精美幻灯美国临床肿瘤学会年会恶性血液病进展

1、Hematologic MalignanciesCCO Independent Conference Coverageof the 2010 American Society of Clinical Oncology Annual Meeting*This program is supported by educational grants from Amgen, Bristol-Myers Squibb, Celgene, Genentech BioOncology, Millennium Pharmaceuticals, Inc., Novartis Oncology, and Pfize

2、r, Inc.About These Slides Our thanks to the presenters who gave permission to include their original data Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may n

3、ot be published or posted online without permission from Clinical Care Options (email )DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing

4、educational grants. The materials may discuss uses and dosages for therapeutic 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 inf

5、ormation and data before treating patients or using any therapies described in these materials.FacultyNicholas J. DiBella, MDCo-Chairman, Hematology Research Committee, US Oncology President, Rocky Mountain Cancer Centers Aurora, ColoradoAn Update on Hematologic Malignancies: Overview PRIMA: rituxim

6、ab maintenance vs observation in patients with follicular lymphoma who responded 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 th

7、erapy DASISION: phase III trial of imatinib vs dasatinib in untreated CP-CML 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, lenalido

8、mide, dexamethasone in newly diagnosed multiple myeloma CALGB 100104: lenalidomide maintenance vs placebo following ASCT in multiple myelomaLymphomasUntreated patients with high tumor burden follicular lymphomaInduction Immunochemotherapy8 cyclesR-CHOP orR-CVP orR-FCMRituximab maintenance375 mg/m2 q

9、8w for 2 yrs(n = 505)Observation(n = 513) Response*(N = 1019)*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 randomization5-yr follow-upSalles GA, et a

10、l. ASCO 2010. Abstract 8004.PRIMA: Rituximab Maintenance 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.1.00.20

11、061218243036Progression-Free RateMosStratified HR: 0.5095% CI: 0.39-0.64P .000182%66%Rituximab maintenance(n = 505)Observation(n = 513)Patients at Risk, n506513472469443411336289230195103821815PRIMA: Benefits of Rituximab Maintenance by SubgroupSalles GA, et al. ASCO 2010. Abstract 8004. Reprinted w

12、ith permission.All 60FLIPI 1FLIPI = 2FLIPI 3R-CHOPR-CVPR-FCMCR/CRuPR0123CategorySubgroupHRnHR*95% CIAllAgeFLIPI indexInductionchemotherapyResponse to induction1018624394216370431768222287212900.490.450.590.380.390.610.430.690.510.520.450.38-0.640.33-0.620.39-0.900.19-0.770.25-0.610.43-0.670.31-0.590

13、.44-1.080.13-2.070.38-0.700.29-0.72Favors MaintenanceFavors Observation*Nonstratified analysis. 60PRIMA: Rituximab Maintenance Associated With Improved ResponsesSalles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission.Response, %Observation(n = 398)*Rituximab(n = 389)*PD40.720.3SD0.30PR

14、7.37.2CR/CRu47.766.8n = 190n = 258Patients with CR/CRu after induction remaining in CR/CRu 5675Patients with PR/SD after induction converting to CR/CRu3045*Patients not evaluated/missing data: n = 16 in observation arm; n = 22 in rituximab arm.Not evaluated in rituximab maintenance arm: n = 2.PRIMA:

15、 Safety During Rituximab MaintenanceSalles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission.100806040200Patients (%)Any AdverseEventGrade 2InfectionsGrade 3/4Adverse EventsGrade 3/4NeutropeniaGrade 3/4InfectionsObservation (n = 508)Rituximab maintenance (n = 501) 1 7.2 mos Reversible t

16、hrombocytopenia most common treatment-related adverse eventSureda 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/Refractory DLBCLInductionConsolidationC1C2C3C4C5C6C7C8ER-GemOxR-GemOxR-GemOxR-GemOxR-GemOxR-

