ALMA UNIVERSITAS TAURINENSIS UNIVERSITA DEGLI STUDI DI TORINO

ALMA UNIVERSITAS TAURINENSIS UNIVERSITA’ DEGLI STUDI DI TORINO Corrado Tarella Divisione Universitaria di Ematologia Terapia di salvataggio del linfoma follicolare - ruolo del trapianto di cellule emopoietiche Corso Nazionale di Aggiornamento in EMATOLOGIA CLINICA R O M A, 8 – 9 Novembre 2006

Terapie di “salvataggio” nei Linfomi Follicolari Quali sono i soggetti maggiormente a rischio di richiedere una terapia di salvataggio ? utilità dei fattori clinici di prognosi

Survival rates according to: (A) the IIL prognostic model and (B) the IPI score Federico M et al. , Blood 2000, 95: 783 -789 Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases

Survival of the 1795 patients according to risk group as defined by the Follicular Lymphoma International Prognostic Index (flipi) – Solal-Céligny et al, Blood 2004, 104: 1258

Variabili Utilizzate per il Calcolo FLIPI Variabili FLIPI Età Stadio Emoglobina LDH No. Sedi Nodali Indice Sfavorevole 60 anni III - IV < 12 gr/dl > limite superiore >4

The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M, Hiddemann W. Blood 2006 Sep 1; 108(5): 1504 -1508

Figure 2. Time to treatment failure of patients with advanced-stage FL treated with front-line CHOP Buske, C. et al. Blood 2006; 108: 1504 -1508 Copyright © 2006 American Society of Hematology. Copyright restrictions may apply.

Figure 1. Time to treatment failure of patients with advanced-stage FL treated with front-line R-CHOP Buske, C. et al. Blood 2006; 108: 1504 -1508 Copyright © 2006 American Society of Hematology. Copyright restrictions may apply.

…. more on FL reports published in 2005 have demonstrated both feasibility and efficacy of radioimmunotherapy (radiolabelled anti-CD 20) in the treatment strategy for FL

Leonard JP et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol. 2005 Aug 20; 23(24): 5696 -704 Portlock CS. Should radioimmunotherapy be an initial treatment option in advanced-stage follicular lymphoma? Nat Clin Pract Oncol. 2005 Jul; 2(7): 346 -7 Kaminski MS et al. 131 I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005 Feb 3; 352(5): 441 -9

Fig 1. Duration of response for all patients Leonard, J. P. et al. J Clin Oncol; 23: 5696 -5704 2005

Fig 2. Progression-free survival for all patients Leonard, J. P. et al. J Clin Oncol; 23: 5696 -5704 2005

Fig 3. Progression-free survival by Follicular Lymphoma International Prognostic Index (FLIPI) risk group Leonard, J. P. et al. J Clin Oncol; 23: 5696 -5704 2005

Terapie di “salvataggio” nei Linfomi Follicolari Quali sono i soggetti maggiormente a rischio di richiedere una terapia di salvataggio ? utilità dei fattori clinici di prognosi Come si può prevedere (e prevenire) una recidiva e quindi una richiesta di terapia di salvataggio ? importanza della risposta clinica e molecolare alla terapia di 1° linea

Leonard JP et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol. 2005 Aug 20; 23(24): 5696 -704 Portlock CS. Should radioimmunotherapy be an initial treatment option in advanced-stage follicular lymphoma? Nat Clin Pract Oncol. 2005 Jul; 2(7): 346 -7 Kaminski MS et al. 131 I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005 Feb 3; 352(5): 441 -9

Figure 3. Progression-free Survival for Patients with a Partial Response and Those with a Complete Response. (57 pts. ) (15 pts. ) Kaminski MS et al. N Engl J Med. 2005; 352(5): 441 -9

Terapie di “salvataggio” nei Linfomi Follicolari Quali sono i soggetti maggiormente a rischio di richiedere una terapia di salvataggio ? utilità dei fattori clinici di prognosi Come si può prevedere una recidiva e quindi una richiesta di terapia di salvataggio ? importanza della risposta clinica e molecolare alla terapia di 1° linea Significato clinico della valutazione della Minimal Residual Disease (MRD)

In vitro purging of Bone Marrow Grafts: the MDR- value in Follicular Lymphoma Gribben et al. N Engl J Med, 1991

