Perrotti A.P. From empiric therapy to guide lines of silent and aggressive linphomas

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Perrotti A.P. From empiric therapy to guide lines of silent and aggressive linphomas

  1. 1. 1 Dalla terapia “empirica”alle linee guida nei Linfomi Indolenti ed Aggressivi Alessio P. Perrotti DH Ematologia Ospedale S.Eugenio - Roma 29 Marzo 2014
  2. 2. 2 Linfocitici 7% Burkitt 1% Linfoblastici 2% T periferici 7% Anaplastici 2% Altri 8% Linfoplasmacitoidi 2% Marginali 8% Diffusi a grandi cellule B 35% Mantellari 6% Follicolari 22% Non-follicolari Distribuzione dei Linfomi Non-Hodgkin
  3. 3. 3 Treatment of non-Hodgkin lymphoma general principles  It is (still ) not possible to select a specific treatment for each type of NHL  Therefore NHL are divided into major subgroups: – Indolent types (follicular lymphoma) – Aggressive types (diffuse large B cell lymphoma) – Very aggressive types (Burkitt)
  4. 4. 4 A practical way to think of lymphoma Category Survival of untreated patients Curability To treat or not to treat Non-Hodgkin lymphoma Indolent Years Generally not curable Generally defer Rx if asymptomatic Aggressive Months Curable in some Treat Very aggressive Weeks Curable in some Treat Hodgkin lymphoma All types Variable – months to years Curable in most Treat
  5. 5. 5 Treatment of non-Hodgkin lymphoma considerations as to choice of therapy • Type of lymphoma (WHO classification) • Ann Arbor stage (I to IV) • localizations • Risk profile/prognostic score of the patient • Which treatment is possible?
  6. 6. 6 non-Hodgkin’s Lymphomas treatment till 1997 • Surgery • Wait and see (indolent lymphoma)
  7. 7. Watch & wait versus immediate treatment for asymptomatic advanced stage indolent NHL: Overall Survival Observation (n = 151) Chlorambucil (n = 153) 100 80 60 40 20 0 0 Years 4 8 12 16 20 24 Cumulativesurvival(%) Median 5-year 10 -year 15 -year Chlorambucil 5.9 years 57% 35% 21% Observation 6.7 years 58% 34% 22% Ardeshna et al, Lancet, 2003; 362: 516
  8. 8. non-Hodgkin’s Lymphomas treatment till 1997 • Surgery • Wait and see (indolent lymphoma) • Radiotherapy: stage I indolent stage I aggressive (+CT!) • (poly) chemotherapy
  9. 9. 9 CHOP Advances in the treatment of aggressive NHL SINGLE DRUG SINGLE DRUG SINGLE DRUG SINGLE DRUG SINGLE DRUG SINGLE DRUG CHOP CHOP CHOP CHOP CHOP 0 100 MACOP-B ProMACE-CytaBOM m-BACOD F-MACHOPACVB
  10. 10. 10 Period 1970-1985 CR rate ~50% Long term survival ~30-35% THE CHOP ERA (1°) Aggressive NHL: Treatment of advanced disease
  11. 11. 11 Period 1985-1993 CR rate 60-85% Long term survival 50-60% The 2nd and 3rd generation era Aggressive NHL: Treatment of advanced disease
  12. 12. 12 SWOG Trial Regimen N°pts RC % EFS % OS % CHOP 225 44 41 54 m-BACOD 223 48 46 52 ProMACECytaBOM 233 56 46 50 MACOP-B 218 51 41 50
  13. 13. 13 CHOP is the gold standard in DLCL Fisher RI et al. N Engl J Med 1993;328:1002–6 100 80 60 40 20 0 0 5 10 15 Overallsurvival(%) CHOP MACOP-B ProMACE-CytaBOM m-BACOD CHOP 6-yrs OS= 42%
  14. 14. 14 The results of the treatment of patients with NHL have been improved impressively by the use of antibodies directed against the lymphoma cells
  15. 15. 15 Immunotherapy has changed the clinical course of NHL * Age-adjusted to 2000 US standard population Adapted from Molina A. Annu Rev Med 2008; 59:237–250. 15 10 5 0 Rateper100,000* NHL mortality Rituximab (1997)Fludarabine (1991) Etoposide (1983) Cisplatin (1978) 20102005200019951990198519801975 90Y ibritumomab tiuxetan (2002) 131I tositumomab (2003)
  16. 16. • Kohler G, Milstein C: “Continuous cultures fused cells secreting antibody of predefined specificity.” Nature 1975; 256:495
  17. 17. 17 Hybridoma Technology B-cell: Produces antibodies cannot be cultured in vitro for a long time Immunisation or Infection Hybridoma cell: Produces monoclonal antibodies Can be cultured indefinitely Myeloma cell: No antibody production. Can be cultured indefinitely Humanisation of antibody
  18. 18. 18 murine 1975 …momab chimeric 1984 …ximab humanised 1988-1991 …zumab Humanisation human 1994–1999 …mumab Immunogenic Less immunogenic Monoclonal antibodies
  19. 19. Rituximab (mabthera®) : a mouse/ human chimeric anti- CD20 monoclonal antibody Murine variable regions bind specifically to CD20 on normal/ malignant B-cells Human K constant regions Human IgG1 Fc domain • interacts with human effector mechanisms (ADCC, CDC) • low immunogenicity
