Treatment of follicular lymphoma

Transcription

1 Treatment of follicular lymphoma Mathias J. Rummel Med. Klinik IV/ V - Hämatologie Klinikum der Justus-Liebig Liebig-Universität Gießen MJR

2 Therapy of Follicular Lymphoma wait and see policy alkylating agents anthracycline-based chemotherapy purine analogs bendamustine unconjugated monoclonal antibodies radiolabelled monoclonal antibodies autologous stem cell transplantation allogeneic stem cell transplantation non-myeloablative allogeneic SCT (DNA vaccination, antisense, etc) NHL Classification Project: OS for 306 patients with follicular NHL: 100% 50% years Adapted from Armitage et al, JCO 1998; 16:

3 Watch & wait or early treatment? Ardeshna KM et al. Watch & wait versus immediate systemic treatment. ent. Lancet 262: 516, 2003 Watchful waiting versus Chlorambucil 10 mg daily contin. prospective randomized, n = 309, recruitement phase Survival watch & wait immediate treatment 5 years 58 % 57 % 10 years 34 % 35 % 15 years 22 % 21 % Median 6,7 years 5,9 years

4 Watch & wait or early treatment? Overall survival Disease-associated associated survival Ardeshna KM et al. Lancet 262: 516, 2003

5 Watch & wait or early treatment? Ardeshna KM et al. Lancet 262: 516, 2003 MJR

6 Watch & wait or early treatment? Watch & wait: time to first treatment Median time to first treatment: 2,6 years Actuarial chance of not needing chemotherapy at 10 yrs was 19% and 40% in patients older than 70 years Ardeshna KM et al. Lancet 262: 516, 2003 MJR

7 Indications for treatment in indolent lymphomas: Stages I, II, limited stage III (up to 5 involved lymph node regions: curative intention? Disease associated symptoms (B-symptoms) Hematopoetic insufficiency: anemia, granulocytopenia, thrombocytopenia openia Rapid tumor progression: doubling of manifestations within 1 year Bulky disease (> 6 cm diameter) Autoimmune phenomens, such as AIHA or ITP Hypogammaglobulinemia with recurrent infections Hyperviskosity syndrome by monoclonal paraproteinemia MJR

8 Indolent Non-Hodgkin Hodgkin-Lymphomas 100 Overall Survival (n=668) (n=513) (n=195) Horning et al. Semin Oncol.. 20 (5, suppl 5): 75-88, Years

9 More Intensive Treatment Does Not Alter Survival in Follicular 1.0 DFS 1.0 OS Cyclophosphamide Cyclophosphamide Proportion disease-free CHOP + bleomycin Proportion surviving CHOP + bleomycin Years from entry Years from entry Peterson BA, et al. J Clin Oncol 2003;21:5 15

10 FND vs Alternating Triple Therapy (ATT) bei indolenten NHL FND (n=73) (max 8 x) ATT (n=69) (max 12 x, 4 jeweils) Fludarabin Mitoxantron Dexamethasone CHOD-B ESHAP NOPP (Cyclophosphamid, Doxorubicin, Vincristin, Dexameth., Bleomycin) (Etoposid, Ara-C, Cisplatin, Prednison) (Mitoxantron, Vincristin, Procarbazin, Prednison) FND ATT FND ATT p ORR (%) Neutropenie (%) Deaths Thrombocytopenie Überleben i d e n t i c a l Infektionen (%) Tsimberidou, MJR McLaughlin, Cabanillas et al. Blood 100, 13, , 4357, 2002

11 Secondary Malignancies after ASCT in Follicular Lymphoma Trial Reference Chemotherapy ASCT GLSG Lenz et al CHOP/IFN (n=236) CHOP/TBI/Cyclo (n=195) 2nd malign 0,0 % n=5 (2 AL, 3 MDS), median follow up 44 months occurred between 9 and 51 months estimated risk of 3,8% at 5 years (only report of hematological malignancies) GOELAMS Deconinck 2nd malign 0,0 % CHVP (n=80) 0,0 % n=10 VCAP/TBI/Cyclo (n=86) n=10,, 7 were fatal, 3 in CR (3 AL, 3 MDS, 2 BC) occurred between 12 and 45 months actuarial risk of 18.6% at 5 years Dana Faber Brown et al all standard chemo plustbi/cyclo (n=605), median follow up 9.5 years 42 solid tumors, 6 non-mds hem. Malignancies, 39 non-melanoma skin cancers, 68 MDS/AML 10-year incidence of secondary malignancies is 21% with 10% non-mds malignancies. Incidence of MDS/AML levels off at 14% at 5 years, incidence of solid tumors increase without plateau

