48. Bayerischer Internisten-Kongress 2009 * München, 8. November Indolente Lymphome. Welche Entität wie behandeln?

Transcription

1 48. Bayerischer Internisten-Kongress 2009 * München, 8. November 2009 Indolente Lymphome Welche Entität wie behandeln? M. Dreyling, Dept. of Medicine III Klinikum Grosshadern LMU/München

2 Indolente (niedrigmaligne) Lymphome

3 Non-Hodgkin-Lymphome: Häufigkeit der Subtypen periph. T 7% sonstige 17% DLBCL 34% CLL, Waldenstroem 6% Mantelzell 6% MALT 8% Follikulär 22%

4 Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom

5 Follikuläres Lymphom: Klinisches Bild ca. 25% aller Lymphome mittleres Alter Jahre ca. 85% Stadium III/IV schleichender Verlauf (mittleres Überleben Jahre) auch im Rückfall empfindlich auf Chemotherapie

6 FLIPI in follikulären Lymphom (n=1795) Survival probability 36% 37% 27% Solal-Celigny, Blood 2004

7 Watch & wait vs. Chlorambucil in asymptomatischen Patienten Disease-specific survival Overall survival Prospective randomised study (follow-up 16 years) : n=309; 65% follicular lymphoma Ardeshna, Lancet 2003

8 Therapie in Stadium III/IV Fazit für die Praxis Dreyling, Ann Oncol 2009

9 Indolentes Lymphom Gesamtüberleben 100 % (n=668) (n=513) (n=195) Horning, Semin Oncol 1993

10 Rituximab bei malignen B-Zell Lymphomen Wirkmechanismus 4 x 375 mg/m2 Rituximab response rate time to progression toxicity Mc Laughlin, JCO % (166 patients) 13 months (responder) Fever, rigors, chills (12% grade III, 3% grade IV)

11 Follikuläres Lymphom (ältere Patienten) Progressions-freies Überleben (R-CHOP) R-CHOP (78/112) Probability median 2.1 y CHOP (37/109) p< years Buske, ASH 2006

12 Follikuläres Lymphom (ältere Patienten) Gesamt-Überleben (R-CHOP) R-CHOP (102/112) CHOP (89/109) Probability 4-y OS: R-CHOP: 90% CHOP: 81 % p=0.039 years Buske, ASH 2006

13 Follikuläres Lymphom BR vs. R-CHOP: Ansprechen B-R (n=232) CHOP-R (n=224) ORR 94 % 93 % CR 41 % 32 % SD 3 % 4 % Prim. refr. 3 % 3 % PD / relapse n = 63 n = 89 Deaths n = 26 n = 27 Rummel ASH 2008

14 Therapie follikulärer Lymphome Fazit für die Praxis Dreyling, Ann Oncol 2009

15 Follikuläres Lymphom Therapie-Konzepte Induction Consolidation maintenance Immuno-chemotherapy! +/- SCT => lymphoma remission => MRD eradication

16 Follikuläres Lymphom Therapie-Konzepte Options 1. Rituximab 2. radio-immunotherapy 3. autologous SCT 4. allogeneic +/- SCT Consolidation maintenance => MRD eradication

17 Erhaltung vs. Beobachtung Remissionsdauer (nur FL) 1,0 0,9 0,8 Kum. Überleben 0,7 0,6 0,5 0,4 0,3 Rituximab (32/55) 0,2 0,1 Observation (23/55) 0, PFS years nach aftertherapieende end of initial therapy (ITT) Forstpointner, Blood 2006 updated p=0.016

18 Follikuläres Lymphom Antikörper-Erhaltungstherapie 100 Progression free survival After complete response to (R-)CHOP 100 Progression free survival After non complete response to (R-)CHOP Overall Logrank test: p= Overall Logrank test: p= med: 52.7 months median: 41.8 months med months med months 0 (years) O N Number of patients at risk : Treatment Observation Rituximab 0 (years) O N Number of patients at risk : Treatment Observation Rituximab van Oers ASH 2008

19 Radioimmunotherapie: 90 Y vs. 131 I 90 Y 131 I Beta radiation path length Gamma emission No Yes Beta emission energy (MeV) Half-life (days) Path length (mm) χ Maximum Mean Yttrium 131 Iodine

20 Follikuläres Lymphom Radioimmunotherapie First line immuno-chemotherapy KI against chemotherapy: individual radioimmunotherapy 1. relapse young patients elderly patients high risk low risk high risk low risk (immuno-) chemotherapy (immuno-) chemotherapy radioimmunotherapy PBSCT studies: +RIT PBSCT studies: +RIT antibody maintenance radioimmunotherapy radioimmunotherapy antibody maintenance >2. relapse (immuno-) chemotherapy radioimmunotherapy experimental therapy (allogeneic transplantation?) Dreyling 2007

