中之一包括在死亡前 6 个月获得 CMR 的 1 名患者视作进展至 AP/BC) 。

**


12





13

细胞遗传学反应的持久性• 553 名接受一线伊马替尼治疗的患者中 456 例 (82%) 达到 CCR• 随机分配至伊马替尼组的 317 名 (57%) 患者仍遵从研究方案继续接受治疗，并获得完全细胞遗传学

反应 (CCR)

达到达到 CCRCCR 的患者的患者 (n = 456; 100%)(n = 456; 100%)达到达到 CCRCCR 的患者的患者 (n = 456; 100%)(n = 456; 100%)

丧失丧失 CCRCCR (n = 79 of 456: 17%) (n = 79 of 456: 17%)

丧失丧失 CCRCCR (n = 79 of 456: 17%) (n = 79 of 456: 17%)

获得获得 CCR CCR (n = 377 of 456: 83%) (n = 377 of 456: 83%)

获得获得 CCR CCR (n = 377 of 456: 83%) (n = 377 of 456: 83%)

继续接受伊马替尼治疗继续接受伊马替尼治疗(n = 25; 5%)(n = 25; 5%)

继续接受伊马替尼治疗继续接受伊马替尼治疗(n = 25; 5%)(n = 25; 5%)

再次获得再次获得 CCRCCR (n = 19; 4%) (n = 19; 4%)

再次获得再次获得 CCRCCR (n = 19; 4%) (n = 19; 4%)

达到达到 MCRMCR (n = 6; 1%)(n = 6; 1%)

达到达到 MCRMCR (n = 6; 1%)(n = 6; 1%)

继续接受伊马替尼治疗继续接受伊马替尼治疗 ((n=298; 65%)n=298; 65%)

继续接受伊马替尼治疗继续接受伊马替尼治疗 ((n=298; 65%)n=298; 65%)

中断伊马替尼治疗中断伊马替尼治疗 (n = 79; 17%)(n = 79; 17%)

中断伊马替尼治疗中断伊马替尼治疗 (n = 79; 17%)(n = 79; 17%)

增加剂量后再次获得增加剂量后再次获得 CCRCCR (n = 6) (n = 6)

增加剂量后再次获得增加剂量后再次获得 CCRCCR (n = 6) (n = 6)


14





15

IRIS PCR 研究

• IRIS 研究方案规定一旦患者获得 CCR 即检测其分子学反应• 其他一些标本由一些地方间断提交，且无论细胞遗传学反应的状

况如何• 在澳大利亚和德国预先计划的亚组研究间断地进行了 PCR 检测，

且无论细胞遗传学反应的状况如何 (n=100)

- 在随访第 7 年时超过 85% 的患者至少在基线和每个随访点接受过 PCR 检测（通过提交大量标本而获得）

• 今天首次公布扩充的数据- Hughes et al. [abstract 334] 11:45 AM; Room 2009-2011 West


16

• 主要分子学反应 (MMR) 和随着时间分子学反应增加的程度

分子学反应率

BCR-ABL% ( 国际性测量评估 )

标本分析时间点（月）

≤0.1% (MMR)

≤0.01%

0

10

20

30

40

50

60

70

80

90

100

获得

的标

本百

分比

%

0 3 6 9 12 15 18 21 24 30 36 42 48 54 60 66 72 78 84

IRIS 7 年数据更新完全数据参看摘要 334

17





18

最常报告的不良事件：一线伊马替尼治疗最常见不良事件 (5 年)

所有级别的 AEs 患者百分比 %

3/4 级 AEs 患者百分比 %

浮肿 60 2

恶心 50 1

肌肉痉挛 49 2

肌肉骨骼痛 47 5

腹泻 45 3

皮疹 / 皮肤异常 40 3

疲乏 39 2

头疼 37 <1

腹痛 37 4

关节痛 31 3

• 2005 年后仅收集到少数不良事件 (SAEs)

• 1-2 年后 ¾ 级不良事件的发生率降低IRIS 7 年数据更新

19

IRIS 研究中 6 年和 7 年发生的 SAEs

无一例外 , 在伊马替尼组过去的 24 个月观察里，未报告新的AEs 事件发生

在第 6 和 7 年，共报告了 13 例怀疑与伊马替尼相关的 SAEs：充血性心力衰竭 (n=3)：在研究入组前所有患者之前存在心脏疾病

第二恶性肿瘤 (n=3)*

肌炎 (n=1)； CK升高 (n=1)；多发性硬化 (n=1)

胰腺炎 (n=1)；呕吐 (n=1)

皮肤炎 (n=1)肾衰竭 (n=1)

* 估计伊马替尼暴露 >400,000 患者年，来自临床研究和自发报告的临床安全性数据分析没有证实接受伊马替尼治疗的患者与一般人群比，恶性肿瘤的发生率增加* 估计伊马替尼暴露 >400,000 患者年，来自临床研究和自发报告的临床安全性数据分析没有证实接受伊马替尼治疗的患者与一般人群比，恶性肿瘤的发生率增加


20





21

IRIS 研究 7 年数据更新：结论• 总生存率 = 86%

• 无事件生存率 =81%；伊马替尼组 7% 进展至 AP/BC

• 研究中 40% 患者中断伊马替尼治疗• 553 名患者中 456 例 (82%) 达到 CCR (82%)

- 那些达到 CCR 的患者中 17% 随后丧失 CCR

- 那些达到 CCR 的患者中 3% 进展为 AP/BC

- 达到 CCR 的 456 名患者中， 10 例 (2%) 死于 CML

- 达到 CCR 的时间与进展至 AP/BC 率无关• 患者获得的 MMR 率和分子学反应程度随着治疗时间增加• 未观察到新的安全性问题• 伊马替尼 400 mg/ 日确定为 CML慢性期初始治疗的标准治疗方案

22

Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP)

• Nilotinib

• Dasatinib

• SKI-606(Bosutinib)?

