BENDAMUSTINE IN HODGKIN LYMPHOMA

CONVEGNO REGIONALE SIE DELEGAZIONE REGIONALE EMILIA ROMAGNA ATTUALITA IN EMATOLOGIA BOLOGNA 06.03.2015 BENDAMUSTINE IN HODGKIN LYMPHOMA Dott.ssa Cinzia Pellegrini Istituto di Ematologia e Oncologia Medica "L&A" Sèragnoli

Bendamustine First synthesized in the 1960 s in Jena, in the former East Germany. Limited data published during the initial period of investigation Used in the treatment of NHL,CLL, Multiple Myeloma, Hodgkin s disease and solid tumors, i.e. Breast cancer and small cell lung cancer Effective in cell lines that are refractory to alkylating agents Only partial cross-resistance with melphalan and cyclophosphamide as a rational for using bendamustine in previously treated patients with low-grade lymphoma

Bendamustine Extensive DNA-damage Like other alkylating agents, it causes intra-stand and inter stand cross-links between DNA bases Tageja N, et al. Cancer Chemother Pharmacol (2010) 66:413-423 More durable and more extensive DNA-damage than other alkylating agents. It is also associated with a relatively slower repair of DNA damage than other alkylating agents.

Bendamustine Apoptosis via a TP53-dependent mechanism; Inhibition of mitotic checkpointsregulating genes, such as CCNB1, As a result of this distinctive activity AURKA profile, and Bendamustine PLK1, this drugs also show limited cross-resitance with agents triggers usually a complex employed phenomenon, for upfront and salvage treatments of HD known including as mitotic anthracyclines, catastrophe, that dacarbazina, cyclophosphamide, ifosfamide, activated non melphalan apoptotic cell and death carmustine. pathway in tumor cells Activates an exonuclease-1 (EXO1) Dna repair Leoni L.M. et al, Clin Canc Res 2008; 14 (1) January 1, 2008

Bendamustine: Development in HL

Bendamustine (Cytostasan) in HD:PALEOZOIC Author n Prev. Rx Herold M et al. (1999) 80 None CVPP vs CVPP/DVBB Dose/ schedule CVPP/DVBB (DNR, BLM, VCR, B) B: 30 mg/m2, d 8-12, q28 ORR 75% vs 87.5% Herold M et al. (1987) Herold M et al. (1998) Hoche D et al. (1984) 43 None CVPP/ ABVB CVPP/ ABVB 100 None CVPP/ABVC vs CVPP/ABVB 73 CVPP DBVCy[B] vs ABVD B: 30 mg/m2, D 8-12, q28 B: 30 mg/m2, D 8-12, q28 DBVCy (DNR, BLM, VCR, Cy) Cy: 50 mg/m2, D 1-5, q 28 93% CR: 81% PR: 12% CR: 81% vs CR: 88% 69% vs 83% Herold M, et al. Med Klin 1987;82:345-9. Herold M, et al, Onkologie 1999; 22: 310-313 Herold, M., et al., Leuk Lymphoma, 1998. 29(Suppl. 1). Hoche D, Arch GeschwulsVorsch 1984;4:333 42.

Bendamustine in HD: MESOZOIC Case reports Author n Previous Rx Dose/ schedule Response D Elia GM et al. (2010) 1 ABVD, BEACOPP, IEV, DHAP, PROVECIP, RT 90 mg/m2, D1+D2 q 4w CR; 6.0 mo.s Magyari F et al. (2011) 1 ABVD, IGEV, ASCT, R-miniBEAM 90 mg/m2 D1+D2 q 4w + Rituximab CR: > 8.0 mo.s Mian M et al. (2013) 2 ABVD, Stanford V BEACOPP, ASCT, allo-sct 90 mg/m2 D1+D2 q 4w + Rituximab + DLI 2 CR: >12 mo.s 9.0 mo.s D Elia GM et al. Leuk Res 2010; 34:e300-1 Magyari F et al. Hematol Oncol. 2011 Oct 28 [Epub]. Mian M. et al. Ann Hematol (2013) 92:121 123

Bendamustine in RR-HL: Fase II Study Moskowitz A. et al. JCO 2013 31:456-460

Bendamustine in RR-HL: Fase II Study Elegibility criteria Biopsy-confirmed relapsed/ refractory classical HL Failure of ASCT or inelegibility Previous Allo-SCT was allowed if relapsed was>6 months from transplantation Patients deemed potentially elegible for Allo-SCT at the time of enrollment were simultaneously offered enrollment onto parallel intent-to-treat study evaluating allosct in relapsed/refractory HL 120 mg/m 2 (d1+d2 ) q28 A total of 6 cycles was planned Moskowitz A. et al. JCO 2013 31:456-460

