精美幻灯(2010美国临床肿瘤学会年会恶性血液病最新进展).ppt

1、June 4-8, 2010Chicago, Illinois,Hematologic MalignanciesCCO Independent Conference Coverageof the 2010 American Society of Clinical Oncology Annual Meeting*,*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through confere

2、nce coverage and other educational programs.,This program is supported by educational grants from Amgen, Bristol-Myers Squibb, Celgene, Genentech BioOncology, Millennium Pharmaceuticals, Inc., Novartis Oncology, and Pfizer, Inc.,About These Slides,Our thanks to the presenters who gave permission to

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5、c products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described i

6、n these materials.,Faculty,Nicholas J. DiBella, MDCo-Chairman, Hematology Research Committee, US Oncology President, Rocky Mountain Cancer Centers Aurora, Colorado,An Update on Hematologic Malignancies: Overview,PRIMA: rituximab maintenance vs observation in patients with follicular lymphoma who res

7、ponded to induction with rituximab plus chemotherapy Phase II trial of panobinostat in relapsed/refractory Hodgkins lymphoma Phase II trial of R-GemOx for patients with relapsed/refractory DLBCL not candidates for high-dose therapy DASISION: phase III trial of imatinib vs dasatinib in untreated CP-C

8、ML ENESTnd phase III trial of nilotinib 300 mg BID or 400 mg BID vs imatinib 400 mg QD in newly diagnosed Ph-positive CP-CML Investigation of azacitidine in chronic myelomonocytic leukemia Investigation of bortezomib, lenalidomide, dexamethasone in newly diagnosed multiple myeloma CALGB 100104: lena

9、lidomide maintenance vs placebo following ASCT in multiple myeloma,Lymphomas,Untreated patients with high tumor burden follicular lymphoma,Induction Immunochemotherapy 8 cycles R-CHOP or R-CVP or R-FCM,Rituximab maintenance 375 mg/m2 q8w for 2 yrs (n = 505),Observation (n = 513),Response* (N = 1019)

10、,*Only patients with CR/CRu/PR randomized to maintenance therapy; 1 patient died during randomization.,Stratified by response to induction, chemotherapy regimen, and geographic location prior to 1:1 randomization,5-yr follow-up,Salles GA, et al. ASCO 2010. Abstract 8004.,PRIMA: Rituximab Maintenance

11、 vs Observation in Patients With FL,PRIMA: Primary Endpoint (PFS) Met at Planned Interim Analysis,Rituximab maintenance reduced the risk of progression by 50%,Salles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission.,1.0,0.8,0.6,0.4,0.2,0,0,6,12,18,24,30,36,Progression-Free Rate,Mos,Str

12、atified HR: 0.5095% CI: 0.39-0.64P .0001,82%,66%,Rituximab maintenance(n = 505),Observation(n = 513),Patients at Risk, n,506513,472469,443411,336289,230195,10382,1815,PRIMA: Benefits of Rituximab Maintenance by Subgroup,Salles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission.,All, 60,F

13、LIPI 1,FLIPI = 2,FLIPI 3,R-CHOP,R-CVP,R-FCM,CR/CRu,PR,0,1,2,3,Category,Subgroup,HR,n,HR*,95% CI,All,Age,FLIPI index,Inductionchemotherapy,Response to induction,1018,624,394,216,370,431,768,222,28,721,290,0.49,0.45,0.59,0.38,0.39,0.61,0.43,0.69,0.51,0.52,0.45,0.38-0.64,0.33-0.62,0.39-0.90,0.19-0.77,0

14、.25-0.61,0.43-0.67,0.31-0.59,0.44-1.08,0.13-2.07,0.38-0.70,0.29-0.72,Favors Maintenance,Favors Observation,*Nonstratified analysis., 60,PRIMA: Rituximab Maintenance Associated With Improved Responses,Salles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission.,*Patients not evaluated/missi