• Imatinib

23

Nilotinib

• Abstract 181 High and Early Rates of Cytogenetic and Molecular Response with Nilotinib 800 Mg Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia in Chronic Phase: Results of a Phase 2 Trial of the GIMEMA CML Working Party

• Gianantonio Rosti1*, Fausto Castagnetti1*, Angela Poerio1*, Massimo Breccia2*, Luciano Levato3*, Adele Capucci4*, Mario Tiribelli5*, Fabio Stagno6*, Alfonso Zaccaria7*, Tamara Intermesoli8*, Bruno Martino9*, Monica Bocchia10*, Michele Cedrone11*, Francesco Bartucci12*, Francesca Palandri1*, Gabriele Gugliotta1*, Nicoletta Testoni1*, Giuliana Alimena13, Giovanni Martinelli1*, Fabrizio Pane, MD14, Giuseppe Saglio15* and Michele Baccarani1*

• 1.Institute of Hematology Seragnoli, Bologna, Bologna, Italy2.University of Rome ?La Sapienza, Italy3.Hematology Unit, Catanzaro, Italy4.Hematology Unit, Brescia, Italy5.Chair of Hematology, Udine, Italy6.Chair of Hematology, Catania, Italy7.Ematologia-Ravenna, Italy8.Chair of Hematology, Bergamo, Italy9.Reggio Calabria Hospital10.Chair of Hematology, University of Siena, Italy11.Hematology Unit, "San Giovanni-Addolorata" Hospital, Roma, Italy12.Novartis Pharma, Origgio (VA), Italy13.Division of Hematology-Dept. of Cellular Biotechnologies and Hematology, University La Sapienza of Rome, Rome, Italy14.F. di Oncologia Ematologica Diagnostica, Azienda Ospedaliera, Napoli, Italy15.Internal Medicine and Hematology, Universit?di Torino - Ospedale San Luigi, Orbassano, Italy

24

Abstract 181

• All 73 patients and 48/73 (66%) completed 3 and 6 months on treatment, respectively.

• Response at 3 and 6 months (ITT): the CHR rate was 100% and 98%, the CCgR rate 78% and 96%, respectively.

• A MMR, defined as a BCR-ABL:ABL ratio < 0.1% according to the International Scale, was achieved by 3% of all treated patients after 1 month on treatment, but this proportion rapidly increased to 22% after 2 months, 59% after 3 months and 74% after 6 months.

• One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation.

25

Abstract 181*

Months 1 2 3 6

CHR 100% 98%

CCgR 78% 96%

MMR 3% 22% 59% 74%

All 73 patients and 48/73 (66%) completed 3 and 6 months on treatment.

MMR, defined as a BCR-ABL:ABL ratio < 0.1%

26

Dasatinib

• Abstract 182 Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP)

• Jorge Cortes, Susan O'Brien*, Gautam Borthakur*, Dan Jones*, Farhad Ravandi*, Charles Koller*, Ofelia Mesina*, Alessandra Ferrajoli*, Jianqin Shan* and Hagop Kantarjian*

• M.D. Anderson Cancer Center, Houston, TX

27

Abstract 182*

Mo on therapy

Percent with CCyR (No. evaluable) P value

Dasatinib Imatinib 400mg

Imatinib 800mg

3 78 (45) 37 (49) 62 (202) 0.0003

6 93 (41) 54 (48) 82 (199) <0.0001

12 97 (35) 65 (48) 86 (197) 0.0001

18 88 (33) 68 (38) 89 (179) 0.004

24 80 (25) 70 (40) 88 (173) 0.006

28

SKI-606(Bosutinib)

• 还没开始

29

Imatinib

• Abstract 185 Cytogenetic and Molecular Response to Imatinib in High Risk (Sokal) Chronic Myeloid Leukemia (CML): Results of An European Leukemianet Prospective Study Comparing 400 Mg and 800 Mg Front-Line

• Abstract 186 International Randomized Study of Interferon Versus STI571 (IRIS) 7-Year Follow-up: Sustained Survival, Low Rate of Transformation and Increased Rate of Major Molecular Response (MMR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib (IM)

30

Imatinib

• Abstract 185 Cytogenetic and Molecular Response to Imatinib in High Risk (Sokal) Chronic Myeloid Leukemia (CML): Results of An European Leukemianet Prospective Study Comparing 400 Mg and 800 Mg Front-Line

• Michele Baccarani1, Fausto Castagnetti2*, Bengt Simonsson3*, Kimmo Porkka4*, Ibrahim C. Haznedaroglu5*, Arnon Nagler6, Francesca Palandri2*, Giovanna Rege Cambrin7*, Luciano Levato8*, Fausto Palmieri9*, Elisabetta Abruzzese10, Ugur 謟 bek11*, Veli Kairisto12*, Hans Bostrom3*, Johann Lanng Nielsen13*, Henrik Hjorth-Hansen14*, Ole Weis-Bjerrum15*, Nicoletta Testoni2*, Giovanni Martinelli16*, Fabrizio Pane, MD17, Giuseppe Saglio7* and Gianantonio Rosti2*