17、GemOxR-GemOxR-GemOxW0W2W4W6W8W10W12W14W16No Follow-upResponsetotreatmentEvaluation of response: if CR, CRu, or PR, start consolidationCycles delayed until:Neutrophils 1 x 109 cells/LPlatelets 100 x 109 cells/LGnaoui TE, et al. ASCO 2010. Abstract 8011.R-GemOx in Relapsed/Refractory DLBCL: Eligibilit

18、y 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 years or older) allowed if Not eligible for high-dose chemotherapy or Previous ASCT Measurable disease ECOG performance score 0

19、-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 regimenGnaoui TE, et al. ASCO 2010. Abstract 8011.R-GemOx in Relapsed/Refractory DLBCL: Response DataResponse, %After 4 Cycles of R-GemOx(

20、n = 48)End of Treatment(n = 48)ORR60.445.8 CR2323 CRu2115 PR178SD48PD1027Death817Gnaoui TE, et al. ASCO 2010. Abstract 8011.R-GemOx in Relapsed/Refractory DLBCL: Safety AnalysisToxicities,* %Safety Population(N = 48)Grade 3Grade 4Hematologic Thrombocytopenia2321 Anemia212 Neutropenia3142 Febrile neu

21、tropenia40Nonhematologic Liver150 Neurologic80 Kidney20*Calculated using National Cancer Institute Common Toxicity Criteria (version 3.0).Gnaoui TE, et al. ASCO 2010. Abstract 803101211290481216NoYes 1 yr 1 yr 1 yr 1 yr 1 yr 1 yrPrevious RituximabDelay From Last Treatment to R-GemOxNo Prev

22、ious RituximabPrevious RituximabP = .0286P = .0166P .0001Median PFS (Mos)R-GemOx: PFS According to Delay From Last Treatment and Previous RituximabGnaoui TE, et al. ASCO 2010. Abstract 8011.R-GemOx in Relapsed/Refractory DLBCL: Conclusions R-GemOx as a salvage regimen demonstrated favorable safety p

23、rofile and produced high ORR in patients with relapsed/refractory DLBCL who were unable to receive high-dose chemotherapy ORR after 4 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 My

24、eloid Leukemia Patients withpreviously untreatedchronic-phaseCML(N = 519)Dasatinib 100 mg/day(n = 259)Imatinib 400 mg/day(n = 260)5-yr follow-upStratified by Hasford risk scoreKantarjian H, et al. ASCO 2010. Abstract LBA6500.DASISION: Randomized Phase III Trial of Imatinib vs Dasatinib in CP-CMLDASI

25、SION: Response DefinitionsKantarjian H, et al. ASCO 2010. Abstract LBA6500. Confirmed CCyR CCyR detected in 2 consecutive 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 perm

26、ission.100806040200CCyR (%)CCyR by 12 MosConfirmed CCyRby 12 MosP = .0011P = .006783727766Dasatinib100 mg QDImatinib400 mg QDDASISION: CCyR and MMR Rates Over Time (ITT)Kantarjian H, et al. ASCO 2010. Abstract LBA6500.Outcome, %Dasatinib(n = 259)Imatinib(n = 260)P ValueCCyR 3 mos5431 6 mos7359 9 mos

27、7867 12 mos8372.0011MMR 3 mos80.4 6 mos278 9 mos3918 12 mos4628 .0001DASISION: 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 imatinibKantarjian H, et al. ASCO 2010. Abstract LBA6500. Reprinted with

28、permission.1008060402000369121518212427MosMMR (%)P .0001 (stratified log rank)Hazard ratio for dasatinibover imatinib: 2.01DasatinibImatinibDASISION: Differences in Adverse Events Rates With Dasatinib vs ImatinibKantarjian H, et al. ASCO 2010. Abstract LBA6500. Reprinted with permission.-0.4-0.200.2

29、0.4Anemia, grade 3/4Neutropenia, grade 3/4Thrombocytopenia, grade 3/4Myalgia*NauseaVomitingRashDiarrheaFatigueHeadacheFluid retentionSuperficial edemaPleural effusionRate difference (dasatinib-imatinib) with exact 95% CIFavors Dasatinib Favors Imatinib*Myalgia = myalgia, muscle inflammation, and MSK

