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ASH2008—CML

ASH2008—CML. 郑宇. Stephen O’Brien, Francois Guilhot, Brian Druker, John Goldman, Andreas Hochhaus, Timothy Hughes, Jerald Radich, Marc Rudoltz, Jeiry 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. 贡 献 者. 研究管理委员会 Brian Druker Richard Larson

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ASH2008—CML

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  1. ASH2008—CML 郑宇

  2. Stephen O’Brien, Francois Guilhot, Brian Druker, John Goldman, Andreas Hochhaus, Timothy Hughes, Jerald Radich, Marc Rudoltz, Jeiry 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 • 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 • 诺华临床试验小组 • Manisha Mone • Jeiry Filian • Insa Gathmann • Tillmann Krahnke • Marc Rudoltz • Alan Hatfield • Elisabeth Wehrle 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. 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

  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1IRIS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？ 疗效 (n = 82; 15%) 仍接受研究用伊马替尼治疗(n = 332; 60%) 获得CCR (n = 317; 57%) 未获得CCR (n = 15; 3%) 其他 (n = 96; 17%) 安全性(n = 43; 8%) 死亡**(n = 26; 60%) 存活(n = 52; 63%) 死亡(n = 30; 37%) 存活(n = 81; 84%) 死亡(n = 15; 16%) 存活(n = 17; 40%) 随机分配接受伊马替尼治疗 的所有患者 (n= 553; 100%) 中断研究用伊马替尼治疗*(n = 221; 40%) **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. 研究中中断伊马替尼治疗患者的生存 中断研究后5年 约85%患者生存 100 90 80 70 60 生存百分比（所有死亡事件）% 50 40 停止伊马替尼治疗后5年 约50%患者生存 30 安全性 (n=30) 疗效 (n=82) 骨髓干细胞移植 (n=16) 其他原因 (n=80) 20 10 0 0 12 24 36 48 60 72 84 96 停止伊马替尼治疗后的时间（月） IRIS 7年数据更新

  9. 总生存（ITT 原则）: 伊马替尼组 100 90 80 70 第7年时估计的 总生存率为86%(94% 仅考虑CML相关死亡) 60 无事件百分比% 50 40 30 生存: 与CML相关的死亡 20 总生存 10 0 0 12 24 36 48 60 72 84 96 从随机分组开始的时间（月） IRIS 7年数据更新

  10. 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

  11. 年事件率： 伊马替尼组 事件丧失CHR,丧失MCR, AP/BC,治疗期间死亡 AP/BC • 7年时KM估计的EFS = 81% • 7年时KM估计的无AP/BC率= 93% 7.5 4.8 事件百分比% 3.3 2.8 * 2.0 1.7 1.6 1.5 0.9 0.8 0.5 0.3 0.4 0 年 *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)。 IRIS 7年数据更新

  12. 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

  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) 获得 CCR (n = 377 of 456: 83%) 达到CCR的患者(n = 456; 100%) 丧失CCR (n = 79 of 456: 17%) 继续接受伊马替尼治疗 (n=298; 65%) 中断伊马替尼治疗 (n = 79; 17%) 继续接受伊马替尼治疗 (n = 25; 5%) 再次获得CCR (n = 19; 4%) 达到MCR (n = 6; 1%) 增加剂量后再次获得CCR (n = 6) IRIS 7年数据更新

  14. 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

  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 IRIS 7年数据更新

  16. 主要分子学反应(MMR) 和随着时间分子学反应增加的程度 100 90 80 ≤0.1% (MMR) 70 ≤0.01% 60 获得的标本百分比% 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 30 36 42 48 54 60 66 72 78 84 分子学反应率 BCR-ABL% (国际性测量评估) 标本分析时间点（月） 完全数据参看摘要334 IRIS 7年数据更新

  17. 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

  18. 最常报告的不良事件：一线伊马替尼治疗 • 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 IRIS 7年数据更新

  20. 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

  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 3months and 74% after 6 months. • One patient progressed at 6 months to  accelerated-blastic phase with the T315I mutation.

  25. Abstract 181* 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*

  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*

  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 19 relapsed within the first 6 months 19 pts who relapsed 15 relapsed within the >= 6 months

  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-fiveof 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*

  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.

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