bendamustine in hodgkin lymphoma - siematologia · bendamustine in hodgkin lymphoma dott.ssa cinzia...
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BENDAMUSTINE IN HODGKIN LYMPHOMA
Dott.ssa Cinzia Pellegrini Istituto di Ematologia e Oncologia Medica "L&A" Sèragnoli
CONVEGNO REGIONALE SIE DELEGAZIONE REGIONALE EMILIA ROMAGNA
ATTUALITA’ IN EMATOLOGIA BOLOGNA 06.03.2015
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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
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Bendamustine • Extensive DNA-damage Like other alkylating agents, it causes intra-stand and inter
stand cross-links between DNA bases
• 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. Tageja N, et al. Cancer Chemother Pharmacol (2010) 66:413-‐423
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• Apoptosis via a TP53-dependent mechanism;
• Inhibition of mitotic checkpoints-regulating genes, such as CCNB1, AURKA and PLK1, this drugs also triggers a complex phenomenon, known as mitotic catastrophe, that activated non apoptotic cell death pathway in tumor cells
• Activates an exonuclease-1 (EXO1) Dna repair
Bendamustine
Leoni L.M. et al, Clin Canc Res 2008; 14 (1) January 1, 2008
As a result of this distinctive activity profile, Bendamustine
show limited cross-resitance with agents usually employed for upfront and salvage treatments of HD including anthracyclines,
dacarbazina, cyclophosphamide, ifosfamide, melphalan and carmustine.
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Bendamustine: Development in HL
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Bendamustine (Cytostasan) in HD:PALEOZOIC
Author n
Prev. Rx
Dose/ schedule ORR
Herold M et al. (1999)
80 None CVPP vs CVPP/DVBB
CVPP/DVBB (DNR, BLM, VCR, B) B: 30 mg/m2, d 8-12, q28
75% vs 87.5%
Herold M et al. (1987)
43 None CVPP/ ABVB
CVPP/ ABVB B: 30 mg/m2, D 8-12, q28
93% CR: 81% PR: 12%
Herold M et al. (1998)
100 None CVPP/ABVC vs CVPP/ABVB
B: 30 mg/m2, D 8-12, q28
CR: 81% vs CR: 88%
Hoche D et al. (1984)
73 CVPP DBVCy[B] vs ABVD
DBVCy (DNR, BLM, VCR, Cy) Cy: 50 mg/m2, D 1-5, q 28
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.
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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
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Bendamustine in RR-HL: Fase II Study
Moskowitz A. et al. JCO 2013 31:456-460
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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
Moskowitz A. et al. JCO 2013 31:456-460
120 mg/m2 (d1+d2 ) q28
A total of 6 cycles was planned
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Bendamustine in RR-HL: Fase II Study
Moskowitz A. et al. JCO 2013 31:456-‐460
Safety
Moskowitz A. et al. JCO 2013 31:456-460
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
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Bendamustine in RR-HL: Fase II Study
Moskowitz A. et al. JCO 2013 31:456-460
Activity
History of ASCT
History of Allo-SCT Refractory disease
No impact on likelihood of responding to
Bendamustine
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Bendamustine in RR-HL: Fase II Study
Moskowitz A. et al. JCO 2013 31:456-460
Activity
68% Achieved Tumor
Regression
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Bendamustine in RR-HL: Fase II Study
Moskowitz A. et al. JCO 2013 31:456-460
PFS: 5.2 MONTHS
The median follow-up of surviving patients
was 3 years
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
- 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
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Bendamustine in RR-HL: Fase II Retrospective Study the Real Life
Corazzelli G et al. (Br J Haematol 2012)
1
n. 41 120 mg/m2, D1+D2 q21/28 100 mg/m2, D1+D2 q21/28 90 mg/m2, D1+D2 q28
ORR: CR: mdr:
Anastasia et al. (ASH 2012)
1 n. 73 120 mg/m2, D1+D2 q28 100 mg/m2, D1+D2 q28 90 mg/m2, D1+D2 q28
ORR: CR: mdr:
Corazzelli G , et al. Br J Haematol 2013, 160, 207–215 Anastasia A, et al. ASH 2012
mdr: median duration of response
Author n Pts. Dose/ schedule Response
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Bendamustine in RR-HL: Retrospective Study
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• 58%: 120 mg/m2 (d1+2 ) q21/28 • 15%: 100 mg/m2 (d1+2 ) q21/28 • 27%: 90 mg/m2 (d1+22 ) q28 • 85%: at least 3 courses • 51 %: 6 courses
Bendamustine in RR-HL: Retrospective Study
• Median ADI*: 60.2 mg/m2 /week (r 34.1 – 80.2) • 25° percentile: 50.1 mg/m2 /wk • 75° percentile: 68.2 mg/m2 /wk *First 3 courses
Real life: 41 pts.
