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Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) with Non-Germinal center B-cell Phenotype is associated with a Higher response to Lenalidomide (L) or in Combination with Rituximab(R). Francisco Hernandez-Ilizaliturri MD Farhana Malik MBBS Myron Czuczman MD.

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Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) with Non-Germinal center B-cell Phenotype is associated with a Higher response to Lenalidomide (L) or in Combination with

Rituximab(R)

Francisco Hernandez-Ilizaliturri MDFarhana Malik MBBSMyron Czuczman MD

Departments of Medical Oncology, Immunology and Pharmacology

Roswell Park Cancer Institute


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

Classification of Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) According to the Hans Criteria Defines Two Groups of Patients with Different Clinical Outcomes Following Systemic Rituximab-Multi Agent Anthracycline-Based Therapy


Evolution in the management of aggressive b cell lymphomas
Evolution in the management of aggressive B-cell lymphomas Lymphoma (DLBCL) According to the Hans Criteria Defines Two Groups of Patients with Different Clinical Outcomes Following Systemic Rituximab-Multi Agent Anthracycline-Based Therapy

  • Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma diagnosed in the Western Hemisphere

  • Patients with DLBCL exhibit a heterogeneous clinical behavior and prognosis

  • Several biomarkers that predict the clinical outcome of DLBCL patients had been identified and validated (i.e. Bcl-2 expression, IPI score or gene profiling studies)

  • The addition of rituximab to systemic chemotherapy has improved the clinical outcome of DLBCL patients, challenging previously established biomarkers of response


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

Distinct types of DLBCL identified by gene expression profiling

Rosenwald et Al, NEJM 2002; 346:1937-47

Studies included patients with DLBCL treated with CHOP or CHOP-like chemotherapy prior to rituximab

Alizadeth A, et al. Nature 2000; 403:503 - 511


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

GCB profiling

GCB

+

-

MUM1

CD10

+

+

-

Non-GCB

Bcl-6

-

Non-GCB

Algorithm for Subtype classification of DLBCL

The concordance rate of the Han’s Algorithm to gene profiling studies is 80%

Hans et al, Blood 2004, 103: 275-282



To study clinical differences between gcb and non gcb dlbcl treated at rpci
To study clinical differences between GCB- and non-GCB DLBCL treated at RPCI

  • Retrospective study of 191 patients DLBCL treated at our Institution between 2000 and 2007 with the following characteristics

    • Previously untreated DLBCL

    • Patients that received front line therapy with rituximab in combination with CHOP or DA-EPOCH

    • Tumor specimen available for immunohistochemistry (IHC) studies

      • CD20, CD10, BCL2, BCL6 and MUM1

    • Patients were excluded from the analysis if any of the following:

      • Incomplete clinical data

      • Transformed lymphoma and primary CNS DLBCL

      • HIV related DLBCL

  • Demographic, clinical and pharmacological (i.e. cumulative doses of rituximab, chemotherapy and growth factor support) were included in the analysis


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

  • Patients were classified as GCB- or non-GCB DLBCL using the Hans algorithm (Hans et al, Blood 2004, 103: 275-282)

  • Differences in end-point studies were evaluated between GCB- and non-GCB patients

    • Repsonse rate

    • Cumulative chemoimmunotherapy doses received

    • Overall survival (OS)

    • Progression free survival (PFS)


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

DLBCL with a non-GCB phenotype by IHC had an inferior PFS following R-CHOP-21 than GCB-DLBCL

Log Rank P = 0.017

GCB DLBCL

Non-GCB DLBCL

The median survival for non-GCB DLBCL was 45.1 months, whereas the median survival for patients with GCB-DLBCL has not be reach.


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

P = 0.037 following R-CHOP-21 than GCB-DLBCL

GCB DLBCL

Non-GCB DLBCL

DLBCL with a non-GCB phenotype by IHC had an inferior overall survival following R-CHOP-21 than GCB-DLBCL

The median survival for non-GCB DLBCL was 75.4 months, whereas the median survival for patients with GCB-DLBCL has not be reach.