• 1.Department of Hematology and Oncological Sciences, University of Bologna, Bologna, Italy2.Dept. Hematology and Medical Oncology, University of Bologna, Bologna, Italy3.Hematology Unit, Uppsala University, Uppsala, Sweden4.Helsinki University Central Hospital, Helsinki, Hematology Research Unit, Finland5.Hematology, Hacettepe University, Ankara, Turkey6.Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel7.Internal Medicine and Hematology, Universit?di Torino - Ospedale San Luigi, Orbassano, Italy8.Hematology Unit, Catanzaro, Italy9.Hematology Unit, Avellino, Italy10.S. Eugenio Hospital, Rome, Italy11.Instanbul University, Instanbul, Turkey12.Turku University Central Hospital, Department of Medicine, Turku, Finland13.Aarhus University Hospital, Aarhus, Denmark14.St Olavs University Hospital, Trondheim, Norway15.Hematology Unit, Rigshospitalet, Copenhagen, Denmark16.Department of Hematology and Oncological Sciences, Seragnoli Institute, University of Bologna, Bologna, Italy17.A.F. di Oncologia Ematologica Diagnostica, Azienda Ospedaliera, Napoli, Italy

31

Abstract 185*

3 months 6 months 12 months

400 800 400 800 400 800

No. of pts 109 108 109 108 109 108

Dropouts(1) 4% 4% 5% 7% 5% 8%

D/C adverse events

1% 2% 4% 4% 4% 7%

Failure(2) 1% 1% 9% 10% 16% 15%

CCgR(3) 19% 25% 49% 52% 58% 64%

MolR>3.0 log(4) 7% 12% 25% 31% 33% 40%

MolR>4.5 log(4) 1% 2% 3% 9% 10% 19%

Transcript level (median)

2.085 1.122 0.378 0.108 0.084 0.036

32

Abstract 185

Conclusions:

• Based on an intention-to-treat analysis, this study did not show a significant benefit of 800 mg over 400 mg in SHR patients, but the patients who could comply with the high dose had a better cytogenetic outcome.

33

STIM

• Abstract 187 Is It Possible to Stop Imatinib in Patients with Chronic Myeloid Leukemia? An Update from a French Pilot Study and First Results from the Multicentre « Stop Imatinib » (STIM) Study

• Francois-Xavier Mahon1*, Francoise Huguet, MD2*, Francois Guilhot, MD3, Laurence Legros, MD, PhD4*, Franck E Nicolini, MD, PhD5, Aude Charbonnier6*, Agnes Guerci, MD7*, Delphine Rea, MD, PhD8*, Bruno R. Varet, MD9, Martine Gardembas, MD10*, Joelle Guilhot3*, Gabriel Etienne11*, Noel-Jean Milpied, MD, PhD12, Emilie Aton13*, Josy Reiffers11* and Philippe Rousselot14*

34

Abstract 187

• The STIM study included 50 pts from 18 centres (20 male, 30 female), with a median age of 62 years (range 32–81 years).

• Of these, 25 pts had received no pre-treatment with IFN.

• By July 2008, 34 pts had a follow up ≥ 6 months.

• Eighteen pts relapsed within the first 6 months: 3 pts in month 2 (M2), 8 pts in M3, 4 pts in M4, and 3 pts in M5. One patient relapsed after more than 6 months (M8).

• Among the 19 pts who relapsed, 11 were not IFN pre-treated and 8 were IFN pre-treated (relapse rate 44% vs 32%).

• Ten IFN pre-treated pts with follow up ≥ 6 months have not relapsed (M12 in 2 pts, M10 in 5 pts, M8 in 1 pt, M7 in 2 pts), and 5 pts with follow up ≥ 6 months who were not IFN pre-treated have not relapsed (M12 in 1 pt, M10 in 1 pt), M8 in 1 pt, M6 in 2 pts).

35

Abstract 187

Mo 1 2 3 4 5 6 7 8

Pts 3 8 4 3 1

19 relapsed within the first 6 months

Mo 0-5 6 7 8 9 10 11 12

IFN pre-treated

10 2 1 5 2

Not IFN pre-treated

5 2 1 1 1

15 relapsed within the >= 6 months

IFN pre-treated Not IFN pre-treated

8(32%) 11(44%)

19 pts who relapsed

36

Abstract 187

• These studies confirm that CMR can be sustained after discontinuation of IM, particularly in pts pre-treated with IFN with a long follow-up (pilot study).

• Among pts in the STIM study who were not pre-treated with IFN, more than half have not relapsed, and 20% have reached a follow-up ≥ 6 months and not relapsed.

• Updated data will be presented but we conclude that it is possible to stop treatment in pts with sustained CMR, even in those treated with IM as a single agent.

37

Cease Imatinib

• Abstract 1102 The Majority of Chronic Myeloid Leukaemia Patients Who Cease Imatinib after Achieving a Sustained Complete Molecular Response (CMR) Remain in CMR, and Any Relapses Occur Early

• • David M Ross1*, Andrew Grigg2*, Anthony Schwarer2, Christopher Arthur2, Kerryn Loftus3*,

Anthony K Mills2*, Robin Filshie2*, Ruth Columbus2*, John Reynolds2*, John F Seymour, MB, BS, PhD, FRACP4*, Susan Branford1* and Timothy Hughes1

• 1.Institute of Medical & Veterinary Science, Adelaide, Australia2.Australasian Leukaemia & Lymphoma Group, Australia3.Novartis Pharmaceuticals, Australia4.Dept of Haematology, Peter MacCallum Cancer Institute, Victoria, Australia

38

Abstract 1102

• Patients were enrolled in two cohorts: imatinib de novo (IM only, n=5) and imatinib after prior interferon therapy (IFN-IM, n=13). The median duration of prior IFN was 39 months. Both cohorts continue to accrue.

• For all 18 patients the median age at study entry was 58 years; 44% were male. The median duration of imatinib treatment was 60 months (R40-89).

