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
Indolente (niedrigmaligne) Lymphome
Non-Hodgkin-Lymphome: Häufigkeit der Subtypen periph. T 7% sonstige 17% DLBCL 34% CLL, Waldenstroem 6% Mantelzell 6% MALT 8% Follikulär 22%
Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom
Follikuläres Lymphom: Klinisches Bild ca. 25% aller Lymphome mittleres Alter 60-65 Jahre ca. 85% Stadium III/IV schleichender Verlauf (mittleres Überleben 15-20 Jahre) auch im Rückfall empfindlich auf Chemotherapie
FLIPI in follikulären Lymphom (n=1795) Survival probability 36% 37% 27% Solal-Celigny, Blood 2004
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
Therapie in Stadium III/IV Fazit für die Praxis Dreyling, Ann Oncol 2009
Indolentes Lymphom Gesamtüberleben 100 % 80 60 1987-1992 (n=668) 1976-1987 (n=513) 1960-1976 (n=195) 40 20 0 60 65 70 75 80 85 90 Horning, Semin Oncol 1993
Rituximab bei malignen B-Zell Lymphomen Wirkmechanismus 4 x 375 mg/m2 Rituximab response rate time to progression toxicity Mc Laughlin, JCO 1998 48% (166 patients) 13 months (responder) Fever, rigors, chills (12% grade III, 3% grade IV)
Follikuläres Lymphom (ältere Patienten) Progressions-freies Überleben (R-CHOP) R-CHOP (78/112) Probability median 2.1 y CHOP (37/109) p<0.0001 years Buske, ASH 2006
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
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
Therapie follikulärer Lymphome Fazit für die Praxis Dreyling, Ann Oncol 2009
Follikuläres Lymphom Therapie-Konzepte Induction Consolidation maintenance Immuno-chemotherapy! +/- SCT => lymphoma remission => MRD eradication
Follikuläres Lymphom Therapie-Konzepte Options 1. Rituximab 2. radio-immunotherapy 3. autologous SCT 4. allogeneic +/- SCT Consolidation maintenance => MRD eradication
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) 0,0 0 1 2 3 4 5 6 PFS years nach aftertherapieende end of initial therapy (ITT) Forstpointner, Blood 2006 updated p=0.016
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 90 90 80 80 70 Overall Logrank test: p=0.003 70 Overall Logrank test: p=0.0006 60 50 med: 52.7 months 60 50 median: 41.8 months 40 40 30 30 20 10 med. 14.4 months 20 10 med. 15.6 months 0 (years) 0 1 2 3 4 5 6 7 8 O N Number of patients at risk : Treatment 38 48 30 16 13 11 6 3 0 Observation 29 49 40 35 31 24 17 9 2 Rituximab 0 (years) 0 1 2 3 4 5 6 7 8 O N Number of patients at risk : Treatment 89 119 66 47 34 27 20 7 1 Observation 71 118 91 76 64 51 29 12 5 Rituximab van Oers ASH 2008
Radioimmunotherapie: 90 Y vs. 131 I 90 Y 131 I Beta radiation path length Gamma emission No Yes Beta emission energy (MeV) 2.3 0.6 Half-life (days) 2.7 8.0 Path length (mm) χ 90 5.3 0.8 Maximum 11.0 2.9 Mean 2.5 0.4 90 Yttrium 131 Iodine
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
Follikuläres Lymphom PR-Patienten 100 Cumulative Percentage 75 50 25 0 At risk: 90 Y-ibritumomab 100 Control 94 Log-rank P <.001 HR 0.36 (95% CI: 0.25-0.51) 0 12 24 36 48 60 months 82 42 58 19 40 11 12 3 90 Y-ibritumomab: n = 100 median 29.6 months Control: n = 94 median 6.7 months 4 1 Morschhauser ASH 2008
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
Follikuläres Lymphom Hochdosis im Rezidiv Event free survival after relapse/pd Survival after relapse/pd Coiffier ASH 2007
Follikuläres Lymphom Rezidivtherapie Dreyling, Ann Oncol 2009
Follikuläres Lymphom Hochdosis in der Primärtherapie Progression-free survival Overall survival Ladetto 2008
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)
Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom
MALT-Lymphom centrocyte-like cells lympho-epithelial lesion Isaacson, Norton: Extranodal Lymphomas (1994)
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
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
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
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
Studien 01/92 und 02/96 Konservative Therapie vs. Gastrektomie 100 median time of observation Cause-specific survival (%) 90 80 70 60 50 40 30 20 10 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 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Months Koch, J Clin Oncol 2005
Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom
Jan Waldenström Incipient myelomatosis or essential hyperglobulinemia with fibrinogenopenia- a new syndrome? 1944, Acta Med Scand 177:216
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
Asymptomatische Patienten Klinischer Verlauf Dhdapkar 2009
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%)
Hyperviskositäts- Syndrom Bleeding symptoms (epistaxis) Headache Blurred vision Tinnitus
Symptomatische Patienten Klinischer Verlauf Dhdapkar 2009
CHOP vs. R-CHOP (LP-IC) Zeit bis zum Therapieversagen Buske Leukemia 2008
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
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
Indolente Lymphome Follikuläres Lymphom Marginalzonenlymphom M. Waldenstroem Mantelzell-Lymphom
MCL: ein Spektrum von Erkrankungen Jares, Nature Rev 2007
Biologische Risikofaktor Zellproliferation II Katzenberger, Blood 2006 Determann, Blood 2008
Kiel vs. GLSG Historische Vergleich Herrmann, JCO 2008
CHOP vs. R-CHOP: MCL Zeit bis zum Therapieversagen Hoster, ASH 2008
Mantelzell-Lymphom Hochdosis-Konsolidierung CR Progression-free survival PR HR 0.30 (95% CI 0.14 0.66) HR 0.60 (95% CI 0.37 0.96) Dreyling ASH 2008
Molekulare Pathogenese des MCL Jares, Nature Reviews 2007
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
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)
Indolente Lymphome Welche Entität wie behandeln? Palliation vs. Kuration? Perspektiven: - Rituximab-Erhaltung - Radioimmunotherapie - molekulare Strategien: Proteasome, IMIDs, mtor Ziel: individuelle und spezifische Therapie!