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Mantle Cell Lymphoma

Mantle Cell Lymphoma. Jan 7 2009 林建廷. 台灣血液癌症發生率在增加. 正常淋巴器官 / 組織. 約有 600 個淋巴結 只有少數位於表淺處可摸到，例如：頸部、腋下和鼠蹊部. 淋巴癌 分期. 若只有一群淋巴節受侵犯則為第一期 有多群淋巴節受侵犯但皆在橫膈膜的同一側則為第二期 若受侵犯的淋巴結分佈跨越橫隔膜則為第三期 而若有肝臟，骨髓或兩個以上之非淋巴器官受侵犯則為第四期. 淋巴癌的分期要做哪些檢查 ?. 抽血 X 光 CT 骨髓 ( 正子攝影 PET/CT). 淋巴癌 分類. 非何杰金淋巴癌的治療 — 簡要版.

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Mantle Cell Lymphoma

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  1. Mantle Cell Lymphoma Jan 7 2009 林建廷

  2. 台灣血液癌症發生率在增加

  3. 正常淋巴器官/ 組織 約有600個淋巴結 只有少數位於表淺處可摸到，例如：頸部、腋下和鼠蹊部

  4. 淋巴癌 分期 若只有一群淋巴節受侵犯則為第一期 有多群淋巴節受侵犯但皆在橫膈膜的同一側則為第二期 若受侵犯的淋巴結分佈跨越橫隔膜則為第三期 而若有肝臟，骨髓或兩個以上之非淋巴器官受侵犯則為第四期

  5. 淋巴癌的分期要做哪些檢查? 抽血 X光 CT 骨髓 (正子攝影 PET/CT)

  6. 淋巴癌 分類

  7. 非何杰金淋巴癌的治療—簡要版

  8. Lymphoma Response Criteria Invisible: CR Very small but no biopsy: CRu <0.7: PR 0.7~1.2: SD >1.2: PD

  9. Mantle cell lymphoma • 6% of NHL (2-3/100,000yrs)~3,000 new cases/yr in US • M:F=3:1, Median age 63 • B-symptoms 33% • Generalized LAD 90% • Extranodal involvement 80%, ~GI tract 9-20% • 80-90% stage III/IV, ~BM involved 64%, ~Splenomegaly 60% • Median OS: 3 - 4 yrs • WHO classified as indolent and aggressive • 25% behavior as indolent (unable to predict) • 75% behavior as aggressive

  10. 50-70% >70% Marginal zone, nodal Lymphoplasmacytoid SLL T-ALCL MALToma FL 30-49% <30% MCL (27%) T-lymphoblastic PTCL Burkitts DLBC Blood 1997 Jun 1;89(11):3909-18 5-yr Overall Survival

  11. Mantle Zone~25% Nodular~30% JCO 1997;15 (4):1664 Diffuse~45% Harris, N. L. ASH Image Bank 2002;2002:100367 Histology • Lymphocytes in the primary lymphoid follicles and mantle zones of secondary follicles • Histologic progression is common, transformation rare • Express • Cyclin D1 • CD19, CD20, CD22 • CD5 • BCL-2 • CD79a, FMC7 • Surface IgM / IgG • Negative • CD10 • CD23 CD148 is a potential marker D/D MCL(+)/CLL(-)ASH 2008, Miguet et al, Abstract 1766 Palutke M et al. Blood 1996 June;87(11):4483

  12. Blastoid variant LN Blastoid Variant Cytology Classic MCL Cytology Blastoid Variant Blood Maslak, P. ASH Image Bank 2004;2004:101031 Kadin, M. ASH Image Bank 2003;2003:100610 Histology

  13. Cytogenetics • t(11;14)(q13;q32):deregulated expression of cyclin D1. • MM~20-30% of cases • MCL~virtually all cases

  14. Mantle Cell Lymphoma: Biology Cell cycle DNA damage response (> 80% MCL have secondary alterations) Deletion 11q22-23 Mutations ATM locus ATR ATM RB1 Stabilization of p53 CHK1-2 p14 M G1 Deletion 9q21 INK4/ARF cdk4/cyclin D1 G2 p16 MDM2 G1/S arrest p21 S Deletion 17q/ mutation p53 p27 p53 RB1 P G1/S arrest Apoptosis DNA repair