39

Abstract 1102

• Ten of 13 IFN-IM patients (77%) remain in CMR, and 7 of these have been in CMR for at least 12 months without treatment (maximum 23 months). The median follow-up in the IM only patients is currently only 7 months (R1-15), and 3/5 remain in CMR.

• All molecular relapses in both groups have occurred within 5 months of stopping imatinib. The median duration of prior imatinib treatment was not different in the 5 patients with loss of CMR (76 months) versus those in stable CMR (60 months; p=0.59). Among the 5 patients with loss of CMR the median time to molecular relapse was 3 months (range 2-5 months). Two relapsing patients lost MMR, and 3 had detectable BCR-ABL mRNA below this level.

• No patient has experienced haematological relapse or developed a kinase domain mutation. At last follow-up all 5 relapsing patients had regained CMR after a median of 5 months of re-treatment with imatinib.

40

Abstract 1102

• Patient-specific DNA Q-PCR assays were developed to test whether minimal residual disease (MRD) was detectable in genomic DNA in patients in CMR defined by RQ-PCR for BCR-ABL mRNA.

• Results are available for 6 patients, 3 of whom have relapsed. One relapsing patient had BCR-ABL DNA detected prior to imatinib withdrawal. In the remaining 2 relapsing patients BCR-ABL DNA was detected after imatinib withdrawal, but 2-3 months prior to the detection of BCR-ABL mRNA by RQ-PCR. BCR-ABL DNA increased by at least 1-log between the time of the first positive result and the detection of molecular relapse by RQ-PCR.

• The 3 patients in stable CMR had no detectable BCR-ABL DNA.

41

Abstract 1102

• In conclusion, with close molecular monitoring imatinib withdrawal in stable CMR appears to be safe: currently all patients are either in stable CMR off treatment or back in CMR after re-treatment.

• Withdrawal of effective treatment outside the setting of a clinical trial is not recommended.

• Monitoring of MRD by genomic DNA Q-PCR was able to detect molecular relapse prior to mRNA RQ-PCR, and shows promise for the prospective identification of patients at high risk of relapse.

• There is an apparent dichotomy of response between early molecular relapse and durable CMR, at least in patients treated with imatinib after IFN.

• It is too early to identify clinical or laboratory factors (such as prior IFN treatment) that may influence the probability of sustained CMR without treatment.

42

2nd Generation TKI

• Nilotinib

• Dasatinib

• SKI-606(Bosutinib)

43

Imatinib-Intolerant -- Nilotinib

• Abstract 3215 Minimal Cross-Intolerance Between Nilotinib and Imatinib in Patients with Imatinib-Intolerant Chronic Myeloid Leukemia in Chronic Phase (CML-CP) or Accelerated Phase (CML-AP)

• Elias Jabbour, MD1*, Hagop M Kantarjian2, Michele Baccarani, MD3*, Philipp D. le Coutre, MD4, Ariful Haque5*, Neil J. Gallagher, MD, PhD6, Jorge Cortes, MD1 and Francis Giles, MD7

• 1.M.D. Anderson Cancer Center, Houston, TX2.The University of Texas M. D. Anderson Cancer Center, Houston, TX3.Institute of Hematology and Medical OncologySeragnoli, Bologna, Italy4.Department of Hematology and Oncology, Charit?- Humboldt-Universitat, Campus Virchow, Berlin, Germany5.Novartis Pharmaceuticals, Florham Park, NJ6.Oncology, Novartis Pharma AG, Basel, Switzerland7.The Institute for Drug Development, CTRC, University of Texas Health Science Center, San Antonio, TX

44

Abstract 3215

• Ninety-five of 321 (30%) CML-CP patients and 27 of 138 (20%) CML-AP patients were included in this subanalysis of cross-intolerance following imatinib intolerance.

• Patients experiencing multiple reasons for imatinib intolerance were counted for each AE category and these included patients (8 CML-CP, 3 CML-AP) with unusual symptoms during imatinib therapy, none of these patients discontinued nilotinib due to the same AE.

• Median dose intensity for nilotinib (CML-CP 688mg/day, range 151-800; CML-AP 769mg/day range 184-1149) closely approximated the planned dose of 800mg/day. Among these patients, 64% of CML-CP and 52% of CML-AP patients experienced dose interruptions, however, the median cumulative duration of dose interruptions were short (CML-CP 24 days, range 1-301; CML-AP 17 days, range 4-234).

45

Abstract 3215

• Of the 72 patients (57 CML-CP, 15 CML-AP) who discontinued imatinib due to non-hematologic AEs, 3/72 (4%) experienced same persistent grade 2 AEs, only 1 patient (1%) experienced a recurrence of same grade 3/4 AE during nilotinib therapy, and none discontinued nilotinib due to cross intolerance. Approximately one-third of patients were imatinib intolerant due to hematologic AEs.

• Of 39 patients (30 CML-CP, 9 CML-AP) with hematologic intolerance to imatinib, 3/39 (8%) experienced same persistent grade 2 hematologic AEs, 20/39 (51%) of patients experienced a recurrence of same grade 3/4 AEs during nilotinib therapy, however, only 7 (18%) discontinued nilotinib and all occurred in CML-CP patients due to thrombocytopenia.

46

Abstract 3215

• Nilotinib therapy exhibited significant efficacy in imatinib-intolerant patients.

• Among the imatinib-intolerant patients included in this subanalysis who did not have complete hematologic response (CHR) at baseline, 90% of patients with CML-CP and 37% with CML-AP achieved a CHR on nilotinib therapy.