In summary
In summary following R-CHOP-21 than GCB-DLBCL

  • Our data suggest that the Hans algorithm can predict clinical outcomes of patients with DLBCL undergoing frontline chemo-immunotherapy

  • Patients with Non-GCB DLBCL while having a comparable initial overall response rate (CR and PR) to R+CHOP had a shorter PFS and OS than GCB-DLBCL

  • Non-GCB DLBCL represent a subgroup of DLBCL for which innovative therapeutic strategies targeting key regulatory pathways in the induction and/or maintenance setting are need in an attempt to improve their PFS and OS


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

CALGB 50303 Phase III Randomized Study of R-CHOP vs. Dose-Adjusted EPOCH-R with Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas

R+CHOP x 6

De Novo CD20+ DLBCL stage II,III or IV

Tumor Biopsy for GEP studies

Randomization

R-DA-EPOCH x 6


Lenalidomide in diffuse large b cell lymphoma dlbcl correlating response with tumor characteristcs

Lenalidomide in diffuse large B-cell lymphoma (DLBCL): Dose-Adjusted EPOCH-R with Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas correlating response with tumor characteristcs


Thalidomide analogues immune mediated inflammatory disease imids in b cell lymphomas

N Dose-Adjusted EPOCH-R with Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas

N

N

H

H

H

2

2

2

Thalidomide analogues: immune-mediated inflammatory disease (IMiDs) in B-cell lymphomas

Thalidomide/IMiDs target MM cells in the bone marrow (BM) microenviroment

O

O

H

C. Thalidomide/IMiD

N

MM cells

O

N

IL-6 TNFa IL-1b 

O

B. Thalidomide/IMiD

Thalidomide

BM stromalcells

O

O

A. Thalidomide/IMiD

ICAM-1

H

N

N

O

BM vessels

VEGF bFGF 

IL-2 IFN

CC-5013 (Revimid)

PBMC

O

O

H

E. Thalidomide/IMiD

D. Thalidomide/IMiD

CD8+ T cellsNK cells

N

N

O

MM = multiple myeloma; VEGF = vascular endothelial growth factorPBMC = peripheral-blood mononuclear cells; NK = natural killerTNF = tumour necrosis factor

O

N

N

N

H

H

H

2

2

2

Davies FE, et al. Blood, 2001;98:210–6Hayashi T, et al. Blood 2002;100:314b (Abstract 4800)

CC-4047 (Actimid)


Nf kb target genes are highly expressed in activated b cell like diffuse large b cell lymphoma
NF-kB target genes are highly expressed in activated B cell-like diffuse large B-cell lymphoma

Courtesy of L. Staudt


Imids in vitro decrease nf b activity and arrest dna synthesis in nhl cells
IMiDs cell-like diffuse large B-cell lymphomain vitro decrease NFB activity and arrest DNA synthesis in NHL cells

CC5013

Raji cells

40,000

30,000

20,000

10,000

0

400,000

300,000

200,000

100,000

0

CPU 48 hoursRaji cells

0 2.5 5 10 20 40

µg/mL

Relative light units

CC4047

400,000

300,000

200,000

100,000

0

CPU 48 hours Raji cells

0 2.5 5 10 20 40

µg/mL

Positivecontrol

CC4047

CC5013

Placebo

Negativecontrol

Hernandez-Ilizaliturri FJ, et al. Clin Can Res 2005;11:5984–92


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

Stromal-1 signature encodes extracellular matrix components and macrophage/myeloid restricted proteins (favourable)



Tumor micro vessel density decreases after treatment with lenalidomide
Tumor micro vessel density decreases after treatment with lenalidomide

Placebo CD31 staining

Lenalidomide CD31 staining

Raji xenografts

Actimid CD31 staining

Bars show meansError bars show mean ± 1.0 SE

125

100

75

50

25

0

*†

*

MVD (vessels/llpf)

Placebo

Lenalidomide

Actimid

*p=0.009†p=0.005

Reddy N, et. al. Br J Haematol 2007, 140:36-45


Lenalidomide induces crs and prs in patients with relapsed and treatment refractory cll
Lenalidomide induces CRs and PRs in patients with relapsed and treatment-refractory CLL