Corazzelli G. et al. British Journal of Haematology, 2013, 160, 207-213
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Bendamustine in RR-HL: Retrospective Study
Corazzelli G. et al. British Journal of Haematology, 2013, 160, 207-213
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Bendamustine in RR-HL: Retrospective Study
Corazzelli G. et al. British Journal of Haematology, 2013, 160, 207-213
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Bendamustine in RR-HL: Retrospective Study
Corazzelli G. et al. British Journal of Haematology, 2013, 160, 207-213
2 years: 20.5% Madian PFS: 11.1 months
2 years OS:47% 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 >
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Bendamustine for Relapsed/Refractory Classical Hodgkin Lymphoma After High Dose Chemotherapy and or Allogeneic Transplant: A Study of
Fondazione Italiana Linfomi (FIL)
Antonella Anastasia, MD1*, Carmelo Carlo-Stella, MD2, Paolo Corradini, MD3, Flavia Salvi4*, Chiara Rusconi5*, Alessandro Pulsoni6*, Stefan Hohaus, MD7*, Patrizia Pregno8*, SimoneEa Viviani, MD9*, Ercole Brusamolino, MD10,11*, Stefano Luminari12*, Laura Giordano, MD13* and Armando Santoro, MD14*
73 patients • rr-HL after ASCT (n = 46) or ASCT+allo-SCT (n = 23)
• 120 mg/m2 (d1+2 ) q28 • 100 mg/m2 (d1+2 ) q28 • 90 mg/m2 (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.
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Bendamustine in RR-HL
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N. Pts ORR CR Cycles Median PFS
Pivotal 34 56 35 4 (1-6) 5.2
Italian NPP1 41 58 31 4 (1-8) -
French NPP 28 50 29 3 (1-12) 5,7
Italian NPP2 73 58 25 4 (1-12) 10
PFS % median DFS
<20% 5 .mos
21% 9 mo.s
11% -
24% 5.1 mo.s
(Unit : %)
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
Bendamustine in RR-HL
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Agents evaluating in HL relapsing after ABMT
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Bendamustine in combination Ongoing Phase I/II trials
drugs
NTC01535924
NTC01657331
NCT01412307
NTC01874054
Gemcitabine + Bendamustine
Brentuximab Ved + Bendamustine
Lenalidomide + Bendamustine
Brentuximab Ved + Bendamustine
schedule G. (dose NR) on d1 B (escalation) on dd 1-2, every 3-4 weeks
BV 1,2 !1,8mg/kg d1 B 60"100mg/m2 dd 1-2 every 3 weeks
Lena 10"25mg x 28 dd B 60 mg dd 1,8,15 every 4 weeks
BV 1.8 mg/kg d1 B 90 mg/m2 dd 1 and 2, every 3 weeks
Sponsor
Ohio University
British Columbia Cancer Agency,
Canada
Istituto Tumori Fond. Pascale
Napoli
Seattle Genetics USA
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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)
Secondary Endpoints: ORR (CR+PR), EFS, PFS
Dose Level Dose
Lenalidomide Bendamustine
1 10 mg dd1-28
60 mg/m2 dd 1,8,15
2 15 mg dd1-28
3 20 mg dd1-28
4 25 mg dd1-28
NTC 01412307 – LEBEN Bayesian Phase I/II
Hematology-‐Oncology and Stem Cell Transplanta^on Unit, Is^tuto Nazionale Tumori, Fond. Pascale, IRCCS – Napoli, Italy
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LeBen for RR-Hodgkin’s Lymphoma
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primary endpoints evaluation Best (EFF/
TOX) Trade-off
[CR+PR] vs [Grade>3
AE ]
LEBEN x 2
LEBEN x 4
Off-study
CR, PR, SD
PD
secondary endpoints
(ORR, EFS)
evaluation
NTC 01412307 – LEBEN Bayesian Phase I/II
Best dose
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LeBen for RR-Hodgkin’s Lymphoma
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LeBen for RR-Hodgkin’s Lymphoma
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LeBen for RR-Hodgkin’s Lymphoma
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Anastasia A. et al POSTER SESSSION ASH 2012
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Anastasia A. et al POSTER SESSSION ASH 2012
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Anastasia A. et al POSTER SESSSION ASH 2012
Mobilization of Hematopoietic stem cells by a Bendamustine-containing regimen in Hodgkin’s Lymphoma
• Dati sui primi 14 pazienti: nessun fallimento
• Raccolta media: 7.8 x106 CD34/kg (range 3.6-15
• Numero mediano di procedure: 1 (range 1-2)
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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
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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 pre- alloSCT 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),
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