15、ng data: n = 16 in observation arm; n = 22 in rituximab arm.Not evaluated in rituximab maintenance arm: n = 2.,PRIMA: Safety During Rituximab Maintenance,Salles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission.,100,80,60,40,20,0,Patients (%),Any AdverseEvent,Grade 2Infections,Grade 3/4

16、Adverse Events,Grade 3/4Neutropenia,Grade 3/4Infections,Observation (n = 508),Rituximab maintenance (n = 501), 1, 1,4,4,35,52,22,37,16,23,PRIMA: Conclusions,2 yrs of rituximab maintenance associated with significantly longer PFS vs observation in patients with follicular lymphoma who responded to in

17、duction with rituximab plus chemotherapy Rituximab maintenance following R-CHOP may benefit previously untreated patients more than relapsed patients HR following R-CHOP in PRIMA: 0.431 HR following R-CHOP in EORTC study of relapsed patients: 0.692 More adverse events associated with rituximab maint

18、enance therapy vs observation, but quality of life not affected Longer follow-up needed to evaluate OS Rituximab maintenance may not be justified unless OS is improved,1. Salles GA, et al. ASCO 2010. Abstract 8004. 2. van Oers MH, et al. J Clin Oncol. 2010;Epub ahead of print.,Sureda A, et al. ASCO

19、2010. Abstract 8007.,Panobinostat Phase II Study in Relapsed/ Refractory Hodgkins Lymphoma,Single-agent, open-label study with Simon optimal 2-stage design Null hypothesis ORR P 15% vs alternative hypothesis ORR P 30% Dose: oral panobinostat 40 mg given 3 times/wk (eg, MWF) in a 21-day treatment cyc

20、le Dose delay and modification allowed for management of adverse events Response assessment every 2 cycles by CT/MRI,Stage 1,Stage 2,Stage 1 analysis,Sureda A, et al. ASCO 2010. Abstract 8007. Reprinted with permission.,Panobinostat in Relapsed/Refractory HL: Heavily Pretreated Patient Population,Su

21、reda A, et al. ASCO 2010. Abstract 8007. Reprinted with permission.,Panobinostat in Relapsed/Refractory HL: Efficacy Data,*Complete normalization defined as radiological regression to normal size of all lymph nodes and nodal masses and complete disappearance of all extranodal lesions (including sple

22、nic and/or hepatic nodules).,Sureda A, et al. ASCO 2010. Abstract 8007. Reprinted with permission.,Panobinostat in Relapsed/Refractory HL: Safety Analysis,Most common ( 10%) treatment-related adverse events (N = 129),Reversible thrombocytopenia is the principal adverse event 7 of 100 patients (7%) w

23、ith grade 3/4 thrombocytopenia discontinued because of this event,Panobinostat in Relapsed/Refractory HL: Conclusions,Panobinostat monotherapy demonstrated durable antitumor activity in heavily pretreated patients with relapsed/refractory Hodgkins lymphoma Disease control rate: 86% Patients with tum

24、or reduction: 71% ORR: 26% Estimated median duration of response: 7.2 mos Reversible thrombocytopenia most common treatment-related adverse event,Sureda A, et al. ASCO 2010. Abstract 8007.,Gnaoui TE, et al. ASCO 2010. Abstract 8011.,Prospective, Multicenter, Phase II Trial of R-GemOx in Relapsed/Ref

25、ractory DLBCL,Induction,Consolidation,C1,C2,C3,C4,C5,C6,C7,C8,E,R-GemOx,R-GemOx,R-GemOx,R-GemOx,R-GemOx,R-GemOx,R-GemOx,R-GemOx,W0,W2,W4,W6,W8,W10,W12,W14,W16,No Follow-up,Responsetotreatment,Evaluation of response: if CR, CRu, or PR, start consolidation,Cycles delayed until: Neutrophils 1 x 109 cel

26、ls/L Platelets 100 x 109 cells/L,Gnaoui TE, et al. ASCO 2010. Abstract 8011.,R-GemOx in Relapsed/Refractory DLBCL: Eligibility,DLBCL diagnosis or Transformed CD20+ indolent lymphoma by World Health Organization classification at relapse 60 years of age or older or younger than 60 years of age (18 ye