• Among all imatinib-intolerant patients included in this subanalysis, MCyR was achieved by 63% and 32% of patients with CML-CP and CML-AP, respectively; CCyR was achieved by 49% of CML-CP and 19% of CML-AP patients.

47

Abstract 3215*

imatinib-intolerant patients

CP AP

CHR 90% 37%

MCyR 65% 32%

CCyR 49% 19%

48

Abstract 3215

Conclusions:

• These results confirm that there is minimal cross-intolerance with nilotinib in imatinib-intolerant CML-CP and CML-AP patients.

• Thrombocytopenia was the only laboratory abnormality leading to imatinib intolerance that has recurred with any significant frequency during nilotinib therapy.

49

Imatinib-Resistant -- Nilotinib

• Abstract 3234 Efficacy and Tolerability of Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) Who Failed Prior Imatinib and Dasatinib Therapy: Updated Results of a Phase 2 Study

• Francis Giles, MD1, Philipp D. le Coutre, MD2, Kapil N. Bhalla, MD3*, Gert J Ossenkoppele, MD, PhD4, Giuliana Alimena, MD5*, Ariful Haque, M.S.6*, Neil J. Gallagher, MD, PhD7 and Hagop M Kantarjian8

• 1.The Institute for Drug Development, CTRC, University of Texas Health Science Center, San Antonio, TX2.Department of Hematology and Oncology, Charit?- Humboldt-Universitat, Campus Virchow, Berlin, Germany3.H. Lee Moffit Cancer Center, University of South Florida, Tampa, FL4.Department of Hematology, VU University Medical Center, Amsterdam, Netherlands5.Division of Hematology-Dept. of Cellular Biotechnologies and Hematology, University La Sapienza, Rome, Italy6.Novartis Pharmaceuticals, Florham Park, NJ7.Oncology, Novartis Pharma AG, Basel, Switzerland8.The University of Texas M. D. Anderson Cancer Center, Houston, TX

50

Abstract 3234

• A total of 37 patients (median age 62 years) with CML-CP were included in the analysis.

• The median time since first diagnosis of CML was 86 months. The median duration of prior imatinib therapy was 40.6 months with 84% being imatinib-resistant and 16% imatinib-intolerant.

• The median duration of prior dasatinib therapy was 6.6 months, with the majority of patients (65%) being intolerant to dasatinib therapy and 32% of patients were dasatinib resistant.

• Approximately half (51%) of the patients discontinued dasatinib due to grade 3/4 laboratory abnormalities or adverse events (AEs) and 32% discontinued due to disease progression.

• The median duration of nilotinib exposure was 218 days (7.3 months; range 43–723 days) and 65% of patients remained on nilotinib at the time of data cut-off. In total, only 4 (11%) patients discontinued nilotinib due to AEs and 9 (24%) discontinued due to disease progression.

51

Abstract 3234*

• For CML-CP patients without complete hematologic response (CHR) at baseline, 81% achieved CHR with nilotinib treatment. The median time to first CHR for patients with confirmed HR was 1 month.

• Major cytogenetic response (MCyR) was achieved in 38% of patients with median time to first MCyR being 1 month and median duration of MCyR being 9.7 months.

• Complete cytogenetic response (CCyR) was achieved in 18% of patients.

• Estimated 1-year overall survival was 97%.

52

Abstract 3234

• The most frequent drug-related non-hematologic AEs on nilotinib were rash (22%), nausea (16%), and pruritus (14%).

• Newly occurring or worsening grade 3/4 hematologic laboratory abnormalities included neutropenia (38%), thrombocytopenia (24%), and anemia (5%).

• Other common grade 3/4 biochemical laboratory abnormalities included elevated lipase (24%), hyperglycemia (11%), elevated alanine aminotransferase (8%), and hypophosphatemia (8%).

• Brief dose interruptions were sufficient to manage most adverse events.

53

Imatinib-Resistant -- Nilotinib

• Abstract 3238 Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

• Hagop M Kantarjian1, Francis Giles, MD2, Kapil N. Bhalla, MD3*, Richard A. Larson, MD4, Norbert Gattermann, MD5, Oliver G. Ottmann, MD6*, Ariful Haque, M.S.7*, Neil J. Gallagher, MD, PhD8, Michele Baccarani, MD9* and Philipp D. le Coutre, MD10

• 1.The University of Texas M. D. Anderson Cancer Center, Houston, TX2.The Institute for Drug Development, CTRC, University of Texas Health Science Center, San Antonio, TX3.H. Lee Moffit Cancer Center, University of South Florida, Tampa, FL4.University of Chicago, Chicago, IL5.Heinrich-Heine-University, D黶 seldorf, Germany6.Department of Medicine, Hematology/Oncology, University Hospital of Frankfurt, Frankfurt, Germany7.Novartis Pharmaceuticals, Florham Park, NJ8.Oncology, Novartis Pharma AG, Basel, Switzerland9.Institute of Hematology and Medical OncologySeragnoli, Bologna, Italy10.Department of Hematology and Oncology, Charit?- Humboldt-Universitat, Campus Virchow, Berlin, Germany

54

Abstract 3238

• A total of 321 CML-CP patients (71% imatinib-resistant; 29% imatinib-intolerant) were evaluated.

• Most patients were heavily pretreated with 72% having received more than 600 mg/day of imatinib prior to study entry. Furthermore, imatinib-intolerant patients could not have achieved prior MCyR on imatinib therapy.

• Median duration of prior imatinib treatment was 33 months (range 0.3–95 months). Dose reductions (25%) and discontinuations (15%) due to adverse events were infrequent on nilotinib therapy and median dose intensity (788 mg/day; range 151-1112 mg/day) closely approximated the planned dose. Median duration of exposure was 465 days (15.5 months).