  • Plasma levels of TNF-, soluble TNF receptor 1 (TNF-R1), interferon (IFN)-, VEGF, bFGF, interleukin (IL)-1β, -2, -6, -8, -10, -12, IL-1 receptor antagonist (IL-1RA), and soluble IL-2 receptor (IL-2R) were measured at different time intervals pre and post-treatment

  • A significant reduction in plasma VEGF level was observed on day 28 in four patients that achieved a response (mean reduction of 55.6pg/mL [± 15.3], p=0.036) and on day 90 in four patients with SD or clinical improvement (mean reduction of 50.9pg/mL [± 3.3], p=0.003).

Ferrajoli A, et al. Blood 2006;108:94a (Abstract 305)


Cytokine secretion by dc after in vitro exposure to lenalidomide
Cytokine secretion by DC after and treatment-refractory CLLin-vitro exposure to lenalidomide

*

20

15

10

5

0

INF-*p=0.014

†p=0.004

pg/mL

*

4,000

3,000

2,000

1,000

0

MCP-1*p<0.001

†p=0.001

*†

pg/mL

DMSO Lenalidomide Actimid

700

600

500

400

300

200

100

0

TNF-a*p=0.013

†p=0.024

*†

*

DMSO Lenalidomide Actimid

pg/mL

*†

DMSO Lenalidomide Actimid

Reddy N, et. al. Br J Haematol 2007, 140:36-45


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md
Differences in the number and pattern of NK cells infiltrating the tumour bed oflymphoma-bearing SCID mice treated with IMiDs

Placebo-treated infiltration of NK-cells(CD49b+) in the periphery of the tumour

Raji xenografts

Bars show meansError bars show mean ± 1.0 SE

60

40

20

0

*

*†

Lenalidomide-treated infiltration ofNK-cells (CD49b+) within the tumour

Tumour infiltrated with NK-cells (%)

Placebo

Lenalidomide

Actimid

*p=0.012†p=0.015

Reddy N, et. al. Br J Haematol 2007, 140:36-45


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md
IMiD enhancement of rituximab-dependent ADCC infiltrating the tumour bed ofex vivo is mediated via co-stimulation of NK-cells by DCs

Co-stimulation with DCs

Without co-stimulation with DCs

30

20

10

0

30

20

10

0

Raji

Raji

DMSO

Lenalidomide

Pomalidomide

Bars show means

DMSO

Lenalidomide

Pomalidomide

Bars show means

p<0.007

Error bars show mean± 1.0 SE

Error bars show mean± 1.0 SE

Specific lysis (%)

Specific lysis (%)

Rituximab Isotype Splenocytes

Rituximab Isotype PBMC

Reddy N, et. al. Br J Haematol 2007, 140:36-45


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md
Pomalidomide in combination with rituximab improves survival in lymphoma-bearing severe combined immunodeficiency (SCID) mice

1.2

1.0

0.8

0.6

0.4

0.2

0

Pomalidomide* + rituximab

Cumulative survival

Pomalidomide

Rituximab*

Placebo

0 20 40 60 80 100 120

Time to development of limb paralysis (days)

*p=0.0012

CI = confidence interval

Hernandez-Ilizaliturri FJ, et al. Clin Can Res 2005;11:5984–92


Lenalidomide in combination with rituximab improves survival in lymphoma bearing scid mice
Lenalidomide in combination with rituximab improves survival in lymphoma-bearing SCID mice

1.2

1.0

0.8

0.6

0.4

0.2

0

Lenalidomide* + rituximab

Cumulative survival

Lenalidomide

Rituximab*

Placebo

0 20 40 60 80 100 120

Time to development of limb paralysis (days)

Hernandez-Ilizaliturri FJ, et al. Clin Can Res 2005;11:5984–92

*p=0.167


Lenalidomide monotherapy in relapsed or refractory aggressive non hodgkin s lymphoma nhl 002
Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma: NHL-002

Patients self-administered oral lenalidomide (25 mg once daily) on days 1 to 21 of every 28-day cycle. Patients continued therapy for 52 weeks as tolerated or until disease progression.

