精美幻灯美国临床肿瘤学会年会恶性血液病进展

1、 An Update on Hematologic Malignancies 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 hono

2、r this intent These slides may not be published or posted online without permission from Clinical Care Options (email ) Disclaimer The materials published on the Clinical Care Options Web site reflect the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 prov

3、iders, or the companies providing 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 discus

4、sed. Readers should verify all information and data before treating patients or using any therapies described in these materials. An Update on Hematologic Malignancies Faculty Nicholas J. DiBella, MD Co-Chairman, Hematology Research Committee, US Oncology President, Rocky Mountain Cancer Centers Aur

5、ora, Colorado An Update on Hematologic Malignancies An Update on Hematologic Malignancies: Overview PRIMA: rituximab maintenance vs observation in patients with follicular lymphoma who responded to induction with rituximab plus chemotherapy Phase II trial of panobinostat in relapsed/refractory Hodgk

6、ins 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-CML ENESTnd phase III trial of nilotinib 300 mg BID or 400 mg BID vs imatinib 400 mg QD in newly diagnosed Ph-pos

7、itive CP-CML Investigation of azacitidine in chronic myelomonocytic leukemia Investigation of bortezomib, lenalidomide, dexamethasone in newly diagnosed multiple myeloma CALGB 100104: lenalidomide maintenance vs placebo following ASCT in multiple myeloma Lymphomas An Update on Hematologic Malignanci

8、es 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) *Only patients with CR/CRu/PR randomized to maintenance therapy; 1 patien

9、t 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 vs Observation in Patients With FL An Update on Hematologic Malignancies

10、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 61218243036 Progression-Free Rate Mos Stratified HR: 0.50 95% CI: 0.39-0.64 P .000

11、1 82% 66% Rituximab maintenance (n = 505) Observation (n = 513) Patients at Risk, n 506 513 472 469 443 411 336 289 230 195 103 82 18 15 An Update on Hematologic Malignancies PRIMA: Benefits of Rituximab Maintenance by Subgroup Salles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission. A

12、ll 60 FLIPI 1 FLIPI = 2 FLIPI 3 R-CHOP R-CVP R-FCM CR/CRu PR 0 1 23 CategorySubgroup HRnHR*95% CI All Age FLIPI index Induction chemotherapy 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 0.19-0.7

13、7 0.25-0.61 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 MaintenanceFavors Observation *Nonstratified analysis. 60 An Update on Hematologic Malignancies PRIMA: Rituximab Maintenance Associated With Improved Responses Salles GA, et al. ASCO 2010. Abstract 8004. Reprinted with pe

14、rmission. Response, %Observation (n = 398)* Rituximab (n = 389)* PD40.720.3 SD0.30 PR7.37.2 CR/CRu47.766.8 n = 190n = 258 Patients with CR/CRu after induction remaining in CR/CRu 5675 Patients with PR/SD after induction converting to CR/CRu 3045 *Patients not evaluated/missing data: n = 16 in observ

15、ation arm; n = 22 in rituximab arm. Not evaluated in rituximab maintenance arm: n = 2. An Update on Hematologic Malignancies PRIMA: Safety During Rituximab Maintenance Salles GA, et al. ASCO 2010. Abstract 8004. Reprinted with permission. 100 80 60 40 20 0 Patients (%) Any Adverse Event Grade 2 Infe

16、ctions Grade 3/4 Adverse Events Grade 3/4 Neutropenia Grade 3/4 Infections Observation (n = 508) Rituximab maintenance (n = 501) 1 7.2 mos Reversible thrombocytopenia most common treatment- related adverse event Sureda A, et al. ASCO 2010. Abstract 8007. An Update on Hematologic Malignancies Gnaoui

17、TE, et al. ASCO 2010. Abstract 8011. Prospective, Multicenter, Phase II Trial of R-GemOx in Relapsed/Refractory DLBCL InductionConsolidation C1C2C3C4C5C6C7C8 E R- GemOx R- GemOx R- GemOx R- GemOx R- GemOx R- GemOx R- GemOx R- GemOx W0W2W4W6W8W10W12W14W16 No Follow-up Response to treatment Evaluation

18、 of response: if CR, CRu, or PR, start consolidation Cycles delayed until: Neutrophils 1 x 109 cells/L Platelets 100 x 109 cells/L An Update on Hematologic Malignancies Gnaoui TE, et al. ASCO 2010. Abstract 8011. R-GemOx in Relapsed/Refractory DLBCL: Eligibility DLBCL diagnosis or Transformed CD20+