30、 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 Low rates of grade 3/4 hematologic toxicity Results support use of dasatinib as first-l

31、ine therapy for patients with newly diagnosed CP-CMLKantarjian H, et al. ASCO 2010. Abstract LBA6500.Patients newly diagnosed withPh-positive CP-CMLwithin 6 mos(N = 846)Nilotinib 300 mg BID(n = 282)Nilotinib 400 mg BID(n = 281)Imatinib 400 mg QD(n = 283)5-yr follow-upStratified by Sokal risk scoreYr

32、 1Larson RA, et al. ASCO 2010. Abstract 6501.ENESTnd: Randomized Phase III Trial of Imatinib vs Nilotinib in Ph-Positive CP-CMLENESTnd: Primary EndpointMMR Rate at 12 Mos (ITT Population)Larson RA, et al. ASCO 2010. Abstract 6501. Saglio G, et al. N Engl J Med. 2010;Epub ahead of print. Reprinted wi

33、th permission.6050403020100MMR (%)P .0001P .0001444322Nilotinib 300 mg BIDNilotinib 400 mg BIDImatinib 400 mg QDn = 282n = 281n = 283ENESTnd: CCyR Rates by 12 Mos and Overall (ITT) Among patients who had a cytogenetic assessment at 18 mos (n = 442/846), the rates of CCyR were Nilotinib 300 mg BID 99

34、%, nilotinib 400 mg BID 99%, imatinib 89%Larson RA, et al. ASCO 2010. Abstract 6501. Reprinted with permission.100806040200CCyR (%)Mo 12Overalln = 282 n = 281 n = 283n = 282 n = 281 n = 283807865858274P .0001P .001P .001P = .017Nilotinib 300 mg BIDNilotinib 400 mg BIDImatinib 400 mg QDLarson RA, et

35、al. ASCO 2010. Abstract 6501.ENESTnd: Conclusions Longer follow-up of ENESTnd trial continues to show superior rates of MMR and CCyR with nilotinib 300 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

36、 Nilotinib generally well tolerated at both doses, grade 3/4 adverse events similar to imatinib According to investigators, these data support use of 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

37、 Ph-positive CP-CML Chronic Myelomonocytic LeukemiaSafety and Efficacy of Azacitidine in CMML Few data are available to guide management of CMML Current 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 10

38、0 mg/m2/day for 5 days Repeated every 4 wks Response criteria Patients considered evaluable for response with 1 azacitidine cycle Assessed by modified International Working Group criteriaCosta RB. ASCO 2010. Abstract 6574.Azacitidine in CMML: Response and Overall SurvivalEfficacyAzacitidine(n = 36)P

39、 ValueORR, %42 CR11 PR3 Hematologic improvement28Overall median OS, mos12 Responders13.02 Nonresponders9Costa RB. ASCO 2010. Abstract 6574.Azacitidine in CMML: Conclusions Retrospective review demonstrated activity of azacitidine in CMML Nearly one half of patients responded to azacitidine Median OS

40、 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 CMMLCosta RB. ASCO 2010.

41、Abstract 6574. Multiple MyelomaUpdated 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 ASCT after 4 cycles After 8

42、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 permission.D 12458911121421BzBzB

43、zBzDexDexDexDexDexDexDexDexLen dailyVRD 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 completed per protocol (n = 6), adverse event (n = 3), cons

44、ent 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 to ASCT (n = 3), adverse event (n = 1), physician

45、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 of response not reached Median PFS and OS not reache

46、d 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 withoutAnderson KC, et al. ASCO 2010. Abstract 8016.Responses Associ

47、ated With Bortezomib, Lenalidomide, Dexamethasone Anderson KC, et al. ASCO 2010. Abstract 8016.33262717112029370102030405060708090100All patients(N = 66)Patients in phase II only(n = 35)CRNear CRVery good PRPRPatients (%)Best ResponsesSummary Combination therapy with bortezomib, lenalidomide, dexame

48、thasone 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% Treatment well tolerated: toxicities mostly low grade and manageable Most frequent