  15. Clinical risk factors: MIPI clinical (PALL: PS, age, LDH, leucocyte count) Hoster, Blood 2008

  16. Mantle cell lymphoma treatment

  17. Rituximab (Meta-analysis) Response rate Overall survival J Natl Cancer Inst 2007;99: 706 – 14

  18. First Line Induction Regimens • Standard~R-CHOP • Woward, CR=48%, PFS=16.6m • GLSG, CR=34%, PFS=15m • Intensive ~ R-HyperCVAD/R-MTX-AC • MDACC, CR=87%, FFS=not reached (67%@3yr) ~Maxi-CHOP/HDAC (Nordic-2) CR=54%, PFS=not reached (66%@6yr) • Purine analog~R-FCM

  19. Time to Treatment Failure R-CHOP vsCHOP (GLSG trial) OS 86% vs 82%@2yrs Lenz, G. et al. J Clin Oncol; 23:1984-1992 2005

  20. OS of GLSG (1996-2004) vs KLSG (1975-1986) 4.8 yrs vs 2.7 yrs Hermann et al, Published Ahead of Print on December 15, 2008

  21. Phase 2 R-HyperCVAD/R-MTXAC (MDACC) • 29% pts not complete scheduled C/T cycles • Poor prognostics = >65yo, high LDH, lack of GI involvement, B2>3mg/L • 8 deaths and 4 t-AML/MDS alternate cycles 1 and 2 Q21D cycle 1, 3, 5, 7R-hyperCVAD cycle 2, 4, 6, 8R-M-A day 1 day 21 Romaguera et al. JCO 2005 Oct 1;23(28):7013-23

  22. OS 82%@3 yrs FFS 64%@3 yrs R-HyperCVAD/R-MTXAC (MDACC) CR=87%, ORR=97% Romaguera, J. E. et al. J Clin Oncol; 23:7013-7023 2005

  23. R-HyperCVAD/R-MTXAC (MDACC) • Too toxic!TRM~8% Romaguera, J. E. et al. J Clin Oncol; 23:7013-7023 2005

  24. Mantle cell lymphoma and transplantation

  25. Upfront ASCT: European MCL NetworkPhase 3 trial 61% CHOP; 26% R-CHOP Dreyling etal, Blood, 2005, Vol. 105, No. 7, pp. 2677-2684

  26. PFS Benefit, no OS Benefit Dreyling etal, Blood, 2005, Vol. 105, No. 7, pp. 2677-2684

  27. Upfront ASCT: Nordic-1 vs Nordic-2 • Phase 2 • CR=54%, ORR=96% • NRM~5% Geisler et al, Blood. 2008;112:2687-2693

  28. Upfront ASCT: Nordic-1 vs Nordic-2 • PFS: 66%@6yrs, No relapse after 5 yrs • OS: 70%@6yrs Geisler et al, Blood. 2008;112:2687-2693

  29. Retrospective EBMT and ABMT Registry supports ASCT in CR1 • 195 patients (new diagnosis and relapsed) • Chemotherapy: varied/not reported • Conditioning regimens: varied • Pts not transplanted in CR1 were 3x more likely to die from MCL • Median survival 59 months *Vandenberghe, E., Ruiz, C., et al., BJH 2002120:793

  30. EBMT Registry ASCT improves OS in CR1 • Patients transplanted in CR1 • 2 year PFS: 65% 5 year PFS: 52% • 2 year OS: 88% 5 year OS: 65% *Vandenberghe, E., Ruiz, C., et al., BJH 2002120:793

  31. 1.0 0.9 0.8 0.7 0.6 Cumulative Proportion Surviving 0.5 0.4 0.3 0.2 0.1 P = 0.0001 0.0 0 10 20 30 40 50 60 70 80 Months Post Transplant ASCT in CR1: OS by B2 Microglobulin B2m < 3 (N=18) B2 m> 3 (N=9) Khouriet al. Cancer 98:2630-2635, 2003

  32. The MD Anderson1 and Fred Hutchinson2 Experience • Allo may have a role as salvage in MCL • Differed by conditioning regimen 1. Khouri, I., Lee,M., et al., JCO 2003;21(3):4407 2. Maris, M., Sandmaier, B., et al., Blood 2004;104(12):3535