55

Abstract 3238

• Overall, nilotinib therapy resulted in rapid and durable hematologic and cytogenetic responses. Of all imatinib-resistant and –intolerant patients, 58% achieved MCyR (1 month median time to MCyR), with 72% of patients having a baseline CHR achieving MCyR. The MCyR rate was 63% in imatinib-intolerant and 56% in imatinib-resistant patients, respectively.

• Overall, 42% of patients achieved a CCyR (50% in imatinib-intolerant and 39% in imatinib-resistant patients, respectively).

• Responses were durable, with 84% of patients maintaining their MCyR at 18 months. Estimated overall survival (OS) rates at 12 and 18 months were 95% and 91%, respectively.

56

Abstract 3238*

Nilotinib therapy

Total imatinib-resistant

imatinib-intolerant

MCyR 58% 56% 63%

CCyR 42% 39% 50%

Estimated overall survival (OS) rates at 12 and 18 months were 95% and 91%, respectively.

Nilotinib therapy resulted in rapid and durable hematologic and cytogenetic responses.

57

Abstract 3238

• Nearly half of all patients (47%) were still receiving nilotinib at the time of cut-off for data analysis. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 biochemical laboratory abnormalities were elevated lipase (16%), hypophosphatemia (15%), hyperglycemia (12%), and elevated total bilirubin (7%).

• Overall, biochemical laboratory abnormalities were transient and clinically asymptomatic. Grade 3/4 non-hematologic adverse events were infrequent with rash, headache, and diarrhea occurring in only 2% of patients. No pleural or pericardial effusions were documented during nilotinib therapy. The most common grade 3/4 hematological laboratory abnormalities included neutropenia (30%), thrombocytopenia (28%), and anemia (10%).

• Overall, QTcF changes greater than 60 milliseconds from baseline were infrequent, occurring in only 8 patients (2.5%), and QTcF prolongation >500 milliseconds was uncommon (<1%), occurring in only 3 patients. Brief dose interruptions were sufficient to manage most adverse events.

58

Abstract 3238

Conclusions:

• Nilotinib is highly effective and produces rapid and durable responses in CML-CP patients who failed prior therapy including imatinib due to resistance or intolerance and is an important treatment option for this patient population.

• Nilotinib is well tolerated with minimal occurrence of grade 3/4 adverse events; safety profile has not changed with longer follow-up.

59

Imatinib-Resistant --Dasatinib

• Abstract 1095 Dasatinib-Associated Major Molecular Responses Are Rapidly Achieved in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Following Resistance, Suboptimal Response, or Intolerance on Imatinib

• Andreas Hochhaus, MD1, Martin C Müller, MD1*, Jerald Radich, MD2, Susan Branford3, Benjamin Hanfstein, MD1*, Philippe Rousselot, MD, PhD4*, Jeffrey H Lipton, MD, PhD5, Eric Bleickardt6*, Ritwik Sinha6* and Timothy P Hughes, MD3*

• 1.III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany2.Fred Hutchinson Cancer Rsch. Ctr., Seattle, WA3.Institute of Medical and Veterinary Science, Adelaide, Australia4.Hôpital Mignot and CIC9504, Versaille, France5.Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada6.Bristol-Myers Squibb, Wallingford, CT

60

Abstract 1095*

Major molecular response (%) Follow-up (months)

3 6 12 24

All analyzed patients (n=1067) 12 22 35 40

Resistant/suboptimal response (n=829) 10 18 29 34

Intolerant (n=238) 22 37 55 63

Phase II studies (013/017) (n=467) 17 27 39 44

Resistant (n=373) 13 21 31 35

Intolerant (n=94) 33 50 69 78

Phase III dose-optimization study (034) (n=600)

9 19 32 38

Resistant/suboptimal response (n=456) 7 16 27 33

Intolerant (n=144) 15 29 46 54

Response by dose schedule

100 mg QD (n=154) 7 18 29 36

70 mg BID (n=146) 9 18 32 38

140 mg QD (n=144) 13 22 32 38

50 mg BID (n=156) 7 17 34 38

61

Imatinib-Resistant --Dasatinib

• Abstract 2128 Dasatinib Is Associated with Rapid and Durable Complete Hematologic Responses in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)

• Delong Liu, MD, PhD1*, Yousif Matloub2*, Jaydip Mukhopadhyay2*, David Liu2* and Stuart L Goldberg3

• 1.New York Medical College, Valhalla, NY2.Bristol-Myers Squibb, Wallingford, CT3.John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ

62

Abstract 2128*

Table 1: Percentage of Dasatinib-Treated Patients with CHR who are Imatinib Resistant (CA180-034 trial)

Best Hematologic Response

Number (%) of Subjects by Treatment Group

QD BID

100 mg N = 124

140 mg N = 123

TotalN = 247

50 mg N = 124

70 mg N = 126

TotalN = 250

CHR 110 (89) 106 (86) 216 (87) 114 (92) 112 (89) 226 (90)

no CHR 14 (11) 17 (14) 31 (13) 10 (8) 14 (11) 24 (10)

63

Imatinib-Resistant -SKI-606

• Abstract 1098 Efficacy and Safety of Bosutinib (SKI-606) in Patients with Chronic Phase (CP) Ph+ Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib

• Jorge Cortes, MD1, Hagop M Kantarjian2, Dong-Wook Kim, MD, PhD3, H. Jean Khoury, MD, FACP4, Anna G. Turkina, MD5*, Zhi-Xiang Shen, MD6*, Tim H Brummendorf, MD7*, Mammen Chandy, MD8*, Steven Arkin, MD9 and Carlo Gambacorti-Passerini, MD10*