49、 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 care for newly diagnosed multiple myelomaAnderson KC, et al. ASCO 2010. Abstract 8

50、016.CALGB 100104: Lenalidomide vs Placebo Maintenance Following ASCT for MMMcCarthy PL, et al. ASCO 2010. Abstract 8017.Lenalidomide 10 mg/day with dose adjustments to 5-15 mg(n = 210)Placebo(n = 208)CRPRSDMelphalan 200 mg/m2+ ASCTRestagingDays 90-100 Stratified based on diagnostic 2M and thalidomid

51、e and lenalidomide use during InductionPatients younger than 70 yrs with stage I-III MM,SD or better following 2 cycles of induction, 1 yr from start of therapy, 2 x 106 CD34+ cells/kg (N = 418)CALGB 100104: Efficacy AnalysisMcCarthy PL, et al. ASCO 2010. Abstract 8017.OutcomeLenalidomide(n =210)Pla

52、cebo (n = 208)P ValueProgression or death, n (%)29 (14)58 (28) .0001 Deaths 11 (5)17 (8) .2Median TTP, mosNot reached25.5-Lenalidomide maintenance therapy following ASCT associated with 58% reduction in progression or death vs placebo Estimated HR: 0.42Median OS not reached for either arm CALGB 1001

53、04: Safety AnalysisMcCarthy PL, et al. ASCO 2010. Abstract 8017.Adverse Events During Maintenance Therapy, n (%)Lenalidomide(n =194)Placebo (n = 174)P ValueHematologic.0001 Grade 361 (31)8 (5) Grade 426 (13)8 (5) Grade 50 (0)0 (0)Nonhematologic.0096 Grade 360 (31)33 (19) Grade 46 (3)5 (3) Grade 53 (

54、2)3 (2)CALGB 100104: Conclusions Maintenance therapy with lenalidomide following ASCT prolongs TTP in patients with multiple myeloma1 TTP (defined as rate of disease progression or death resulting from any cause) reduced by 58% vs placebo Toxicities more common with lenalidomide Discontinuation rate

55、 for any AE: 13% Findings of CALGB 100104 consistent with interim results of randomized IFM20005-221. McCarthy PL, et al. ASCO 2010. Abstract 8017.2. Attal M, et al. ASCO 2010. Abstract 8018.Summary PRIMA demonstrated rituximab maintenance associated with significantly longer PFS vs observation in p

56、atients with follicular lymphoma Panobinostat monotherapy active in heavily pretreated patients with relapsed/refractory Hodgkins lymphoma Salvage therapy with R-GemOx safe, effective in relapsed/refractory DLBCL Dasatinib and nilotinib each appear to be superior to imatinib as first-line treatment

57、options for CP-CML Bortezomib, lenalidomide, dexamethasone demonstrated durable activity in newly diagnosed multiple myeloma Lenalidomide maintenance significantly extended TTP vs placebo following ASCT in multiple myelomaGo Online for More CCO Coverage of Clinical Oncology Data From Chicago!Capsule

58、 Summaries of all the key data, plus Expert Analysis panel discussions exploring the clinical implicationsExpert Highlights: download mp3 files and listen to our experts review the highlights of this conferenceDownloadable PowerPoint slides patients with high tumor burden follicular lymphomaInductio

59、n Immunochemotherapy8 cyclesR-CHOP orR-CVP orR-FCMRituximab maintenance375 mg/m2 q8w for 2 yrs(n = 505)Observation(n = 513) Response*(N = 1019)*Only patients with CR/CRu/PR randomized to maintenance therapy; 1 patient died during randomization.Stratified by response to induction, chemotherapy regime

60、n, and geographic location prior to 1:1 randomization5-yr follow-upSalles GA, et al. ASCO 2010. Abstract 8004.PRIMA: Rituximab Maintenance vs Observation in Patients With FL PRIMA: Rituximab Maintenance Associated With Improved ResponsesSalles GA, et al. ASCO 2010. Abstract 8004. Reprinted with perm