Bendamustine in RR-HL: Fase II Study Safety Toxicity and Treatment Reduction and Delays Biopsy-confirmed relapsed/ refractory classical HL Failure of ASCT or inelegibility Previous Allo-SCT was allowed if relapsed was>6 months from transplantation Moskowitz A. et al. JCO 2013 31:456-460 Moskowitz A. et al. JCO 2013 31:456-460

Bendamustine in RR-HL: Fase II Study Activity History of ASCT History of Allo-SCT Refractory disease No impact on likelihood of responding to Bendamustine Moskowitz A. et al. JCO 2013 31:456-460

Bendamustine in RR-HL: Fase II Study Activity 68% Achieved Tumor Regression Moskowitz A. et al. JCO 2013 31:456-460

Bendamustine in RR-HL: Fase II Study Allo-SCT Outcome - 5 Patients (20%) underwent allo-sct directly after treatment with Bendamustine - The median number of cycles of B. before allosct was 4-4 pt had achieved CRs and 1 PR at time of allosct The median follow-up of surviving patients was 3 years - Since undergoing allo-sct, 2 pt have remained in remission 19 and 31 months and 3 pt relapsed at 100 days, 16 months and 21 months after Allo-SCT PFS: 5.2 MONTHS Moskowitz A. et al. JCO 2013 31:456-460

Bendamustine in RR-HL: Fase II Retrospective Study the Real Life Author n Pts. Dose/ schedule Response Corazzelli G et al. (Br J Haematol 2012) Anastasia et al. (ASH 2012) 1 n. 41 120 mg/m2, D1+D2 q21/28 100 mg/m2, D1+D2 q21/28 90 mg/m2, D1+D2 q28 1 n. 73 120 mg/m2, D1+D2 q28 100 mg/m2, D1+D2 q28 90 mg/m2, D1+D2 q28 ORR: CR: mdr: ORR: CR: mdr: mdr: median duration of response Corazzelli G, et al. Br J Haematol 2013, 160, 207 215 Anastasia A, et al. ASH 2012

Bendamustine in RR-HL: Retrospective Study

Bendamustine in RR-HL: Retrospective Study Real life: 41 pts. 58%: 120 mg/m 2 (d1+2 ) q21/28 15%: 100 mg/m 2 (d1+2 ) q21/28 27%: 90 mg/m 2 (d1+22 ) q28 85%: at least 3 courses 51 %: 6 courses Median ADI*: 60.2 mg/m 2 /week (r 34.1 80.2) 25 percentile: 50.1 mg/m 2 /wk 75 percentile: 68.2 mg/m 2 /wk *First 3 courses Corazzelli G. et al. British Journal of Haematology, 2013, 160, 207-213

Bendamustine in RR-HL: Retrospective Study Corazzelli G. et al. British Journal of Haematology, 2013, 160, 207-213

Bendamustine in RR-HL: Retrospective Study 2 years: 20.5% Madian PFS: 11.1 months Median PFS was not influenced by disease status relapsed/ refractory, previous single vs tandem SCT,, and ADI of bendamustine (60 mg/ mq per week or > 2 years OS:47% Madian PFS: 11.1 months Corazzelli G. et al. British Journal of Haematology, 2013, 160, 207-213

Bendamustine for Relapsed/Refractory Classical Hodgkin Lymphoma After High Dose Chemotherapy and or Allogeneic Transplant: A Study of Fondazione Italiana Linfomi (FIL) Antonella Anastasia, MD 1*, Carmelo Carlo-Stella, MD 2, Paolo Corradini, MD 3, Flavia Salvi 4*, Chiara Rusconi 5*, Alessandro Pulsoni 6*, Stefan Hohaus, MD 7*, Patrizia Pregno 8*, SimoneEa Viviani, MD 9*, Ercole Brusamolino, MD 10,11*, Stefano Luminari 12*, Laura Giordano, MD 13* and Armando Santoro, MD 14* 73 patients rr-hl after ASCT (n = 46) or ASCT+allo-SCT (n = 23) 120 mg/m 2 (d1+2 ) q28 100 mg/m 2 (d1+2 ) q28 90 mg/m 2 (d1+2 ) q28 ORR: 58% (25% CR; 33% PR) Median time to response: 3.4 months (r 1.4-10) Median response duration: 5.1 months (r 0.1-23) Severe hematologic toxicity was observed in 20/69 pts (29%); grade 3-4 neutropenia, thrombocytopenia and anemia were observed in 11 (16%), 11(16%) and 4(6%)pts, respec^vely.