21 Follikuläres Lymphom PR-Patienten 100 Cumulative Percentage At risk: 90 Y-ibritumomab 100 Control 94 Log-rank P <.001 HR 0.36 (95% CI: ) months Y-ibritumomab: n = 100 median 29.6 months Control: n = 94 median 6.7 months 4 1 Morschhauser ASH 2008

22 Therapie des follikulären Lymphoms group 1 fit patient organ function functional status life expectancy comorbidity risk of toxicity Go go intensive therapy => long term remissions group 2 compromised patient organ function functional status life expectancy comorbidity risk of toxicity Slow go less intensive therapy => reduction of lymphoma group 3 Frail patient organ function functional status life expectancy comorbidity risk of toxicity No go supportive therapy => control of syptoms

23 Follikuläres Lymphom Hochdosis im Rezidiv Event free survival after relapse/pd Survival after relapse/pd Coiffier ASH 2007

24 Follikuläres Lymphom Rezidivtherapie Dreyling, Ann Oncol 2009

25 Follikuläres Lymphom Hochdosis in der Primärtherapie Progression-free survival Overall survival Ladetto 2008

26 Follikuläres Lymphom Erhaltung/Konsolidierung GLSG Studien 2009/10 < 65 years compromised medically non-fit R-CHOP R-CHOP/R-FCM/R-MCP R+/- Bendamustin R-maintenance +/-PBSCT +/-Rituximab maintenance Ritux maintenance < 65 years Mini transplant (phase II) Relapse R-FC/R-CHOP R-maintenance +/-Zevalin R-Gemox (phase II)

27 Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom

28 MALT-Lymphom centrocyte-like cells lympho-epithelial lesion Isaacson, Norton: Extranodal Lymphomas (1994)

29 MALT ist assoziiert mit chronischer Antigen-Stimulation (1) MALT Splenic Nodal +/- autoantigens - Thyroid Hashimoto thyroiditis - Salivary gland Myoepithelial sialoadenitis +/ - Sjögren S. - Lung Lymphoid interstitial pneumopathy

30 MALT ist assoziiert mit chronischer Antigen-Stimulation (2) MALT Splenic Nodal +/- autoantigens +/- microbial pathogens Stomach Small intestine (IPSID) Skin Ocular adnexa H. Pylori C. Jejuni B. Burgdorferi C. Psitacci Hepatitis C virus

31 Gastrisches MALT-Lymphom Pathogenese chronic infection by H.p. T- lymphocytes normal mucosa Autoimmun gastritis MALT low grade lymphoma high grade lymphoma antigen-driven proliferation autonomous growth Farinha JCO 2005

32 Gastrisches MALT-Lymphom Behandlung früher Stadien Microbial pathogen DEPENDENT - MALT lymphoma Treatment of the pathogen - Eradication of HP : 97% - CR : 60% - 80% - Response : 3 to 28 months! After 5 years = 71% Molecular remission is unfrequent Usefulness of monoclonality determined by PCR? Wündisch JCO 2005

33 Studien 01/92 und 02/96 Konservative Therapie vs. Gastrektomie 100 median time of observation Cause-specific survival (%) study 01/92 study 02/96 42 months stages I + II all histologic subtypes 96 months conservative approach n = 105 (censored 97) surgical approach n = 79 (censored 68) conservative approach n = 332 (censored 313) surgical approach n = 60 (censored 53) P.Koch 611JCO Months Koch, J Clin Oncol 2005

34 Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom

35 Jan Waldenström Incipient myelomatosis or essential hyperglobulinemia with fibrinogenopenia- a new syndrome? 1944, Acta Med Scand 177:216

36 2nd international WM workshop Diagnostische Kriterien IgM monoclonal gammopathy of any concentration Bone marrow infiltration with small lymphocytes, plasmacytoid cells and plasma cells Diffuse, interstitial or nodular pattern of infiltration. NB paratrabecular pattern follicular lymphoma requires exclusion with lymph node biopsy and/or t(14;18) PCR Immunophenotype: sig+ CD19+ CD20+ CD5- CD10- CD23- Owen, Clin Lymphoma 2000

37 Asymptomatische Patienten Klinischer Verlauf Dhdapkar 2009

38 Pathogenese der klinischen Symptomatik HCT, PLT, WBC Hyperviscosity syndrome >1.8 CP (72%) >4.0 CP (6%) Adenopathy, SM <18% Fatigue, Constitutional Sxs Cytokinemia? IgM neuropathy (20%) Autoimmune D/O (15%) Cryoglobulinemia (<5%) Cold agglutinemia (<5%)