O

O

O

H

N

N

O

Wiernik P, et al. Journal of Clinical Oncology, 26; 2008: 4952-4957

N

H

2


Lenalidomide monotherapy in relapsed or refractory aggressive non hodgkin s lymphoma
Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma

The estimated median duration of response was 6.2 months (range, 0 to 12.8 months), and median PFS was 4.0 months (range, 0 to 14.5 months).

Wiernik P, et al. Journal of Clinical Oncology, 26; 2008: 4952-4957


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

Confirmation of the Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Relapsed or Refractory Diffuse Large-B-Cell Lymphoma: Results of An International Study (NHL-003)

  • NHL-003 evaluated the efficacy of single-agent lenalidomide in patients with relapsed/refractory aggressive NHL that hadreceived at least one prior treatment and had measurable disease (Median 3, range 1-6)

  • Lenalidomide was administered at 25mg/day p.o. on days 1–21 of a 4-week cycle until disease progression or unacceptable toxicity

  • Results in patients with DLBCL (N=73) demonstrated:

    • The overall response rate to lenalidomide was 29% (21/73)

    • While some complete response were observed (4%, 3/73), most of the patients achieved a partial remission (25%, 18/73).

    • Eleven patients (15%) had stable disease

    • The most common grade3 or 4 adverse events were neutropenia (32%), thrombocytopenia(15%), asthenia (8%) and anemia (7%).

Czuczman M, et al. Blood (ASH Annual Meeting Abstracts) 2008 112: 268a


Algorithm for subtype differentiation

GCB Monotherapy in Patients with Relapsed or Refractory Diffuse Large-B-Cell Lymphoma: Results of An International Study (NHL-003)

GCB

+

-

MUM1

CD10

+

+

-

Non-GCB

Bcl-6

-

Non-GCB

Algorithm for Subtype Differentiation

Iqbal J et al. Leukemia 2007, 1–12

Hans et al, Blood 2004, 103: 275-282


Can we predict clinical response to lenalidomide in dlbcl patients
Can we predict clinical response to Lenalidomide in DLBCL patients?

  • Retrospective study of patients with DLBCL treated with lenalidomide at Roswell Park Cancer Institute (RPCI)

  • Patients were divided into two cohorts using the criteria proposed by Hans et al and Igbal et al :

    • Germinal center B-cell-like (GCB)

    • Non-GCB

  • Tumor biopsies are routinely stained for MUM1, CD10, Bcl-6 and Ki67 by the Pathology Department at RPCI

  • Responses to lenalidomide were assessed by standard and/or revised Cheson criteria

  • Differences in response rate, duration of response to lenalidomide and overall survival were analyzed using the software program SPSS 14


Can we predict clinical response to lenalidomide in dlbcl patients1
Can we predict clinical response to Lenalidomide in DLBCL patients?

  • Sample size 19, 11F/8M

  • Histological Diagnosis:

    • DLBCL = 13

    • FL and DLBCL (Composite) = 5

    • Transformed NHL = 1

  • IHC classification of the patients:

    • Non-GCB = 9

    • GBC = 9

    • Unknown = 1 (Bcl-6 positive, T-cell rich DLBCL)

  • Median Age 64 (43 to 89)

  • Median number of prior therapies = 4 (2 – 13)

  • Median cycles of lenalidomide = 3 (1 – 20)


Differences in response rate between non gcb and gcb like dlbcl to lenalidomide

* patients?

*P = 0.011

*

Differences in response rate between Non-GCB and GCB-like DLBCL to lenalidomide

Median number of prior treatment: Non-GCB = 4.88 (+/- 1.03) vs. GCB = 4.33 (+/- 0.64), Chi square P = 0.46

No differences in IPI score, histology, stage or other demographic characteristics were seen at time of lenalidomide Rx between the two groups


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

Progression free survival following Lenalidomide therapy in DLBCL according to histological subtype


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

Progression free survival following Lenalidomide therapy in DLBCL according to histological subtypepure DLBCL