27、ars or older) allowed if Not eligible for high-dose chemotherapy or Previous ASCT,Measurable disease ECOG performance score 0-2 Relapse after first or second response of PR or better Response less than PR following first-line treatment Previous treatment with 1 anthracycline-containing regimen,Gnaou

28、i TE, et al. ASCO 2010. Abstract 8011.,R-GemOx in Relapsed/Refractory DLBCL: Response Data,Gnaoui TE, et al. ASCO 2010. Abstract 8011.,R-GemOx in Relapsed/Refractory DLBCL: Safety Analysis,*Calculated using National Cancer Institute Common Toxicity Criteria (version 3.0).,Gnaoui TE, et al. ASCO 2010

29、. Abstract 8011.,11.4,4.2,3,10,12,11,2,9,0,4,8,12,16,No,Yes, 1 yr, 1 yr, 1 yr, 1 yr, 1 yr, 1 yr,Previous Rituximab,Delay From Last Treatment to R-GemOx,No Previous Rituximab,Previous Rituximab,P = .0286,P = .0166,P .0001,Median PFS (Mos),R-GemOx: PFS According to Delay From Last Treatment and Previo

30、us Rituximab,Gnaoui TE, et al. ASCO 2010. Abstract 8011.,R-GemOx in Relapsed/Refractory DLBCL: Conclusions,R-GemOx as a salvage regimen demonstrated favorable safety profile and produced high ORR in patients with relapsed/refractory DLBCL who were unable to receive high-dose chemotherapy ORR after 4

31、 cycles: 60% Patients with early relapse ( 1 yr from last treatment) and previous rituximab treatment had shortest PFS duration with R-GemOx salvage therapy,Chronic Myeloid Leukemia,Patients with previously untreated chronic-phase CML (N = 519),Dasatinib 100 mg/day (n = 259),Imatinib 400 mg/day (n =

32、 260),5-yr follow-up,Stratified by Hasford risk score,Kantarjian H, et al. ASCO 2010. Abstract LBA6500.,DASISION: Randomized Phase III Trial of Imatinib vs Dasatinib in CP-CML,DASISION: Response Definitions,Kantarjian H, et al. ASCO 2010. Abstract LBA6500.,Confirmed CCyR CCyR detected in 2 consecuti

33、ve assessments CCyR No Ph-positive metaphases in bone marrow MMR BCR-ABL 0.1%,DASISION: CCyR Rate by 12 Mos (ITT),Kantarjian H, et al. ASCO 2010. Abstract LBA6500. Reprinted with permission.,100,80,60,40,20,0,CCyR (%),CCyR by 12 Mos,Confirmed CCyRby 12 Mos,P = .0011,P = .0067,83,72,77,66,Dasatinib10

34、0 mg QD,Imatinib400 mg QD,DASISION: CCyR and MMR Rates Over Time (ITT),Kantarjian H, et al. ASCO 2010. Abstract LBA6500.,DASISION: Patients More Likely to Achieve MMR at Any Time With Dasatinib,In patients achieving MMR, median time to MMR 6.3 mos with dasatinib vs 9.2 mos with imatinib,Kantarjian H

35、, et al. ASCO 2010. Abstract LBA6500. Reprinted with permission.,100,80,60,40,20,0,0,3,6,9,12,15,18,21,24,27,Mos,MMR (%),P .0001 (stratified log rank),Hazard ratio for dasatinibover imatinib: 2.01,Dasatinib Imatinib,DASISION: Differences in Adverse Events Rates With Dasatinib vs Imatinib,Kantarjian

36、H, et al. ASCO 2010. Abstract LBA6500. Reprinted with permission.,-0.4,-0.2,0,0.2,0.4,Anemia, grade 3/4Neutropenia, grade 3/4Thrombocytopenia, grade 3/4Myalgia*NauseaVomitingRashDiarrheaFatigueHeadacheFluid retentionSuperficial edemaPleural effusion,Rate difference (dasatinib-imatinib) with exact 95