12 Follicular lymphoma CHVP + IFN 209 CHOP + auhsct 192 Sebban. Blood, 2006;108:2540

13 CHVP + IFN 209 CHOP + auhsct 192 Sebban. Blood, 2006;108:2540

14 Clinical trials comparing transplantation (SCT) versus conventional therapy (CT) Reference year pro- spect. rand. multi center age n / yrs time versus PFS Difference in Overall Survival Ladetto 2008 yes yes yes (5) 1st line CHOP+R SCT > CT no 80% at 4 yrs for both Lenz 2005 yes yes yes (4) 1st line chemo SCT > CT n.r. short obs.. 2 yrs Sebban 2006 yes yes yes (7) 1st line chemo 33 vs 40 mo no 76 vs 71% at 7 yrs Deconninck 2005 yes yes yes (7) 1st line chemo SCT > CT** no 78 vs 84% at 5 yrs Schouten 2003 yes yes yes (4) 2nd line chemo SCT > CT no SCT > CT, p = Freedman 1999 no Rohatiner 2007 no Ingram 2008 no no no no no (10) 3 prior tx 42% at 8 yrs* 66% at 8 yrs no,, (7) 3 priot tx 48% at 10 yrs 54% at 10 yrs no,, (13) 2 prior tx 56% at 3 yrs* 67% at 3 yrs * DFS, ** EFS, n.r.. = not reported

15 ASCT in follicular lymphomas ASCT is an appropriate treatment choice for younger patients with chemosensitive recurrent follicular lymphoma ASCT remains investigational in the initial treatment of follicular lymphoma No demonstrated overall survival benefit Possible improvement in overall survival by adding Rituximab in treatment strategies Increase of 2nd malignancies ASH, 2005 MJR

16 Does combined immunochemotherapy with rituxan improve overall survival in patients with indolent non-hodgkin s lymphoma compared to chemotherapy alone? A Meta-Analysis Holger Schulz, Nicole Skoetz, Julia F. Bohlius, Sven Trelle, Alexander Greb, Thilo Kober and Andreas Engert Cochrane Review Cochrane Haematological Malignancies Group (CHMG) Internal Medicine I, University of Cologne.

17 Overall survival: : Meta-Analysis Total Group Study HR [95%-CI) Weight [%] HR [95%-CI) Lenz Baez Forstpointner Marcus Hiddemann Herold Total (95% CI) ( ) Favors R + Chemo Favors Chemo Total events: 100/ /718 Test for heterogeneity: (P = 0.60), I² = 0%

18 Intergroup phase III trial: study design R A N D O M I Z E D CHOP every 21 days maximum 6 cycles Rituximab + CHOP every 21 days maximum 6 cycles CR PR R A N D O M I Z E D Observation Rituximab maintenance* Van Oers MHJ, et al. Abstract, ASH 2005 *375mg/m 2 every 3 months for 2 years or until relapse

19 Intergroup phase III trial Progression free survival Progression free survival from 2nd randomization Overall Logrank test: p< Hazard ratio: 0.40 from 2nd randomization (years) O N Number of patients at risk : Treatment Observation Rituximab maintenance median: 51.6months Observation median: 15 months Mabthera

20 EORTC van Oers Abstr. ASH 2005 (Maint 1 x R, q 3 mo, up to 2 yrs Induction n=465, Maint n=334, med. foll. up 33 months observation maintenance Rituximab PFS* (months) p < after CHOP after CHOP-R p = after CR after PR OS (3 years) 77.1% 85.1% p = ** * after 2nd randomization ** HR = 0.52 MJR

21 EORTC van Oers Abstr. ASH 2005 (Maint 1 x R, q 3 mo, up to 2 yrs Induction n=465, Maint n=334, med. foll. up 33 months observation maintenance Rituximab PFS* (months) p < after CHOP after CHOP-R p = after CR after PR OS (3 years) 77.1% 85.1% p = ** * after 2nd randomization ** HR = 0.52 MJR

22 EORTC van Oers Abstr. ASH 2005 (Maint 1 x R, q 3 mo, up to 2 yrs Induction n=465, Maint n=334, med. foll. up 33 months observation maintenance Rituximab PFS* (montths) p < after CHOP after CHOP-R p = after CR after PR OS (3 years) 77.1% 85.1% p = ** * after 2nd randomization ** HR = 0.52 MJR

