bendamustine in hodgkin lymphoma - siematologia · bendamustine in hodgkin lymphoma dott.ssa cinzia...
Post on 16-Feb-2019
226 Views
Preview:
TRANSCRIPT
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
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
• 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
• 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.
Bendamustine: Development in HL
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.
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
Moskowitz A. et al. JCO 2013 31:456-460
120 mg/m2 (d1+d2 ) q28
A total of 6 cycles was planned
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
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
Bendamustine in RR-HL: Fase II Study
Moskowitz A. et al. JCO 2013 31:456-460
Activity
68% Achieved Tumor
Regression
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
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
Bendamustine in RR-HL: Retrospective Study
• 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
Bendamustine in RR-HL: Retrospective Study
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
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 >
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.
Bendamustine in RR-HL
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
Agents evaluating in HL relapsing after ABMT
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
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
LeBen for RR-Hodgkin’s Lymphoma
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
LeBen for RR-Hodgkin’s Lymphoma
LeBen for RR-Hodgkin’s Lymphoma
LeBen for RR-Hodgkin’s Lymphoma
Anastasia A. et al POSTER SESSSION ASH 2012
Anastasia A. et al POSTER SESSSION ASH 2012
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)
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 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),
top related