37、% CI,Favors Dasatinib,Favors Imatinib,*Myalgia = myalgia, muscle inflammation, and MSK pains.,Conclusions,Dasatinib associated with superior efficacy compared with imatinib for first-line treatment of CP-CML Higher and faster rates of CCyR, confirmed CCyR, and MMR Dasatinib generally well tolerated

38、Low rates of grade 3/4 hematologic toxicity Results support use of dasatinib as first-line therapy for patients with newly diagnosed CP-CML,Kantarjian H, et al. ASCO 2010. Abstract LBA6500.,Patients newly diagnosed withPh-positive CP-CML within 6 mos (N = 846),Nilotinib 300 mg BID (n = 282),Nilotini

39、b 400 mg BID (n = 281),Imatinib 400 mg QD (n = 283),5-yr follow-up,Stratified by Sokal risk score,Yr 1,Larson RA, et al. ASCO 2010. Abstract 6501.,ENESTnd: Randomized Phase III Trial of Imatinib vs Nilotinib in Ph-Positive CP-CML,ENESTnd: Primary EndpointMMR Rate at 12 Mos (ITT Population),Larson RA

40、, et al. ASCO 2010. Abstract 6501. Saglio G, et al. N Engl J Med. 2010;Epub ahead of print. Reprinted with permission.,60,50,40,30,20,10,0,MMR (%),P .0001,P .0001,44,43,22,Nilotinib 300 mg BID,Nilotinib 400 mg BID,Imatinib 400 mg QD,n = 282,n = 281,n = 283,ENESTnd: CCyR Rates by 12 Mos and Overall (

41、ITT),Among patients who had a cytogenetic assessment at 18 mos (n = 442/846), the rates of CCyR were Nilotinib 300 mg BID 99%, nilotinib 400 mg BID 99%, imatinib 89%,Larson RA, et al. ASCO 2010. Abstract 6501. Reprinted with permission.,100,80,60,40,20,0,CCyR (%),Mo 12,Overall,n = 282,n = 281,n = 28

42、3,n = 282,n = 281,n = 283,80,78,65,85,82,74,P .0001,P .001,P .001,P = .017,Nilotinib 300 mg BID,Nilotinib 400 mg BID,Imatinib 400 mg QD,Larson RA, et al. ASCO 2010. Abstract 6501.,ENESTnd: Conclusions,Longer follow-up of ENESTnd trial continues to show superior rates of MMR and CCyR with nilotinib 3

43、00 mg BID or 400 mg BID vs imatinib 400 mg QD in newly diagnosed Ph-positive CP-CML Lower event rates (progression or death) with nilotinib vs imatinib Nilotinib generally well tolerated at both doses, grade 3/4 adverse events similar to imatinib According to investigators, these data support use of

44、 nilotinib as standard first-line therapy for CML On June 17, 2010, the FDA approved nilotinib for the treatment of adult patients with newly diagnosed Ph-positive CP-CML,Chronic Myelomonocytic Leukemia,Safety and Efficacy of Azacitidine in CMML,Few data are available to guide management of CMML Cur

45、rent study a records review of CMML patients (N = 38) treated with azacitidine at 1 institution Azacitidine administration 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days Repeated every 4 wks Response criteria Patients considered evaluable for response with 1 azacitidine cycle Assessed by modifi

46、ed International Working Group criteria,Costa RB. ASCO 2010. Abstract 6574.,Azacitidine in CMML: Response and Overall Survival,Costa RB. ASCO 2010. Abstract 6574.,Azacitidine in CMML: Conclusions,Retrospective review demonstrated activity of azacitidine in CMML Nearly one half of patients responded

47、to azacitidine Median OS significantly longer in responding vs nonresponding patients Azacitidine generally well tolerated Cytopenia most frequent adverse event (25%) Azacitidine should be evaluated in combination with novel agents to determine if it further improves response rates and survival in C