19、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 0-2 Relapse after first or second respon

20、se of PR or better Response less than PR following first-line treatment Previous treatment with 1 anthracycline-containing regimen An Update on Hematologic Malignancies Gnaoui TE, et al. ASCO 2010. Abstract 8011. R-GemOx in Relapsed/Refractory DLBCL: Response Data Response, %After 4 Cycles of R-GemO

21、x (n = 48) End of Treatment (n = 48) ORR60.445.8 CR2323 CRu2115 PR178 SD48 PD1027 Death817 An Update on Hematologic Malignancies Gnaoui TE, et al. ASCO 2010. Abstract 8011. R-GemOx in Relapsed/Refractory DLBCL: Safety Analysis Toxicities,* %Safety Population (N = 48) Grade 3Grade 4 Hematologic Throm

22、bocytopenia2321 Anemia212 Neutropenia3142 Febrile neutropenia40 Nonhematologic Liver150 Neurologic80 Kidney20 *Calculated using National Cancer Institute Common Toxicity Criteria (version 3.0). An Update on Hematologic Malignancies Gnaoui TE, et al. ASCO 2010. Abstract 8011. 11.4 4.2 3 10 12 11 2 9

23、0 4 8 12 16 NoYes 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 = .0286P = .0166P .0001 Median PFS (Mos) R-GemOx: PFS According to Delay From Last Treatment and Previous Rituximab An Update on Hematologic Malignancies

24、 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 cycles: 60%

25、 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 An Update on Hematologic Malignancies Patients with previously untreated chronic-phase CML (N = 519) Dasatinib 100 mg/day (n = 259

26、) Imatinib 400 mg/day (n = 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 An Update on Hematologic Malignancies DASISION: Response Definitions Kantarjian H, et al. ASCO 201

27、0. Abstract LBA6500. Confirmed CCyR CCyR detected in 2 consecutive assessments CCyR No Ph-positive metaphases in bone marrow MMR BCR-ABL 0.1% An Update on Hematologic Malignancies DASISION: CCyR Rate by 12 Mos (ITT) Kantarjian H, et al. ASCO 2010. Abstract LBA6500. Reprinted with permission. 100 80

28、60 40 20 0 CCyR (%) CCyR by 12 Mos Confirmed CCyR by 12 Mos P = .0011 P = .0067 83 72 77 66 Dasatinib 100 mg QD Imatinib 400 mg QD An Update on Hematologic Malignancies DASISION: CCyR and MMR Rates Over Time (ITT) Kantarjian H, et al. ASCO 2010. Abstract LBA6500. Outcome, %Dasatinib (n = 259) Imatin

29、ib (n = 260) P Value CCyR 3 mos5431 6 mos7359 9 mos7867 12 mos8372.0011 MMR 3 mos80.4 6 mos278 9 mos3918 12 mos4628 .0001 An Update on Hematologic Malignancies DASISION: Patients More Likely to Achieve MMR at Any Time With Dasatinib In patients achieving MMR, median time to MMR 6.3 mos with dasatini

30、b vs 9.2 mos with imatinib Kantarjian H, et al. ASCO 2010. Abstract LBA6500. Reprinted with permission. 100 80 60 40 20 0 0369121518212427 Mos MMR (%) P .0001 (stratified log rank) Hazard ratio for dasatinib over imatinib: 2.01 Dasatinib Imatinib An Update on Hematologic Malignancies DASISION: Diffe

31、rences in Adverse Events Rates With Dasatinib vs Imatinib Kantarjian H, et al. ASCO 2010. Abstract LBA6500. Reprinted with permission. -0.4-0.20 0.20.4 Anemia, grade 3/4 Neutropenia, grade 3/4 Thrombocytopenia, grade 3/4 Myalgia* Nausea Vomiting Rash Diarrhea Fatigue Headache Fluid retention Superfi

32、cial edema Pleural effusion Rate difference (dasatinib-imatinib) with exact 95% CI Favors Dasatinib Favors Imatinib *Myalgia = myalgia, muscle inflammation, and MSK pains. An Update on Hematologic Malignancies Conclusions Dasatinib associated with superior efficacy compared with imatinib for first-l

33、ine 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-line therapy for patients with newly diagnosed CP-CML Kantarjian H, et al. ASCO 2010. Abstract LBA

34、6500. An Update on Hematologic Malignancies Patients newly diagnosed with Ph-positive CP-CML within 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-up Stratified by Sokal risk score Yr 1 Larson RA, et al. ASCO 2010. Abstract 6501