23 Intergroup phase III trial Overall survival Overall survival from 2nd randomization Overall Logrank test: p=0.011 Hazard ratio: 0.52 from 2nd randomization R-maintenance 3 yrs 85.1 % observation 3 yrs 77.1 % (years) O N Number of patients at risk : Treatment Observation Mabthera

24 Randomized studies Rituximab maintenance Study Group Treatment Entities Induction SAKK 1st line Relapsed Follicular Mantle cell Rituximab ECOG 1st line Follicular Small lymphocytic CVP Hainsworth Relapsed Refractory Follicular Small lymphocytic Rituximab GLSG Relapsed Refractory Follicular Manle cell R-FCM vs FCM EORTC Relapsed Refractory Follicular R-CHOP vs CHOP

25 Overall PFS for Treatment Groups The 4-year 4 overall PFS is 52% in the 90 Y-ibritumomab arm compared with 31% in the control arm 100 Cumulative Percentage Log-rank P =.0001 HR 0.45 (95% CI: ) 90 Y-ibritumomab arm Median PFS: 53.8 months N = 207 control arm Median PFS: 13.8 months N = Y-ibritumomab Control months

26 Effect of Treatment Arm on PFS by First-line Treatment and Response to First-line Treatment PFS No. of Patients Control 90 Y-Ibritumomab Hazard Ratio No. Failed Median PFS, mo No. of Patients No. Failed Median PFS, mo (95% CI)* First-line treatment* CHOP CVP/COP CHOP-like > 67 Fludarabine Chlorambucil Rituximab combination > > ( ) 2.25 ( ) 2.11 ( ) 1.11 ( ) 2.76 ( ) 1.39 ( ) *Note: FIT was not powered to detect significant differences in outcomes according to individual types of induction therapy.

27 Overall Survival All patients 19 deaths Control 8 deaths 90 Y-ibritumomab 11 deaths At current follow-up no significant difference in overall survival was observed between treatment arms (P =.593) No significant difference in incidence of secondary malignancies 6 secondary malignancies in 90 Y-ibritumomab arm vs 5 in control arm No additional toxicities or congenital malformations detected

28 Secondary Malignancies That Have Emerged During Extended Follow-up Control Arm Mammary carcinoma Basocellular epithelioma Endometrial carcinoma Papillary carcinoma of thyroid Basocellular carcinoma of the skin 90 Y-Ibritumomab Arm AML after MDS* AML** Lung cancer (now in remission) Pancreas carcinoma Basal cell carcinoma skin Basocellular carcinoma of the skin * Patient achieved a CR after 6 cycles of FC from Sept 2003 until Feb He received 90 Y-ibritumomab in 04/2004. Pat progressed in 09/2004, and received radiotherapy in 12/2004 AML was recorded in Aug 2007 ** Patient received 8 cycles of CHOP as the induction regimen (described in Morschhauser et al. J Clin Oncol. 2008;26: ).

29 Subsequent Management After PD Treatment After PD Control (n = 137) 90 Y-Ibritumomab (n = 103) Chemotherapy (incl. involved-field radiotherapy), n (%) 9 (7) 6 (6) Radiotherapy, n (%) 0 6 (6) Total patients receiving 90 Y-ibritumomab, n (%) 11 (8) 1 (1) Rituximab monotherapy, n (%) 22 (16) 15 (15) Rituximab-containing chemotherapy combination, n (%) 47 (34) 26 (25) Allogeneic transplantation,* n (%) 2 (1) 1 Autologous transplantation,* n (%) 27 (20) 10 (9) Total patients receiving rituximab, n (%) 93 (68) 50 (49) No treatment given 30 (22) 39 (38) *Most patients received rituximab as part of salvage or ASCT.

30 Patients in Control and 90 Y-Ibritumomab Arms Achieved Comparable Responses to Second-Line Therapy Response to Second-Line Therapy After Progressive Disease, % Control (n = 108) Responders 90 Y-Ibritumomab (n = 63) CR 42% 49% CRu 14% 8% PR 18% 24% No response 27% 19%

31 Standard of care in pts with indolent lymphomas There is still a role for watch & wait in asymptomatic patients Combined Immuno-Chemotherapy is the standard of care R-chemotherapy plus R-maintenance appears as the optimal strategy for patients with relapsed disease Which chemotherapy in combination with Rituximab? Chlorambucil-based based (MCP), F-based F (FCM), CHOP-like, CVP Role of bendamustine in this setting is under investigation R-maintenance after 1st-line R-containing R regimens? PRIMA study addresses this question, first results at ASH 2010 StiL NHL study proves duration of maintenance SAKK study proves duration of maintenance after R MJR