Disease-free survival according to PCR status in FCL patients Freedman et al, Blood 1999, 94: 3325 -3333

APO x 2 DHAP x 2 VP-16 2 g/sqm CTX 7 g/sqm PBPC/BM harvest MOLECULAR TIMEPOINTS Tarella C et al, Leukemia 2000; 14: 740 -7 MITOX + L-PAM + PBPC autograft I-HDS SCHEME FOR BM+, INDOLENT LYMPHOMAS

A. DFS according to the PCR of stem cell harvests; B. DFS according to the post-transplant MRD status Introducing the concept: “occult lymphoma cells do influence the clinical outcome also in unpurged transplants” Corradini, P. et al. J Clin Oncol; 2004

On a multivariate analysis, two factors only had a significant impact on both Overall Survival and Event Free Survival: Ø CR achievement Ø Molecular Remission achievement

THE RECENTLY CONCLUDED 2 nd GITMO TRIAL IN POOR-RISK FCL AT DISEASE ONSET RITUXIMAB-supplemented HDS versus RITUXIMAB-supplemented CHOP 29 active Centers 136 patients enrolled and evaluable

R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 136 EFS: CHOP-R vs R-HDS 1 0, 9 0, 8 66 % 0, 7 0, 6 0, 5 R-HDS p<0, 001 0, 4 0, 3 36 % 0, 2 CHOP-R 0, 1 0 0 12 24 36 48 60 72 84 Ladetto M et al, ASH 2006

PRELIMINARY PCR RESULTS v A stable molecular remission (MR) was achieved in 26% of CHOP-R patients and 78% of R-HDS patients (p<0. 001) v A persistent MR was associated to an improved PFS (p<0. 001) regardless of the treatment received v the superior outcome of R-HDS compared to CHOP-R is largely explained by its higher rate of MRs achievement

R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 136 PFS: PCR NEG vs POS 1 0, 9 67 -76 % 0, 8 0, 7 PCR NEG 0, 6 p<0. 001 0, 5 0, 4 0, 3 0, 2 0, 1 25 -32 % 0 0 12 24 PCR POS 36 48 60 72 84 Ladetto M et al, ASH 2006

R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 136 PFS: PCR NEG vs POS 1 0, 9 0, 8 0, 7 PCR NEG 0, 6 p<0. 001 0, 5 0, 4 0, 3 0, 2 0, 1 PCR POS 0 0 12 24 36 48 60 72 84

The extremely poor outcome of patients with persistent MRD following induction therapy ► should we treat all MRD +ve patients even in the absence of overt clinical manifestations ? ► how should we manage those (few) patients with MRD persistently positive following intensive chemo-immunotherapy ? Is allogeneic transplantation the first treatment choice for these patients ?

R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 136 PFS: PCR NEG vs POS 1 0, 9 0, 8 0, 7 PCR NEG 0, 6 p<0. 001 0, 5 0, 4 0, 3 0, 2 0, 1 PCR POS 0 0 12 24 36 48 60 72 84

The extremely good outcome of patients achieving molecular remission (MR) ► is autograft really useful or still required for those patients achieving clinical and molecular remission before the final myeloablative phase ? ► should we consider Rituximab maintenance in all responsive patients, including those who have achieved clinical and molecular remission ?

possible therapeutic implications of MRD analysis post-autograft Rituximab administration “tailored” on the molecular monitoring of the minimal residual disease

Relationship between post-graft PCR status and clinical outcome the lesson learned from two cases treated at diagnosis with R-HDS RITUXIMAB Pt. 1 COMPLETE REMISSION R-HDS +3 +6 0 post-EDX PBPC post-ARA-C PBPC Pt. 2 +8 +10 +19 +33 +23 +46 MONTHS POST-AUTOGRAFT PCR + PCR - R-HDS RELAPSE 0 post-EDX PBPC post-ARA-C PBPC +38 +8 PCR - +13 +19 +25 MONTHS POST-AUTOGRAFT PCR + PCR -

