RADIOIMMUNOTHERAPY FOR TREATMENT OF NON- HODGKIN S LYMPHOMA

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1 RADIOIMMUNOTHERAPY FOR TREATMENT OF NON- HODGKIN S LYMPHOMA Pier Luigi Zinzani Institute of Hematology and Medical Oncology L. e A. Seràgnoli University of Bologna, Italy Slovenia, October

2 Zevalin 1st-line in FL (1) Treatment regimen: 1 Day Month Y-ibritumomab tiuxetan, day 8: 15 MBq/kg BW, platelet count /mm³, 11 MBq/kg BW, platelet count > /mm³ and < /mm³ (max MBq) Rituximab 250 mg/m 2 day 1 and 8 Rituximab maintenance therapy 375 mg/m 2 /w x 4; q6 months for 2 years Multicentre phase II study. Interim analysis after 10 patients, planned 23 patients Median age 58 (40-82) years 50% stage IV Sweetenham et al. Blood 104(11):720a, abstr 2633 (2004)

3 Zevalin 1st-line in FL (2) Response rate (%) ORR 62 CR Response rates (n=8): ORR: 100% CR: 62% Safety: 38% grade 3 cytopenia non-haematologic adverse events only grade I Sweetenham et al. Blood 104(11):720a, abstr 2633 (2004)

4 Zevalin as Consolidation after 1st-line Chemoimmunotherapy in FL (1) Week * 8 Rituximab 375 mg/m 2 i.v. R-CHOP or R-CVP (q3w, 3 cycles) Rituximab 250 mg/m 2 day 1 and 8 Zevalin 15 MBq/kg BW; *interval at least 5 weeks Shipley et al. Proc ASCO 23(16S):579s, abstr 6577 (2005)

5 Zevalin as Consolidation after 1stline Chemoimmunotherapy in FL (2) Study details Multicentre phase II study (Follow-up: median 24 months) Age median (range) Ann Arbor stage II Ann Arbor stage III Ann Arbor stage IV Chemoimmunotherapy with R-CHOP Chemoimmunotherapy with R-CVP Complete response (CR and CRu) after chemoimmunotherapy (n=40) after Zevalin (n=39) Progression free survival after 2 years n=42 (evaluable with respect to total therapy: n=39) 53 (33-82) years 12% 28% 60% 86% 14% 30% 66% 85% Shipley et al. Proc ASCO 23(16S):579s, abstr 6577 (2005)

6 Zevalin in 1st line with chemoimmunotherapy in follicular NHL (3) Response rates after chemoimmunotherapy and after Zevalin Progression free survival PR CR/CRu Response rate (%) Progression free survival (%) after chemoimmunotherapy after Zevalin Months Shipley et al. Proc ASCO 23(16S):579s, abstr 6577 (2005)

7 Zevalin as Consolidation after 1stline Chemoimmunotherapy in FL (4) 16 patients with previously untreated follicular NHL were included in a phase II study in Pittsburgh. Treatment: 3 x R-CHOP, followed by Zevalin (w +4) and 4 x rituximab (w +5 till +9) Median age 59.4 years, 14/16 stage III/IV, 11/16 FLIPI intermediate or high risk Response (CR) following R-CHOP or Zevalin (n=16): CT: 38.5% 81% PET-negative: 53.3% 100% PET-CT: 26.7% 80% DeMonaco NA et al. J Clin Oncol 24(Suppl 18):444s, abstr 7589 (2006)

8 Zevalin in 1st line with chemoimmunotherapy in follicular NHL (5) Response rates according to CT, PET or PET-CT after R-CHOP or 12 weeks after consolidation with Zevalin PR CR Response rate (%) R-CHOP Zevalin CT R-CHOP Zevalin PET DeMonaco NA et al. Blood 106 (11):689A, abstr 2449 (2005) R-CHOP Zevalin PET _ CT

9 EU/Canada: FIT (First-line Indolent Trial) Phase III consolidation study Newly diagnosed follicular NHL Stage III - IV Remission induction chemotherapy* NR PD Start of study CR /PR No inclusion 90 Y- ibritumomab tiuxetan No further Treatment *Left to the discretion of the treating physician, e.g. CLB, CHOP, CVP, fludarabine etc. (incl. rituximab after last protocol ammendment) This study included MRD monitoring and QoL assessment