Response rate in dlbcl with a non gcb phenotype by ihc treated with rituximab and lenalidomide
Response rate in DLBCL with a non-GCB phenotype by IHC treated with rituximab and lenalidomide

  • Patients with refractory/relapsed NHL treated at University of Bologna with rituximab in combination with lenalidomide (mean number of cycles =4)

    • Tissue array submitted to RPCI for MUM-1, Bcl-6, and CD10 IHC

  • Histological Diagnosis (revised and re-classified at RPCI):

    • DLBCL = 10

    • FL3a/b = 3

    • Transformed NHL = 1

  • IHC classification of the patients by the Hans algorithm was feasible in 10pts:

    • Non-GCB = 8

    • GBC = 0

    • Other (FL) = 2

  • ORR for all cases submitted = 50% (7/14)

  • ORR for Non-GCB = 50% (4/8)


In summary1
In summary treated with rituximab and lenalidomide

  • Lenalidomide monotherapy or in combination with rituximab are active salvage therapies in relapsed/refractory DLBCL

  • Our data strongly suggest that two previously identified groups of patients with DLBCL (GCB vs. non-GCB) appear to have dramatically different degrees of responsiveness to lenalidomide with or without rituximab in the relapsed/refractory setting

  • Tumor specimens from patients treated at two additional institutions (i.e. Mayo Clinic and the John Theurer Cancer Center at Hackensack University Medical Center) are currently being evaluated and classified in order to further validate our findings


Francisco hernandez ilizaliturri md farhana malik mbbs myron czuczman md

CD10 treated with rituximab and lenalidomide

Bcl-6

MUM1

Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma

Immuno-histochemistry (IHC)

Gene expression profiling (GEP)

Relapsed/Refractory DLBCL (N=49)

Biopsy

Proceed to Part B if clinically indicated

Part A Bortezomib (N=23)

ABC DLBCL (N=5)

GCB DLBCL (N=10)

ABC DLBCL (N=12)

GCB DLBCL (N=12)

Treat until disease progression or maximum allowable cycles

DLBCL subtype classification by GEP or IHC

Part B Bortezomib + DA-EPOCH (N=44)

ABC DLBCL (N=12)

GCB DLBCL (N=15)

Treat until disease progression or maximum allowable cycles

Dunleavy et al. Blood. 2009; 113:6069-76


Overall study schema for proposed phase iii registrational trial of lenalidomide in r r dlbcl
Overall study schema for proposed Phase III registrational trial of lenalidomide in r/r DLBCL

Lenalidomide

N=25

Lenalidomide

N=74

Non-GCB

Non-GCB

Control

N=25

Control

N=74

Relapse Refractory DLBCL

Stratify by

IHC subtyping

Lenalidomide

N=25

Lenalidomide

N=74

GCB

GCB

Control

N=25

Control

N=74

Stage 1

N = 100

Stage 2

N = 148 or 296

Go/No-go Analysis


Lymphoma translational research group lenalidomide project
Lymphoma Translational Research Group Lenalidomide project trial of lenalidomide in r/r DLBCL

Medical Oncology/immunology

Myron S. Czuczman M.D.

Francisco J. Hernandez-Ilizaliturri M.D.

Asher Chanan-Khan M.D.

Zale Berstein M.D.

Jeyanthi Ramanarayanan M.D.

Philip McCarthy M.D.

Kelvin Lee M.D., Ph.D.

Navine Bangia Ph.D.

Elizabeth Repasky Ph.D.

Departments of Hematology, Anatomic Pathology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

Thomas Witzig MD

William Macon MD

Department of Hematology and Pathology, Bologna University School of Medicine, Bologna, Italy,

Pier Luigi Zinzani MD

Stefano A. Pileri MD

The John Theurer Cancer Center at Hackensack University Medical Center, Hackensack NJ.

Andrew Goy MD

Pathology/molecular diagnostics

Maurice Barcos M.D.

George Deeb M.D.

Paul Wallace Ph.D.

Peter Sterostick Ph.D.

Ann Marie Block Ph.D.

IMIDs pre-clinical project

Malik Farhana MBBS

Nishitha Reddy M.D.

Beata Holkova M.D.