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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

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),