BENDAMUSTINE IN HODGKIN LYMPHOMA - Siematologia · BENDAMUSTINE IN HODGKIN LYMPHOMA Dott.ssa Cinzia Pellegrini Istituto di Ematologia e Oncologia Medica "L&A" Sèragnoli CONVEGNO

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%


43 None CVPP/ ABVB

CVPP/ ABVB B: 30 mg/m2, D 8-12, q28

93% CR: 81% PR: 12%


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


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/m2 (d1+d2 ) q28

A total of 6 cycles was planned


Moskowitz A. et al. JCO 2013 31:456-‐460

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



Activity

History of ASCT

History of Allo-SCT Refractory disease

No impact on likelihood of responding to

Bendamustine



Activity

68% Achieved Tumor

Regression



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


•  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







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




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),

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BENDAMUSTINE IN HODGKIN LYMPHOMA - Siematologia · BENDAMUSTINE IN HODGKIN LYMPHOMA Dott.ssa Cinzia Pellegrini Istituto di Ematologia e Oncologia Medica "L&A" Sèragnoli CONVEGNO