35、. ENESTnd: Randomized Phase III Trial of Imatinib vs Nilotinib in Ph-Positive CP-CML An Update on Hematologic Malignancies ENESTnd: 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 with

36、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 = 282n = 281n = 283 An Update on Hematologic Malignancies ENESTnd: CCyR Rates by 12 Mos and Overall (ITT) Among patients who had a cytogenetic assessment at 18 mos (n = 442

37、/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 12Overall n = 282 n = 281 n = 283n = 282 n = 281 n = 283 80 78 65 85 82 74 P .0001 P .001 P .001 P = .01

38、7 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD An Update on Hematologic Malignancies 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 300 mg BID or 400 mg BID vs imatinib

39、 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 nilotinib as standard first-line t

40、herapy 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 An Update on Hematologic Malignancies Safety and Efficacy of Azacitidine in CMML Few data are available to guide management of CMML

41、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 100 mg/m2/day for 5 days Repeated every 4 wks Response criteria Patients considered evaluable for response with 1 azacitidine cycle Assessed by mod

42、ified International Working Group criteria Costa RB. ASCO 2010. Abstract 6574. An Update on Hematologic Malignancies Azacitidine in CMML: Response and Overall Survival Efficacy Azacitidine (n = 36) P Value ORR, %42 CR11 PR3 Hematologic improvement28 Overall median OS, mos12 Responders13 .02 Nonrespo

43、nders9 Costa RB. ASCO 2010. Abstract 6574. An Update on Hematologic Malignancies Azacitidine in CMML: Conclusions Retrospective review demonstrated activity of azacitidine in CMML Nearly one half of patients responded to azacitidine Median OS significantly longer in responding vs nonresponding patie

44、nts 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 CMML Costa RB. ASCO 2010. Abstract 6574. Multiple Myeloma An Update on Hematologic

45、Malignancies 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 ASCT after 4 cycles After 8 cycles, responding

46、 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 12458911121421 BzBzBzBz DexDexDexDe

47、xDexDexDexDex Len daily An Update on Hematologic Malignancies 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 completed per protocol (n = 6), a

48、dverse 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 to ASCT (n = 3), adverse

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

50、dian duration 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 wi

51、thout Anderson KC, et al. ASCO 2010. Abstract 8016. An Update on Hematologic Malignancies 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 I

52、I only (n = 35) CR Near CR Very good PR PR Patients (%) Best Responses An Update on Hematologic Malignancies 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,

53、 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 grade 3/4 adverse events: neutropenia (14%) and lymphopenia (14%) 6% of patients experienced deep vein thrombosis or pulmonar

54、y embolism Bortezomib, lenalidomide, dexamethasone may offer basis for a future standard of care for newly diagnosed multiple myeloma Anderson KC, et al. ASCO 2010. Abstract 8016. An Update on Hematologic Malignancies CALGB 100104: Lenalidomide vs Placebo Maintenance Following ASCT for MM McCarthy P

55、L, 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 Restaging Days 90-100 Stratified based on diagnostic 2M and thalidomide and lenalidomide use during Induction Patients younger than 70 yrs with

56、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) An Update on Hematologic Malignancies CALGB 100104: Efficacy Analysis McCarthy PL, et al. ASCO 2010. Abstract 8017. OutcomeLenalidomide (n =210) Placebo (n = 208) P Value Progre

57、ssion or death, n (%)29 (14)58 (28) .0001 Deaths 11 (5)17 (8) .2 Median TTP, mosNot reached25.5- Lenalidomide maintenance therapy following ASCT associated with 58% reduction in progression or death vs placebo Estimated HR: 0.42 Median OS not reached for either arm An Update on Hematologic Malignanc

58、ies CALGB 100104: Safety Analysis McCarthy PL, et al. ASCO 2010. Abstract 8017. Adverse Events During Maintenance Therapy, n (%) Lenalidomide (n =194) Placebo (n = 174) P Value Hematologic.0001 Grade 361 (31)8 (5) Grade 426 (13)8 (5) Grade 50 (0)0 (0) Nonhematologic.0096 Grade 360 (31)33 (19) Grade

59、46 (3)5 (3) Grade 53 (2)3 (2) An Update on Hematologic Malignancies 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 for any AE: 13% Findings of CALGB 100104 consistent with interim results of randomized IFM20005-22 1. McCarthy PL, et al. ASCO 2010. Abstract 8017. 2. Attal M, et al. ASCO 2010. Abstract 8018. An Update