• 1.M.D. Anderson Cancer Center, Houston, TX2.The University of Texas M. D. Anderson Cancer Center, Houston, TX3.Hematology, St. Mary's Hospital, Seoul, South Korea4.Emory University, Atlanta, GA5.Hematology Research Center, Russia6.Rui Jin Hospital, China7.Universitäts-Klinikum Hamburg-Eppendorf, Hamburg, Germany8.Christian Medical College Hospital, India9.Wyeth Research, Cambridge, MA10.University Milano Bicocca, Monza, Italy

64

Abstract 1098

• The phase I portion of this study identified a treatment dose of 500 mg daily and showed evidence of clinical efficacy. The phase II portion of the study to investigate the efficacy and safety of bosutinib in patients (pts) with CP Ph+ CML who have failed imatinib therapy is ongoing.

• Preliminary data for 283 treated pts, median age 54 yrs (range 18 – 91 yrs) and 52% male are reported. A subset of pts received treatment in addition to imatinib, including interferon (91 pts), dasatinib (71 pts), nilotinib (7 pts) and stem cell transplant (13 pts). Among pts who failed imatinib (and received no other tyrosine kinase inhibitor treatment), 137 were imatinib-resistant (all received imatinib ≥600mg) and 64 pts were imatinib-intolerant; median duration of bosutinib treatment to date is 7.7 mos (range 0.2 – 28.2 mos) and 4.5 mos (range 0.5 – 21.5 mos), respectively.

65

Abstract 1098

• Among 67 imatinib-resistant pts evaluable for hematological response, 53 (79%) had complete hematological response (CHR).

• Of 84 imatinib-resistant pts evaluable for cytogenetic response, 34 (40%), achieved a major cytogenetic response (MCyR), including 24 (29%) with a complete cytogenetic response (CCyR).

• Of 34 pts with MCyR, 31 have maintained their response to date.

• Of 60 evaluable imatinib-resistant pts, 20 (33%) achieved major molecular response, 10 (17%) of which were complete.

• Among imatinib-intolerant pts, 22 of 29 evaluable (76%) achieved CHR, and 13 of 22 evaluable (59%) achieved MCyR, including 11 (50%) with CCyR.

• Of 25 evaluable imatinib-intolerant pts, 7 (28%) achieved major molecular response, 5 (20%) of which were complete.

66

Abstract 1098*

Pts CHR MCyR CCyR

imatinib-resistant

84 53(67) 34(40%) 24(29%)

60(evaluable) 20(33%) 10(17%)

imatinib-intolerant

29 22(76%) 13(59%) 11(50%)

25(evaluable) 7(28%) 5(20%)

67

Abstract 1098

• Of 105 pts with baseline samples tested for mutations, 17 different mutations were found in 45 pts (43%).

• CHR occurred in 5/6 pts (83%) with P-loop mutations and 13/17 (76%) with non-P-loop mutations; MCyR occurred in 3/6 pts (50%) and 11/24 pts (46%), with P-loop and non-P-loop mutations, respectively.

68

Abstract 1098

• Treatment was generally well tolerated. • The most common adverse events among treated pts (n=283) wer

e gastrointestinal (nausea, vomiting, diarrhea), these were usually grade 1 – 2, manageable and transient, diminishing in frequency and severity after the first 3 – 4 weeks of treatment.

• Grade 3 -4 non-hematologic toxicity occurring in ≥5% of pts were diarrhea (8%), rash (8%) and increased ALT (5%). 27 pts (10%) reported grade 1/2 fluid retention adverse events, including 21 pts with edema, and 6 pts with effusions: 4 pleural, 1 pericardial, and 1 pleural and pericardial. A single patient experienced grade 3 pleural effusion possibly related to bosutinib with concomitant pneumonia and a pre-treatment history of recurrent pleural effusions.

• Grade 3 – 4 hematologic laboratory abnormalities included thrombocytopenia in 65 pts (23%), neutropenia in 37 pts (13%) and anemia in 17 pts (6%). 124 pts (44%) had at least 1 temporary treatment interruption and 85 pts (30%) had at least 1 dose reduction due to toxicity. 37 pts (13%) have permanently discontinued treatment due to adverse event.

69

Abstract 1098

Conclusions:

• Bosutinib is effective in pts with CP CML with resistance or intolerance to imatinib across a range of mutations.

• Unlike other tyrosine kinase inhibitors, bosutinib does not significantly inhibit PDGFR or c-kit, and this may be responsible for the relatively favorable toxicity profile with few pts experiencing hematologic toxicity or fluid retention.

70

Imatinib-Resistant -SKI-606

• Abstract 1101 Bosutinib (SKI-606) Demonstrates Clinical Activity and Is Well Tolerated in Patients with AP and BP CML and Ph+ ALL

• Carlo Gambacorti-Passerini1*, Enrico Maria Pogliani, MD2, Michele Baccarani, MD3*, Giovanni Martinelli4*, Hagop M Kantarjian5, Mammen Chandy6*, H. Jean Khoury, MD, FACP7, Dong-Wook Kim8*, Tim H Brummendorf9*, Steven Arkin, MD10 and Jorge Cortes11*

• 1.University Milano Bicocca, Monza, Italy2.Hematology, New Hospital San Gerardo, Monza, Italy3.Dept. Hematology and Medical Oncology, University of Bologna, Bologna, Italy4.Department of Hematology and Oncological Sciences, Seragnoli Institute, University of Bologna, Bologna, Italy5.The University of Texas M. D. Anderson Cancer Center, Houston, TX6.Christian Medical College Hospital, India7.Emory University, Atlanta, GA8.Division of Hematology, St. Mary's Hospital, Seoul, South Korea9.Hubertus Wald-University Cancer Center, Hamburg-Eppendorf (UCCH), University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany10.Wyeth Research, Cambridge, MA11.The University of Texas M.D. Anderson Cancer Center, Houston, TX

71

Abstract 1101

• Preliminary data for 101 subjects, median age 51.5 yrs (range 18 – 84 yrs) and 56% male are reported. 44 pts were in AP, 35 in BP, 21 had Ph+ ALL, and 1 was unclassified.