  33. Novel Agents Proteosomeinhibitors Mammalian target of rapamycin (mTOR) inhibitors Thalidomide

  34. Relapsed MCL

  35. 2 Line-- Single Agent Bortezomib • Phase 2 studies in relapsed MCL • Velcade 1.3~1.5mg/m2 days 1,4,8,11 Q21D • Fisher R et al. JCO 2006;24:early release online 10.1200/JCO.2006.07.9665 • O’Connor, O., Wright, J., et al., JCO 2005; 23(4):676 • Goy, A., Young, A., et al., JCO 2005;23(4):667 • Strauss et al, JCO 2006 • Belch et al, Ann Onc 2007

  36. PINNACLE Phase 2 PINNACLE CR or CRu Continue treatment for 4 cycles beyond initial documentation, up to 17 cycles EVALUATE Bortezomib 1.3 mg/m2 D1, 4, 8, 11 Q21D PR or SD maxi 17 cycles PD Discontinue Enroll completed in June 2005 (N = 155) 35 centers in the US, UK and Germany Fisher et al. JCO 2006; 24: 4867-4874

  37. Phase 2 PINNACLE Parameter N (%) No. of prior lines of therapy for MCL 1 84 (54) 2 65 (42) 3 6 (4) Received prior regimen containing Anthracycline/mitoxantrone 152 (98) Alkylating agents 150 (97) Rituximab 149 (96) At least 2/3 of the above 155 (100) All 3 of the above 141 (91) Prior high intensity therapy* 58 (37) Prior radioimmunotherapy / radiation therapy 8/29 (5/19) *High-intensity regimens defined as stem cell transplant, Hyper-CVAD/ICE/ESHAP/DHAP; all ± rituximab Fisher et al. JCO 2006; 24: 4867-4874

  38. Important Things • CR rate=8% • ORR rate=33% • Median time to response: 1.3m (2 cycles) Time to First Response MCL All Patients Follicular Lymphoma % Pts Responding Median Time to First Response MCL = 5 weeks (~2 cycles) Follicular = 11 weeks (~ 4 cycles) Time (weeks) Fisher et al. JCO 2006; 24: 4867-4874 O’Connor et al. JCO 2005 O’Connor et al. ICML 2005

  39. Bortezomib is Synergistic with Cytarabine • Case 1: B 1.5mg/m2, D1, D4 Ara-C 1000mg/m2, D2, D3 /Q21D • Case 2: B 1.5mg/m2, D1, D4 Ara-C 1000mg/m2, D2, D3 Rituximab 375mg/m2, D0 /Q28D Weigert et al, Germany, Leukemia (2007) 21, 524–528

  40. Bortezomib is Synergistic with Rituximab/ Cyclophosphamide in vitro and in vivo Wang et al, MDACC, Leukemia (2008) 22, 179–185

  41. Bortezomib Combination in MCL * All PET- negative; †evaluable following 4 cycles Blum et al. ASH 2006, abstract # 2768

  42. 2-Line Single Agent Temsirolimus (Torisel) • Phase 2 1.JCO. 2005 Aug 10;23(23):5347-56 2. Cancer. 2008 Aug 1;113(3):508-14

  43. 2-Line Single Agent Temsirolimus (Torisel) • Phase 3 ASCO 44th annual meeting, 2008 Jun

  44. compromised patient elderly patient (>65) young patient (<65) First line conventional R-chemo (e.g. R-CHOP) Rituximab maintenance ? radioimmunotherapy ? Dose-intensifiedR-chemo (either sequential:e.g. R-CHOP =>ASCT or R-HyperCVAD/MTXAC) watch & wait ? Rituximab monotherapy Chlorambucil Bendamustin First relapse R-chemo (e.g. R-FC, R-Bendamustin) molecular approaches ASCT radioimmunotherapy ? Rituximab maintenance ? High tumor load: R-chemo (e.g. R-FC) allo-transplant ? radioimmunotherapy ? Rituximab maintenance ? R-chemo (e.g. R-Bendamustin) molecular approaches Higher relapse molecular approaches: Bortezomib, CCI-779, Thalidomide/Lenalidomide, Flavopiridol (preferable in combination) repeat previous therapy (long remissions) Dreyling ASCO 2006

  45. NCCN 2008 V3

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