10 EU/Canada: FIT (First-line Indolent Trial) Country Number of active study centers No further Number of patients treatment 90 Y-I T TOTAL Belgium Canada Denmark France Germany Italy Norway Portugal Spain Sweden Switzerland NL UK Total Primary objective To detect a prolongation of the progression-free survival period by 50% (increase of PFS from 30% to 45% at 4 years) Data will be presented at ASH 2007

11 Phase II study of sequential FM and 90 YIbritumomab of untreated indolent (non-follicular) NHL patients FM q28 x 6 cycles 90 Y Ibritumomab tiuxetan 6-10 weeks after FM Enrolled 26 patients Restage 4-6 weeks after FM

12 Main patients characteristics (n=26) Median age (range) 61(45-82) Sex male/female 13/13 Stage III 4 Stage IV 22 (85 %) Bone marrow involvement 20 (80%) Extranodal involvement 6 (23%) Bulky disease 2 (8%) Histology Marginal zone Lymphoplasmacytic lymphoma Small lymphocytic lymphoma 10 (40%) 8 (30%) 8 (30%)

13 Clinical response after FM (n=26) CR 13 (50 %) PR 8 (30%) PD 5 (20%)

14 Clinical response after Zevalin (n=20) After FM After Zevalin CR 13 (65 %) 20 (100 %) PR 7 (35 %) /

15 Duration of hematologic toxicity Variable Baseline Nadir (range) ANC, cells/mm ( ) 700 ( ) Days from Baseline to Nadir 41 (30-51) Median duration for patients with grade 3 or 4 Nadir (days) 30 (17-56) Platelets, cells/mm ( ) 23 (11-120) 35 (29-50) 36 (20-104) Hemoglobin, g/dl 13.4 ( ) 9 (7.2-14) 45 (30-51) 38 (25-104)

16 Hematological toxicity after Zevalin (n=20) Anemia grade III-IV 7 (27 %) Neutropenia grade III-IV 11 (42 %) Thrombocytopenia grade III-IV 16 (61 %) Patients who required transfusion 6 (22 %) Antibiotic 5 Febrile neutropenia 1(4%) Hospitalization due to FN 1

17 Phase II study of sequential FM (oral fludarabine and mitoxantrone) and 90 YIbritumomab of untreated follicular NHL patients (FLUMIZ) FM q28 x 6 cycles 90 Y Ibritumomab tiuxetan 6-10 weeks after FM Enrolled 61 patients Restage 4-6 weeks after FM

18 Main patients characteristics (n=61) Median age (range) 54 (30-72) Male/Female 25/37 Stage II 6 (10%) Stage III 20 (32%) Stage IV 36 (58%) Bone marrow involvement 31 (51%) Extranodal involvement 5 (8%) Bulky disease 15 (25%)

19 Clinical response after FM (n=61) CR 37 (61%) CRu 6 (10%) PR 17 (27%) PD 1 (2%)

20 Clinical response after Zevalin (n=57) After FM After Zevalin CR (96%) PR 17 2 (4%)

21 CR 43 PR pts (70%) 3 pts (18%) Not eligible Zevalin CR pts PR 2 2 pts (12%)

22 Bcl-2 monitoring Patients evaluable for Bcl-2 23 Bcl-2 + before Zevalin 18 Molecular CR 14 (78%) Molecular relapse 2/14 (11%) 2/9 (22%) * Median follow-up for molecular analysis 12 months * These patients are alive, with complete response

23 Hematological toxicity after Zevalin Anemia grade III-IV 13 (28 %) Neutropenia grade III-IV 30 (65 %) Thrombocytopenia grade III-IV 36 (78 %) Patients who required transfusion 21 (46 %) Antibiotic 20 (43%) Febrile neutropenia 5 (11 %) Hospitalization due to FN 2 (4%) Infections 7 (15%)

24 Duration of hematologic toxicity Variable Baseline Nadir (range) ANC, cells/mm ( ) 644 ( ) Days from Baseline to Nadir 42 (31-158) Median duration for patients with grade 3 or 4 Nadir (days) 30 (3-105) Platelets, cells/mm ( ) 23 (2-133) 35 (23-61) 35 (8-116) Hemoglobin, g/dl 13.7 ( ) 9.7 ( ) 53 (31-60) 42 (26-121)