• Prior therapy in addition to imatinib included interferon (35 pts), dasatinib (40 pts), nilotinib (15 pts) and stem cell transplant (11 pts). 49 pts failed imatinib (and received no other tyrosine kinase inhibitor [TKI]) and 52 pts failed both imatinib and other TKIs, with median duration of bosutinib treatment to date 4.4 mos (range 0.3 – 21.3 mos) and 2.0 mos (range 0.3 – 18.8), respectively.

•

72

Abstract 1101

• Among pts with no TKI exposure other than imatinib, complete hematological response (CHR) was obtained in 12/25 evaluable pts (48%), including 7/11 pts (64%) with AP-CML, 4/11 pts (36%) with BP-CML and 1 pt with Ph+ ALL.

• Major cytogenetic response (MCyR) was achieved in 16/22 evaluable pts (73%) with no TKI exposure other than imatinib, including 9/13 pts (69%) with AP-CML and 6/8 pts (75%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR.

• Major molecular response (MMR) was achieved in 9/25 evaluable pts (36%) with no TKI exposure other than imatinib, including 1/7 pts (14%) with AP-CML, 4/10 pts (40%) with BP-CML and 4/8 pts (50%) with Ph+ ALL.

73

Abstract 1101*

Pts AP BP Ph+ALL

Total 25 11 11 3

CHR 12 7 4 1

Pts AP BP Ph+ALL

Total 22 13 8 1

MCyR 16 9 6 1

Pts AP BP Ph+ALL

Total 25 7 10 8

MMR 9 1 4 4

74

Abstract 1101*

• Among pts with other TKI exposure in addition to imatinib, CHR was obtained in 3/15 evaluable pts (20%), all with AP-CML; MCyR was achieved in 6/20 evaluable pts (30%), including 3/12 pts (25%) with AP-CML and 2/7 pts (29%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR.

• Of the 20 pts with other TKI exposure in addition to imatinib who were evaluable for MMR, 1 pt with Ph+ ALL (5%) achieved this response.

75

Abstract 1101

• Of 60 pts with baseline samples tested for mutations, 15 different mutations were found in 32 pts (53%), including 8 instances of T315I.

• CHR occurred in 2/8 evaluable pts (25%) with non-P-loop mutations; the 1 evaluable pt with a P-loop mutation did not achieve CHR. MCyR occurred in 4/11 evaluable pts (36%) with non-P-loop mutations and in 1/2 evaluable pts (50%) with P-loop mutations.

76

Abstract 1101

• Treatment was generally well tolerated.

• The most common adverse events among treated pts (n=101) were gastrointestinal (diarrhea [66%], nausea [46%] and vomiting [42%]) but these were usually grade 1 – 2, manageable and transient, reducing in frequency and severity after the first 3 – 4 weeks of therapy.

• Grade 3 – 4 non-hematologic toxicities occurring in ≥ 5% of pts were diarrhea (7%), vomiting (6%), pneumonia (6%) and increased ALT (5%). Fluid retention was reported as grade 1 – 2 in 18 pts and grade 3 – 4 in only 3 pts (including 2 pleural effusions, neither related to bosutinib).

• Grade 3 – 4 hematologic laboratory abnormalities reported include thrombocytopenia (68%), neutropenia (48%) and anemia (37%). 38 pts had at least 1 temporary treatment interruption and 22 pts had at least 1 dose reduction due to toxicity. 11 pts have permanently discontinued treatment due to adverse event.

77

Very Elderly, Children and Adolescents

• Abstract 1096 Treatment with Imatinib in Very Elderly (> 75 Years) CML Patients

• Abstract 3241 Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia: Interim Results of the CA180-018 Phase I Study from the ITCC Consortium

• Abstract 3233 Nilotinib in Elderly Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) with Imatinib Resistance or Intolerance: Efficacy and Safety Analysis

78

Deletions of Chromosome

• Abstract 2110 Prognostic Impact of Deletions of Derivative Chromosome 9 on Patients (PTS) with Chronic Myelogenous Leukemia (CML) in Chronic Phase Treated with Nilotinib or Dasatinib

• Abstrat 2117 Loss of the Y Chromosome in Philadelphia-Positive Cells Predicts a Poor Response of CML Patients to Imatinib Mesylate Therapy

79

2nd cancer

• Abstract 2125 Malignancies Occurring during Therapy with Tyrosine Kinase Inhibitors (TKI) for Chronic Myeloid Leukemia (CML) and Other Hematologic Malignancies

80

结论

• 在 2008 年，大多数诊断为 CML慢性期的患者都能预期有长期缓解和较高的生活质量。

• 对于治疗失败的那 20％到 30％患者，二线抑制药物是较好的可选治疗方案。

• 但是，一旦疾病进入加速期，只要患者合适，都应进行异基因干细胞移植。

• 更重要的是，似乎直接作用于 BCR-ABL酪氨酸激酶的疗法不能根治疾病，因为它们不能杀灭 CML 干细胞。

81

Thank You

ash2008—cml 郑宇. stephen o’brien, francois guilhot, brian druker, john goldman, andreas...

Documents