Rituximab Induces Effective Clearance of Minimal Residual Disease in Molecular Relapses of Mantle Cell Lymphoma. Ladetto M, Magni M, Pagliano G, De Marco F, Drandi D, Ricca I, Astolfi M, Mantoan B, Lobetti Bodoni C, Zanni M, Boccadoro M, Gianni AM and Tarella C. Off therapy 6 months MCL-77 R-HDS MCL-81 R-HDS MCL-57 R-HDS MCL-51 12 months 24 months 36 months 48 months 60 months 72 months R-HDS = PCR negative = PCR positive Biol Blood and Marrow Transpl. In press Rituximab 375 mg/sqm 4 courses Rituximab 375 mg/sqm 2 courses

Terapie di “salvataggio” nei Linfomi Follicolari Quali sono i soggetti maggiormente a rischio di richiedere una terapia di salvataggio ? utilità dei fattori clinici di prognosi Come si può prevedere una recidiva e quindi una richiesta di terapia di salvataggio ? importanza della risposta clinica e molecolare alla terapia di 1° linea Quale è la terapia di salvataggio nei linfomi follicolari ? recenti risultati con chemio-immunoterapia e possibile ruolo dell’ “alta dose” + autotrapianto

The role of conventional chemotherapy + Rituximab for both Induction and Maintenance in the management of relapsed/refractory disease

Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin's lymphoma, both in patients with and without rituximab during induction: results of a prospective randomized phase III intergroup trial. van Oers MH, Klasa R, Marcus RE, et al Blood 2006 Jul 27; [Epub ahead of print] * * * * * Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide and mitoxantrone (R-FCM) in patients with relapsed and refractory follicular and mantle cell lymphomas - results of a prospective randomized study of the German low grade lymphoma study group (GLSG). Forstpointner R, Unterhalt M, Dreyling M, et al Blood 2006 Aug 31; [Epub ahead of print]

EORTC 20981 Intergroup Study Rituximab in remission induction and maintenance treatment of relapsed follicular NHL: a phase III randomised clinical trial MHJ van Oers, M. Van Glabbeke, I. Teodorovic, C. Rozewicz R. Klasa, R. E. Marcus, M. Wolf, E Kimby, A. Hagenbeek

Nordic Lymphoma Group South African Non-Hodgkin’s Lymphoma Clinical Trials Group SAKK -

EORTC 20981 - Study Design Primary endpoint: Follicular NHL, first or second relapse Response rates R A N D O M I Z E D PFS 6 x R-CHOP 6 x CHOP R A N D O M I Z E D CR, PR SD, PD Off Study * Rituximab maintenance: 375 mg/m 2 q 3 months until progression or for a max. of 2 years Rituximab maintenance* Observation

EORTC 20981 – Treatment Schedules l Induction: – CHOP q 21 d x 6 cycles • Cyclophosphamide 750 mg/m 2 IV d 1 • Doxorubicin 50 mg/m 2 IV d 1 • Vincristine 1. 4 mg/m 2 IV d 1 • Prednisone 100 mg PO d 1– 5 – R-CHOP q 21 d x 6 cycles • CHOP + rituximab 375 mg/m 2 IV d 1 l Maintenance treatment – Rituximab 375 mg/m 2 q 3 months until progression or maximum of 2 years

Prior chemotherapy CHOP R-CHOP Type of prior chemotherapy 1 regim. - single agent 41 % 39 % 1 regim. - polychemo. 40 % 38 % 2 regimen 18 % 21 % Other <1% 1% Best response to prior chemotherapy CR 32 % 33 % PR 51 %

Intergroup phase III trial response to induction therapy CHOP R-CHOP CR 34 ( 18. 1 % ) 55 ( 30. 4 % ) PR 101 (53. 7%) 95 (52. 5%) NC 20 (10. 6%) 14 (7. 7%) PD 18 (9. 6%) 5 (2. 8%) Death- NHL 1 (0. 6%) Death- Tox 1 (0. 5%) Not assess. 14 (7. 4%) 11 (6. 1%) Total 188 181 P= 0. 0004 Mantel. Haenszel test for trend

Intergroup phase III trial Progression free survival from first randomisation 100 90 P=0. 0007 (logrank test) 80 70 60 R-CHOP median: 30 months 50 40 30 20 CHOP median: 20 months 10 0 (years) 0 O N 123 231 96 234 1 2 3 Number of patients at risk : 126 52 17 157 76 27 4 5 5 6 Induction CHOP R-CHOP