25 R-CHOP Followed by 90 Y Ibritumomab Tiuxetan in DLBCL (ECOG-E3402): Study Schema R-CHOP 2 cycles CR R-CHOP 2 cycles PR, CRu, or SD R-CHOP 4 cycles R E R E G I S T E R Stable or progressive disease off-study 90 Y Ibritumomab tiuxetan therapeutic regimen R E G I S T E R CT or CT+/PET Observation CT+/PET+ IFRT 30 Gy Study chair: Thomas Witzig. National Cancer Institute. Available at Protocol ID: ECOG-E3402. CT, computed tomography; PET, positron emission tomography

26 Phase II Study of Sequential R-CHOP and 90 Y Ibritumomab for Elderly High-Risk Patients with Untreated DLBCL R-CHOP q 21 6 cycles + darbepoetin 90 Y Ibritumomab tiuxetan 6 9 weeks after R-CHOP Re-stage between cycle 4 and 5 Restage 4 5 weeks after R-CHOP Restage weeks after RIT Hamlin et al. Blood ; 106 (11). Abstract 926. Poster Session Saturday.

27 Randomized Trial of 90 Y Ibritumomab Tiuxetan vs Observation After Front-line CHOP-R Randomization (start of the trial) Patients with untreated stage II-IV DLBCL, age 60 CHOP + Rituximab CR/CRu 90 Y Ibritumomab tiuxetan (0.4 mci/kg) Observation Primary end point: Overall survival Study chair: Franck Morschhauser

28 Phase II (Hovon) Study in DLBCL: 90 Y Ibritumomab Tiuxetan Consolidation for Partial Responders Patients with untreated DLBCL Chemo* + Rituximab PR PET scan PET + or 90 Y ibritumomab tiuxetan (0.4 mci/kg) *CHOP or CHOP-like regimen Study chair: Ton Hagenbeek

29 Integrating 90 Y Ibritumomab Tiuxetan with Chemotherapy in DLBCL Rituximab Followed by mci/kg 90 Y ibritumomab tiuxetan Rituximab Followed by mci/kg 90 Y ibritumomab tiuxetan Week CHOP-R CHOP-R CHOP-R CHOP-R Study chair: Tim Illidge

30 Z in localized 1st line Aggressive Lymphoma (SWOG-S0313, Miller) Regimen Standard Dose CHOP q21d x 3 3 wks Involved field radiotherapy 5d/wk for 4 5 wks 3 6 wks Zevalin Therapeutic Regimen Occurs over a period of weeks Patients are followed up every 6 months for 2 years and then annually thereafter. R E S T A G E

31 Phase II study of sequential CHOP and 90 YIbritumomab of elderly untreated DLCBL patients: Bologna CHOP q21 x 6 cycles 90 Y Ibritumomab tiuxetan 6-10 weeks after CHOP Restage 4-6 weeks after CHOP Enrolled 20 patients

32 Patients characteristics (n=20) Histology Follicular grade 3 DLBCL 9 11 Median Age, yr (range) 68 (61-84) Stage II 6 (30 %) Stage III-IV 14 (70 %) Bone marrow involvement 5 (25 %) Extranodal involvement 7 (35 %) Bulky disease 2 (10 %) B symptoms 2 (10 %)

33 Hematological toxicity after Zevalin Anemia grade Neutropenia grade (60 %) Thrombocitopenia grade (35 %) Nadir (median) Week 5 Median duration nadir 4 weeks Patients who required transfusion 2 (10 %) Antibiotic 5 (25 %) Febrile neutropenia 3 (15 %) Hospitalization due to FN 1

34 Clinical response after Zevalin After CHOP After Zevalin CR 15 (75 %) 19 (95 %) PR 5 (25 %) 1 (5 %)

35 Duration of hematologic toxicity Variable Baseline Nadir (range) ANC, cells/mm ( ) 800 ( ) Days from Baseline to Nadir 39 (20-60) Median duration for patients with grade 3 or 4 Nadir (days) 32 (10-66) Platelets, cells/mm ( ) 42 (9-187) 35 (20-43) 22 (10-49) Hemoglobin, g/dl 13.5 ( ) 11.8 ( ) 43 (20-60) /

36 Untreated Elderly (> 60 years) DLBCL, stage II-IV, CD20+ (Bologna) Phase II: CHOP21-R x 4 + Zevalin Phase III:R CHOP21- R x 8 CHOP21- R x 4 + Zevalin

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