39 Hyperviskositäts- Syndrom Bleeding symptoms (epistaxis) Headache Blurred vision Tinnitus

40 Symptomatische Patienten Klinischer Verlauf Dhdapkar 2009

41 CHOP vs. R-CHOP (LP-IC) Zeit bis zum Therapieversagen Buske Leukemia 2008

42 Primärtherapie des M. Waldenström Therapeutic class Agents Evidence for Efficacy Level of recommendatio n Nucleoside analogues plus alkylators Cladribine or Fludarabine plus cyclophosphamide IIa B Nucleoside analogues plus rituximab Fludarabine plus rituximab Cladribine plus rituximab [10] IIa B Nucleoside analogues plus alkylators and rituximab Cladribine, cyclophosphamide and rituximab Fludarabine, cyclophosphamide and rituximab Pentostatin, cyclophosphamide and rituximab IIa III III B C C Cyclophosphamide based combination therapy plus rituximab CHOP and rituximab Cyclophosphamide, Dexamethasone and rituximab IIa IIa B B Immunomodulatory drugs plus rituximab Thalidomide and rituximab IIa B Monoclonal antibody Rituximab (standard or extended schedule) IIa B Nucleoside analogues Cladribine or Fludarabine IIa B Alkylator agents Chlorambucil IIa B 4th IWWM Dimopoulos,JCO 2009

43 Rezidivtherapie des M. Waldenström Therapeutic class Agents Evidence for Efficacy Level of recommendation Alkylator agents Nucleoside analogues Monoclonal antibody Nucleoside analogues plus alkylators Chlorambucil Cladribine or Fludarabine Rituximab (standard or extended schedule) Alemtuzumab Cladribine or Fludarabine plus cyclophosphamide IIa Ib IIa IIa IIa B A B B B Nucleoside analogues plus rituximab Fludarabine plus rituximab IIa B Nucleoside analogues plus alkylators and rituximab Combination chemotherapy plus rituximab Thalidomide Bortezomib Stem cell transplant Cladribine, cyclophosphamide and rituximab Fludarabine, cyclophosphamide and rituximab Pentostatin, cyclophosphamide and rituximab CHOP and rituximab Thalidomide alone or in combination with dexamethasone Bortezomib alone HDM with ASCT Allo-SCT IIb III III III IIa IIa IIa III B C C C B B B C 4th IWWM Dimopoulos,JCO 2009

44 Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom

45 MCL: ein Spektrum von Erkrankungen Jares, Nature Rev 2007

46 Biologische Risikofaktor Zellproliferation II Katzenberger, Blood 2006 Determann, Blood 2008

47 Kiel vs. GLSG Historische Vergleich Herrmann, JCO 2008

48 CHOP vs. R-CHOP: MCL Zeit bis zum Therapieversagen Hoster, ASH 2008

49 Mantelzell-Lymphom Hochdosis-Konsolidierung CR Progression-free survival PR HR 0.30 (95% CI ) HR 0.60 (95% CI ) Dreyling ASH 2008

50 Molekulare Pathogenese des MCL Jares, Nature Reviews 2007

51 young patient (<65) elderly patient (>65) compromised patient dose-intensified immuno-chemotherapy (either sequential: e.g. R-CHOP =>PBSCT or R-Hyper-CVAD) high tumor load: immuno-chemotherapy (e.g. R-FC) allo-transplant? radioimmunotherapy? Rituximab maintenance? First line treatment conventional immuno-chemotherapy (e.g. R-CHOP) Rituximab maintenance? radioimmunotherapy? 1. relapse immuno-chemotherapy (e.g. R-FC, R-Bendamustin) molecular approaches? autologous PBSCT radioimmunotherapy? Rituximab maintenance? higher relapse molecular approaches: Bortezomib, CCI-779, Thalidomide/ Lenalidomide, Flavopiridol (preferable in combination) repeat previous therapy (long remissions) watch & wait? Rituximab monotherapy Chlorambucil Bendamustin immunochemotherapy (e.g. R-Bendamustin) molecular approaches Dreyling ASCO 2006

52 Indolente Lymphome Welche Entität wie behandeln? Risiko-adaptierte Therapie Immuno-Chemotherapie überlegen (OR, PFS, OS) Individuelle Chemotherapie in symptomatischen Patienten (cave: MCL) Hochdosistherapie im Rezidiv (cave: MCL)

53 Indolente Lymphome Welche Entität wie behandeln? Palliation vs. Kuration? Perspektiven: - Rituximab-Erhaltung - Radioimmunotherapie - molekulare Strategien: Proteasome, IMIDs, mtor Ziel: individuelle und spezifische Therapie!