Event-free probability Progression-free Survival from Maintenance Randomisation (ITT) 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Rituximab: median 42 mths Observation: median 14 mths p<0. 0001 (Log Rank) HR 0. 39 (95% CI: 028; 0. 55) 0 6 12 18 24 30 36 42 48 54 60 66 Study month Patients at risk: Observation 167 128 82 50 35 22 11 6 2 0 0 0 Rituximab 167 144 119 93 74 50 29 16 6 3 0 0

Event-free probability Overall Survival from Maintenance Randomisation (ITT) 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Rituximab Observation p=0. 0039 (Log-Rank) HR 0. 44 (95% CI: 0. 25; 0. 78) 0 6 12 18 24 30 36 42 48 54 60 66 Study month Patients at risk: Observation 167 161 139 117 90 69 39 23 10 5 2 1 Rituximab 167 161 146 122 103 80 55 32 12 6 2 0

Maintenance – Efficacy Summary Efficacy Parameter Kaplan-Meier Estimate of Median Time to Event (Months) Observation Rituximab (N = 167) (N=167) Hazard Ratio Log. Rank p-value Primary Progression-free survival 14 42 <0. 0001 0. 39 NR NR 0. 0039 0. 44 Time to new lymphoma treatment 20 39 <0. 0001 0. 50 Disease-free survival 17 54 0. 0003 0. 33 Secondary Overall Survival Exploratory

Event-free probability Progression-free Survival after Maintenance Randomisation in Patients with CHOP Induction (ITT) 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Rituximab: median 38 mths Observation: median 12 mths p<0. 0001 (Log-Rank) HR 0. 29 (95% CI: 0. 18; 0. 46) 0 6 12 18 24 30 36 42 48 54 60 66 1 1 0 0 14 7 2 2 9 0 49 29 12 8 Study month 5 67 56 42 31 22 Patients at risk: Observation 69 Rituximab 76

Event-free probability Progression-free Survival after Maintenance Randomisation in Patients with R-CHOP Induction (ITT) 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Rituximab: median 52 mths Observation: median 22 mths p=0. 0071 (Log-Rank) HR 0. 54(95% CI: 0. 35; 0. 85) 0 6 12 18 24 Patients at risk: Observation 98 Rituximab 91 30 36 42 48 54 60 66 Study month 79 53 38 27 17 10 5 1 0 0 0 77 63 51 43 28 15 9 4 1 0 0

Summary of Progression-free Survival in Subgroups (Strata) Median Progression-free Survival Observation Rituximab p-value (Log-Rank) Overall Population 14 months 42 months <0. 0001 CHOP 12 months 38 months <0. 0001 R-CHOP 22 months 52 months CR 14 months 53 months PR 14 months 38 months 0. 0071 0. 0008 <0. 0001 Hazard Ratio (95% CI) 0. 39 (0. 28; 0. 55) 0. 29 (0. 18; 0. 46) 0. 54 (0. 35; 0. 85) 0. 36 (0. 19; 0. 67) 0. 46 (0. 31; 0. 67)

Infections – Summary l Higher incidence of infections (all grades) with maintenance treatment (25 vs 45%) l Mainly grade 1 -2 infections, few grade 3 -4 infections (3% vs. 11%) l Mostly URTI (Nasopharyngitis, Sinusitis, Rhinitis), LRTI (Bronchitis, LRTI other), Herpes zoster/simplex l Few cases reported as SAEs (0 vs 5%) l No fatal infection during maintenance treatment over 2 years considered treatment related l No sign of cumulative toxicity for infection over 2 years

Overall Summary of Rituxan Maintenance Results in Study EORTC 20981 l Rituxan maintenance treatment showed significant benefits in terms of: – Progression-free Survival – Overall Survival – After CHOP and R-CHOP induction regimen – In patients with CR and PR l Relatively mild toxicity, no new or unexpected AEs l Positive Risk-Benefit assessment

Rituximab maintenance after FCM + rituximab in relapsed FL and MCL: study design R a n d o Advanced m stage i relapsed z a or refractory t FL or MCL i o n * 4 x FCM + rituximab 4 x FCM CR, PR F=fludarabine 25 mg/m 2/d days 1 3 C=cyclophosphamide 200 mg/m 2/d days 1 3 M=mitoxantrone 8 mg/m 2/d day 1 R a n d o m i z a t i o n 4 x Rituximab (month 3) 4 x Rituximab (month 9) Observation only *Randomisation stopped after 147 patients when a significant improvement in OS was observed for the R-FCM therapy; all subsequent patients received R-FCM and all presented data relates to maintenance after R-FCM only Hiddemann W et al, Blood 2005, 106: 270 a (abstract 920)