48、MML,Costa RB. ASCO 2010. Abstract 6574.,Multiple Myeloma,Updated Analysis of Phase I/II Trial of VRD in Newly Diagnosed Multiple Myeloma,Phase 1 up to eight 3-wk cycles at 5 dose levels; phase II dose: 25 mg/1.3 mg/m2 lenalidomide/bortezomib + 20-mg dexamethasone Patients with PR could proceed to AS

49、CT after 4 cycles After 8 cycles, responding patients could receive maintenance 3-wk cycles of lenalidomide (Days 1-14), and wkly bortezomib (Days 1, 8), at doses tolerated at end of cycle 8 plus dexamethasone 10 mg (Days 1, 2, 8, 9),Anderson KC, et al. ASCO 2010. Abstract 8016. Reprinted with permi

50、ssion.,D 1,2,4,5,8,9,11,12,14,21,Bz,Bz,Bz,Bz,Dex,Dex,Dex,Dex,Dex,Dex,Dex,Dex,Len daily,VRD in Newly Diagnosed MM: Patient Disposition at Longer Follow-up,N = 66 On treatment: 15% Received 8 cycles of all 3 agents: 59% Discontinued cycle 8: n = 28 (42%); proceeded to ASCT (n = 13), treatment complete

51、d per protocol (n = 6), adverse event (n = 3), consent withdrawn (n = 3), death (n = 1), physician decision (n = 1), nonprotocol therapy (n = 1) Discontinued during maintenance: n = 28 (42%); treatment completed per protocol (n = 10), disease progression (n = 8), consent withdrawn (n = 4), proceeded

52、 to ASCT (n = 3), adverse event (n = 1), physician decision (n = 1), other (n = 1) Overall, proceeded to ASCT: 47%,Anderson KC, et al. ASCO 2010. Abstract 8016.,VRD in Newly Diagnosed MM: Updated Outcomes,Median follow-up: 27.3 mos Patient survival without disease progression: n = 44 Median duration

53、 of response not reached Median PFS and OS not reached Estimated 24-mo PFS: 68% (95% CI: 55% to 78%) Estimated 24-mo OS: 95% (95% CI: 86% to 98%) At 1 yr, 53 patients had not progressed (26 with ASCT, 27 without ASCT) No significant difference in PFS between those with ASCT and those without,Anderso

54、n KC, et al. ASCO 2010. Abstract 8016.,Responses Associated With Bortezomib, Lenalidomide, Dexamethasone,Anderson KC, et al. ASCO 2010. Abstract 8016.,33,26,27,17,11,20,29,37,0,10,20,30,40,50,60,70,80,90,100,All patients(N = 66),Patients in phase II only(n = 35),CR,Near CR,Very good PR,PR,Patients (

55、%),Best Responses,Summary,Combination therapy with bortezomib, lenalidomide, dexamethasone active in newly diagnosed multiple myeloma patients All patients achieved PR or better with high rates of CR, near CR, or very good PR Estimated 2-yr OS rate (with option for ASCT if in PR after 4 cycles): 95%

56、 Treatment well tolerated: toxicities mostly low grade and manageable Most frequent grade 3/4 adverse events: neutropenia (14%) and lymphopenia (14%) 6% of patients experienced deep vein thrombosis or pulmonary embolism Bortezomib, lenalidomide, dexamethasone may offer basis for a future standard of

57、 care for newly diagnosed multiple myeloma,Anderson KC, et al. ASCO 2010. Abstract 8016.,CALGB 100104: Lenalidomide vs Placebo Maintenance Following ASCT for MM,McCarthy PL, et al. ASCO 2010. Abstract 8017.,Lenalidomide 10 mg/day with dose adjustments to 5-15 mg (n = 210),Placebo (n = 208),CR PR SD,Melphalan 200 mg/m2 + ASCT,RestagingDays 90-100,Stratified based on diagnostic 2M and thalidomide and lenalidomide use during Induction,Patie