Bendamustine in RR-HL

Bendamustine in RR-HL N. Pts ORR CR Cycles Median PFS Pivotal 34 56 35 4 (1-6) 5.2 Italian NPP1 French NPP Italian NPP2 41 58 31 4 (1-8) - 28 50 29 3 (1-12) 5,7 73 58 25 4 (1-12) 10 PFS % (Unit : %) median DFS <20% 5.mos 21% 9 mo.s 11% - 24% 5.1 mo.s Responses mostly achieved between 3-4 cycles Remarkable early response rate but relative short duration Strategies for early consolidation or maintenance need to be devised Moskowitz AJ, J Clin Oncol 2013, 31:456; Ghesquieres H, Leuk & Lymphoma, 2013 54:2399; Corazzelli G, Br J Haematol 2013, 160: 207; Anastasia A, 54th ASH Meeting 2012,Abstr 3652

Agents evaluating in HL relapsing after ABMT

Bendamustine in combination Ongoing Phase I/II trials drugs schedule Sponsor NTC01535924 Gemcitabine + Bendamustine G. (dose NR) on d1 B (escalation) on dd 1-2, every 3-4 weeks Ohio University NTC01657331 Brentuximab Ved + Bendamustine BV 1,2!1,8mg/kg d1 B 60"100mg/m 2 dd 1-2 every 3 weeks British Columbia Cancer Agency, Canada NCT01412307 Lenalidomide + Bendamustine Lena 10"25mg x 28 dd B 60 mg dd 1,8,15 every 4 weeks Istituto Tumori Fond. Pascale Napoli NTC01874054 Brentuximab Ved + Bendamustine BV 1.8 mg/kg d1 B 90 mg/m2 dd 1 and 2, every 3 weeks Seattle Genetics USA

NTC 01412307 LEBEN Bayesian Phase I/II An open non-randomized multicenter Phase 1/2 dose finding study of Lenalidomide in Combination with Bendamustine (LeBen) in relapsed and primary refractory Hodgkin Lymphoma Primary Endpont: Dose-finding at best Trade-off for Efficacy / Toxicity (ie, CR+PR vs Grade>3 AE) Dose Level Lenalidomide Dose Bendamustine Secondary Endpoints: ORR (CR+PR), EFS, PFS 1 10 mg dd1-28 2 15 mg dd1-28 3 20 mg dd1-28 60 mg/m2 dd 1,8,15 Hematology- Oncology and Stem Cell Transplanta^on Unit, Is^tuto Nazionale Tumori, Fond. Pascale, IRCCS Napoli, Italy 4 25 mg dd1-28

LeBen for RR-Hodgkin s Lymphoma

NTC 01412307 LEBEN Bayesian Phase I/II LEBEN x 2 primary endpoints evaluation Best (EFF/ TOX) Trade-off [CR+PR] vs [Grade>3 AE ] CR, PR, SD Best dose LEBEN x 4 secondary endpoints (ORR, EFS) evaluation PD Off-study

LeBen for RR-Hodgkin s Lymphoma

Anastasia A. et al POSTER SESSSION ASH 2012

Mobilization of Hematopoietic stem cells by a Bendamustinecontaining regimen in Hodgkin s Lymphoma Dati sui primi 14 pazienti: nessun fallimento Raccolta media: 7.8 x10 6 CD34/kg (range 3.6-15 Numero mediano di procedure: 1 (range 1-2) Anastasia A. et al POSTER SESSSION ASH 2012

Bendamustine in Hodgkin Lymphoma: Phase II studies & real life retrospective studies Significant response rate Favorable toxicity profile: - manageable/expected hematologic toxicity (thrombocytopenia, infection) -mild non-hematologic toxicity Adequate response duration Response independent from prior: - chemosensitivity status, - ASCT, allo-sct - Bendamustine ADI Short time to best response (2-4 cycles) Early CRs mantained Early PRs do not usually upgrade

Bendamustine in Hodgkin Lymphoma Does it work? Yes, it does! How it works? May be differently than in B-NHL (???) Can we combine it with other agents in rr-hl? Yes, we can! How? Why? 1.To cytoreduce preallosct 2. To palliate 3. As a platform for combination with target-based agents Image: L. Leoni. Clinical Advances in Hematology & Oncology 2011,9 (S 19),