Rituximab maintenance after FCM + rituximab in relapsed FL and MCL: outcome l 174 patients evaluable for the second randomization, 136 of whom had received R-FCM induction l In these patients – median DR not reached in the R-maintenance arm vs 17 months for observation (p=0. 0024). – Benefit for rituximab maintenance demonstrated for both FL and MCL Hiddemann W et al, Blood 2005, 106: 270 a (abstract 920)

Rituximab maintenance after FCM + rituximab in relapsed follicular lymphoma: response duration 10. 0 0. 9 Probability 0. 8 Rituximab (32/41) 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0 Observation (21/40) p=0. 035 0 1 2 3 4 5 6 7 Years after end of initial therapy Hiddemann W et al, Blood 2005, 106: 270 a (abstract 920)

Is there any role for the intensive therapy with autograft, possibly supplemented with Rituximab (both in Induction and Maintenance ? ) in the management of relapsed/refractory disease

H C Schouten et al. (CUP trial) High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin’s Lymphoma: Results From the Randomized European CUP Trial J Clin Oncol, 2003, Vol 21: 3918 -3927

Progression-free survival for patients randomized to three arms Schouten et al. , JCO 2003

Overall survival for patients randomized to three arms Schouten et al. , JCO 2003

The addition of Rituximab to high-dose programs with autograft seems now mandatory in B-cell lymphoma, particularly in FCL patients, in order to I. Increase tumour cytoreduction ii. Exploit its in vivo purging effect prior to PBPC harvesting

THE RECENTLY CONCLUDED 2 nd GITMO TRIAL IN POOR-RISK FCL AT DISEASE ONSET RITUXIMAB-supplemented HDS versus RITUXIMAB-supplemented CHOP 29 active Centers 136 patients enrolled and evaluable

Treatment for relapse/progression R-CHOP R-HDS TOTAL Minimal treatment(Rituximab +/-RT) 3 6 9 Conventional chemo-therapy (fludarabine-containing) 7 4 11 R-HDS 27* 2 29 Allograft 0 1 1 NV 5 5 10 TOTAL 42 18 60 * 14 RELAPSED AND 13 POORLY RESPONSIVE

Response after treatment for relapse/progression TOTAL CR Minimal treatment(Rituximab +/-RT) 9 4 (44%) Conventional chemo-therapy (fludarabine-containing) 11 5 (45%) R-HDS 29 21 (72%) Allograft 1 1 (100%)

R-HDS vs CHOP-R RANDOMIZED TRIAL OS ACCORDING TO TREATMENT ARM 1 0, 9 0, 8 0, 7 0, 6 0, 5 p NS 0, 4 0, 3 0, 2 0, 1 0 0 12 24 36 48 60 72 84 Ladetto M et al, ASH 2006

Benefits of autologous transplantation l Feasible procedure with low toxicity (TRM < 2 - 5%) l Effective treatment both in patients relapsing after conventional chemotherapy or with poor prognostic features at disease onset

Rationale of allogeneic stem cell transplantation for relapsed indolent NHL Ø avoiding tumor contamination of the graft Ø exploiting the graft-versus-lymphoma effect, that may overcome the chemoresistance of refractory lymphoma cells

Should we consider a large multicenter study comparing Rituximabsupplemented conventional (FCM ? ) vs. intensified (R-HDS ? ) vs. RIC-allograft (“Corradini-schedule”? ) in the management of relapsed/refractory disease ?

AKNOWLEDGEMENTS Cattedra di Ematologia Università di Torino Dir. Prof. M. Boccadoro Lymphoma Team: Marco Ladetto Daniele Caracciolo Irene Ricca Manuela Zanni Luciana Bergui Paolo Gavarotti Federica De Marco Sonia Vallet Prof. Alessandro Pileri Istituto Tumori di Milano Paolo Corradini Alessandro Massimo Gianni ALL THE ENROLLING CENTERS Intergruppo Italiano Linfomi