  20. 20. 20 Anti-CD20 (Rituximab= Mabthera®) mechanism of action Adapted from Male D, et al., Advanced Immunology 1996: 1.1–1.16 Malignant B-cell Complement CD20 CD20 Direct induction of apoptosis Killer Leukocyte
  21. 21. 21 The pivotal study • 166 patients with relapsed or refractory low-grade or follicular lymphoma (FL) • MabThera monotherapy (375 mg/m2, once-weekly for 4 weeks) • Non-bulky disease (<10 cm) • At least 1 prior chemotherapy McLaughlin P, J Clin Oncol 1998
  22. 22. 22 Grade 3-4 toxicities • Infusion-related reactions • Cytopenia (1 or more lineages) • Cardiac events • Pulmonary events (BOOP) • Infections • Stevens-Johnson syndrome • Abdominal pain Grade 3-4 toxicities are rare with MabThera monotherapy
  23. 23. 23 CHOP ± Rituximab in DLCL in the elderly (60-80 yr)Probabilityofevent-freesurvival Years 0 1 2 3 4 5 p=0.00001 51% CHOP + rituximab 29% CHOP 1.0 0.8 0.4 0.6 0.2 Coiffier et al.
  24. 24. 24 DLCL in the elderly : Rituximab improves overall survival Years 1.0 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 p=0.01 59% Rituximab + CHOP 47% CHOP Probabilityofoverallsurvival Coiffier et al.
  25. 25. 25 INDICAZIONI LNH RCP RITUXIMAB • Follicolare III-IV stadio non trattato in associazione a chemioterapia • Mantenimento nel Follicolare rispondente alla induzione • Monoterapia nel Follicolare III-IV stadio chemioresistente o in recidiva dopo chemioterapia • Linfoma non Hodgkin CD20+ diffuso a grandi cellule B in associazione a CHOP
  26. 26. 26 INDICAZIONI LEGGE 648/96 PER RITUXIMAB • LNH a cellule B (CD20+) di qualunque istologia in associazione con regimi vari di polichemioterapia impiegati per il trattamento di 1° linea o di salvataggio, inclusi i regimi di condizionamento pretrapianto di cellule staminali emopoietiche determinazione AIFA 18.05.2011
  27. 27. 27 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 60 72 84 96 108 120 Follow-up, months FLIPI 0-1 FLIPI 2 FLIPI 3-5 Overall Survival Follicular lymphoma without Rituximab (1988-2003) FLIPI OS% 5-yr HR (CI95) P 0-1 89 (82-93) 1.00 2 72 (61-81) 2.96 (1.69-5.17) <0.001 3-5 52 (39-64) 5.13 (2.95-8.90) <0.001 3-5 vs 2 1.73 (1.07-2.80) 0.025
  28. 28. 28 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 60 72 Follow-up, months FLIPI 0-1 FLIPI 2 FLIPI 3-5 Overall Survival Follicular lymphoma with Rituximab (2003-2010) FLIPI OS% 5-yr 0-1 91 (78-96) 2 93 (85-96) 3-5 86 (77-91) Log-rank test: P=0.027
  29. 29. 29 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 60 Follow-up, months IPI 0-1 IPI 2 IPI 3 IPI 4-5 Overall Survival DLBCL without Ritux (1988-2003) 01
  30. 30. 30 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 60 Follow-up, months IPI 0-1 IPI 2 IPI 3 IPI 4-5 Overall Survival DLBCL with Ritux (2003-2007) 1
  31. 31. 31 non-Hodgkin’s Lymphomas Treatment (after 1997) • Surgery • Wait and see (indolent lymphoma) • Radiotherapy: stage I indolent stage I aggressive (+CT!) • (poly) chemotherapy • Immuno-chemotherapy • Transplantation • New drugs
  32. 32. 32 Nathan Fowler, Sattva Neelapu, Fredrick Hagemeister, Peter McLaughlin, Larry W. Kwak, Jorge Romaguera, Michelle Fanale, Luis Fayad, Robert Orlowski, Michael Wang, Francesco Turturro, Yasuhiro Oki, Linda Lacerte, Felipe Samaniego Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX, USA Fowler N, Neelapu S, Hagemeister F, et al. Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study. Oral presentation at: Annual Meeting and Exposition of the American Society of Hematology 2012; December 8-11; Atlanta, GA. Abstract 901 Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study
  33. 33. 33 Fowler et al: Results Efficacy All evaluable patients (n = 103) SLL (n = 30) MZL (n = 27) FL (n = 46) ORR, n (%) 93 (90) 24 (80) 24 (89) 45 (98) CR/CRu, n (%) 66 (64) 8 (27) 18 (67) 40 (87) PR, n (%) 27 (26) 16 (53) 6 (22) 5 (11) SD, n (%) 8 (8) 4 (13) 3 (11) 1 (2) PD, n (%) 2 (2) 2 (7) 0 0 Projected 36-months PFS, % 78 66 89 81 33 CRu, unconfirmed CR; PD, progressive disease; SD, stable disease. Fowler N, Neelapu S, Hagemeister F, et al. Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study. Oral presentation at: Annual Meeting and Exposition of the American Society of Hematology 2012; December 8-11; Atlanta, GA.
  34. 34. 34 GRAZIE PER LA ATTENZIONE

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