32 Bendamustine plus Rituximab versus CHOP plus Rituximab in the First rst-line Treatment of Patients with Indolent and Mantle Cell Lymphoma First Results of a Randomized Phase III Study of the StiL (Study Group indolent Lymphomas, Germany) Mathias J. Rummel, U. von Grünhagen, N. Niederle, F. Rothmann, H. Ballo, E. Weidmann, M. Welslau, G. Heil, H. Dürk, M. Stauch, C. Losem, A. Matzdorff, C. Balser, K. Schalk, D. Kofahl-Krause, Krause, U. Kaiser, W. Knauf, A. Banat, D. Hoelzer, W. Brugger on the behalf of the StiL Giessen, Cottbus, Leverkusen, Potsdam, Offenbach, Frankfurt, Aschaffenburg, Lüdenscheid, Hamm, Kronach, Neuss, Saarbrücken, Marburg, Limburg, Hannover, Hildesheim, Villingen-Schwenningen. Germany

33 Bendamustine plus Rituximab (B-R) R B B-R B-R B-R B-R B-R Tag B = Bendamustine 90 mg/qm day R = Rituximab 375 mg/qm day Randomization CHOP plus Rituximab (CHOP-R) R CHOP CHOP-R CHOP-R CHOP-R CHOP-R CHOP-R Tag CHOP day Rituximab 375 mg/qm day MJR

34 Patients characteristics B-R R vs CHOP-R 30 th Nov 2008 B-R R CHOP-R 462 evaluable pts. (n=235) (n=227) Age (median) 64 yrs 64 yrs Age > 70 yrs. 23 % 24 % Age > 60 yrs. 63 % 63 % Stage IV 79 % 76 % B-Symptoms 40 % 28 % IPI > 2 (n=162) 37 % 38 % FLIPI % 20 % FLIPI 2 45 % 33 % FLIPI > 3 46 % 47 % LDH > 240 U/l 38 % 32 % Bone marrow 69 % 67 % Bulky disease 28 % 26 % MJR

35 Toxicity B-R R vs CHOP-R 462 patients evaluable, interim (not final analysis) B-R (n=235) CHOP-R (n=227) Alopecia 0 % 91 % Leucocytopenia 3/4 14 % 38 % G-CSF used 5 % 21 % Inf. complications 31 % 41 % PNP (any grade) 4 % 9 % MJR

36 Results, interim (not final9 analysis B-R R vs CHOP-R 454 patients evaluable for response, median observation period 27 months 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 MJR

37 Bendamustine-R vs CHOP-R Conclusion In this analysis consisting of 462 randomized patients Bendamustine plus Rituximab is not inferior to CHOP-R in regard to efficacy and is again associated with less toxicity The final results with a longer observation up to 36 months and with full analysis of all randomized patients (n=549) will further define the role of Bendamustine plus Rituximab in the treatment algorithm of patients with indolent and mantle cell lymphoma

38 Bendamustine-Rituximab + 2 vs 4 yrs Rituximab Randomized Phase III Study of the StiL Follicular Lymphoma R Bendamustine-Rituximab + 2 years Rituximab q 2 months Bendamustine-Rituximab + 4 years Rituximab q 2 months

39 B-R + Watch & Wait vs B-R + 2 years Rituximab Randomized Phase II Studies of the StiL Immunocytoma Marginalzone Mantle cell (for mantle cell not eligible for APBSCT) R Bendamustine-Rituximab + Watch & Wait Bendamustine-Rituximab + 2 years Rituximab q 2 months

40 Standard of care in pts with indolent lymphomas Which chemotherapy in combination with Rituximab? - Chlorambucil-based based (MCP), F-based F (FCM), CHOP-like, CVP - Role of bendamustine in this setting is under investigation The analysis with 462 randomized patients shows that B-R B R is not inferior to CHOP-R R in regard to efficacy while being associated with less toxicity The final results (longer observation) will further define the role r of B-R B R in the treatment algorithm of patients with indolent and mantle cell l lymphoma Does B-R B R have the potential to change standard approaches in NHL? R-maintenance after 1st-line R-containing R regimens? PRIMA study addresses this question, first results at ASH 2010 NHL StiL study: duration of maintenance after B-R B SAKK study: duration of maintenance after R-monotherapy R