Management Updates in CBCL

Youn H. KimDepartment of Dermatology

Multidisciplinary Cutaneous Lymphoma GroupStanford Comprehensive Cancer Center

Disclosure of Conflicts of Interest

Youn H. Kim, M.D.

Management Updates in CBCL

Investigator in clinical trials supported by Coley/Pfizer, Transgene

Management Update in CBCL

Handout will be available next week at web site:cutaneouslymphoma.stanford.edu

Primary cutaneous B-cell Lymphomas

New WHO-EORTC Classification

Marginal zone B-cell lymphoma

Follicle center lymphoma

Diffuse large B-cell lymphoma, leg-type

Diffuse large B-cell lymphoma, otherBlood Blood 2005;105:2005;105:3768-853768-85

IndolentIndolent

IntermediateIntermediateAggressiveAggressive

PC Marginal-Zone B-cell Lymphoma

• Indolent BCL of mature small B-cells including MZ (centrocyte-like) cells, lymphoplasmacytoid cells, plasma cells– Previously designated immunocytoma, part of extranodal MZ MALT

lymphomas– MZ B-cells: CD20+, CD79a+, bcl-2+, CD5-, CD10-, bcl-6-– Plasma cells: CD138+, CD79a+, freq. CD20-, monotypic light chain– Molecular/Genetic

• 40-60% clonal IgH gene rearrangement• t(14;18)(q32;q21) of IGH gene on 14 and MLT gene on 18• t(3;14)(p14.1;q32) of IGH and FOXP1 genes

• Red-violaceous plaques or tumor nodules commonly on extremities (esp. arms) or trunk; solitary or commonly multifocal– European reports of a/w B burgdorferi (esp. ears), not a/w US cases– 5-yr DSS near 100%

PC Follicle-Center Lymphoma

• Tumor of neoplastic follicle center cells, mix of centrocytes and centroblasts (not in sheets), w/ a follicular, follicular and diffuse, or diffuse growth pattern– CD20+, CD79a+, may show monotypic light chain expression– Bcl-6+, CD10 (+ in follicular, - in diffuse), CD5-, CD43-, bcl-2- or

faint+, mum-1-– Molecular/Genetic

• 50-70% clonal IgH rearrangement by PCR• Lack t(14:18), minority of positive reports• Inactivation of p15, p16 tumor suppressor genes in 10%, 30%

• Solitary, grouped, or multifocal plaques or tumor nodules, preferentially on scalp, forehead, trunk– 5-yr DSS 95%

PC Diffuse Large B-cell Lymphoma, Leg-Type

• PCLBCL w/ predominance or confluent sheets of centroblasts and immunoblasts– CD20+, CD79a+, monotypic light chain expression– Bcl-2+ (strong), bcl-6+/-, CD10-, mum-1+– Lack t(14;18) despite strong bcl-2– Inactivation of p15, p16 in 11%, 44%; chromosomal imbalances in

85% w/ gains of 18q, 7p, loss of 6q; translocations of myc, bcl-6, IgH– Frequent clonal IgH gene rearrangement by PCR

• Rapidly growing red-violaceous tumor(s), most commonly on leg(s), but can affect non-leg sites– Common in elderly, particularly females– Less favorable prognosis w/ increased risk of development of

extracutaneous disease (5-yr DSS 35-50%); solitary tumor presentation w/ better prognosis

PCBCL, Stanford Experience, n = 138

70(41-90)48(15 -80)52(17-88)Age median

33%100%95%DSS, 5-year

17%38%48%RFS, 5-year

Leg 5

Arm 1

H/N 31%

Arms 34%

Torso 26%

H/N 53%

Arm 12%

Torso 27%

Sites for localized disease

332026% Generalized

66/3461/3969/31% Male/Female

Diffuse Large Cell Lymphoma-leg type

(n=9)

Marginal Zone Lymphoma

(n=49)

Follicle Center Lymphoma

(n=80)

Indolent CBCL (MZL/FCL), when relapse occurs, majority are limited to skin and respond well to salvage therapy

DSS, n = 280 Dutch patientsDSS, n = 280 Dutch patients Willemze, Curr Op Oncol, 2006Willemze, Curr Op Oncol, 2006

Differential gene expression patterns, Differential gene expression patterns, PCFCL vs. DLBCL leg-type PCFCL vs. DLBCL leg-type Hoefnagel et al, Blood 2005Hoefnagel et al, Blood 2005

Cutaneous B-cell Lymphoma

Diagnosis• Clinical suspicion

• Adequate tissue sampling with biopsy– Adequately wide and deep– Incisional/excisional biopsy or > 6 mm punch

== Avoid small punch or shave biopsy• Important role of immunohistochemistry and/or molecular/genetic

studies

ISCL/EORTC Recommendations for Staging Evaluation in Cutaneous Lymphomas other than MF/SS

• Complete history/ROS and physical examination

• Laboratory studies– CBC, comprehensive serum chemistries, serum LDH– flow cytometric studies if indicated

• Imaging studies– Contrast-enhanced CT chest, abdomen & pelvis alone or with whole

body 18F-FDG-PET; include CT or U/S of neck if indicated– Integrated PET/CT

LNs > 1.0 cm in short axis and /or have significantly increased PET activity should be sampled for tissue examination (an excisional bx is preferable whenever possible)

ISCL/EORTC Recommendations for Staging Evaluation in Cutaneous Lymphomas other than MF/SS

• Bone marrow biopsy and aspirate– Required in CLs with intermediate to aggressive clinical behavior as

categorized in the WHO-EORTC classification– Should be considered in CLs with indolent clinical behavior but not

required unless indicated by other staging assessments

At the time of this proposal, there is not a unified standard for bone marrow examination as part of the staging evaluation in cutaneous lymphomas with indolent clinical behavior. The clinician should follow the standard of care of their regional practice

• Additional studies as clinically indicated

TNM Classification System for Primary Cutaneous Lymphomas other than MF/SS:

A Proposal of the ISCL and the Cutaneous Lymphoma Task Force of the EORTC

Y Kim, R Willemze, N Pimpinelli, S Whittaker, E Olsen, A Ranki, R Dummer, and R Hoppe

For the ISCL and the Cutaneous Lymphoma Task Force of the EORTCIn Press, Blood

Proposed T Classification• Extent and distribution of primary cutaneous involvement

T1 solitary skin involvement

T2 regional skin involvementMultiple lesions limited to 1 body region or 2 contiguous body

regions

T3 generalized skin involvementMultiple lesions involving 2 non-contiguous or > 3 body regions

Size criteria of 5, 15, 30 cm are arbitrary to distinguish small/limited from greater/extensive tumor involvement within T1, T2

Lower Back & Buttock

LBB

Upper BackUB

Right Lower Leg & Feet

RLLF

Right Upper LegRUL

Right Lower Arm & Hand

RLAH

Right Upper ArmRUA

Left Lower Leg & Feet

LLLF

Left Upper LegLUL

Abdominal & Genital

AG

Left Lower Arm & Hand

LLAH

Left Upper ArmLUA

ChestC

Head & NeckHN

HN

C

LLAH

LUA

AG

LUL

LLLF

RLAH

RUA

RUL

RLLF

RLAH

RUA

RUL

RLLF

LBB

UB

Body regions in non-MF/SS T-classificationBody regions in non-MF/SS T-classification

Indolent PCBCL (MZL/FCL)Treatment• Solitary/regional (T1-2)

– Excision– Radiation Therapy (RT)– Observation

• Generalized (T3)– RT for symptomatic lesions– Topical treatments

• NM, imiquimod, retinoids– Systemic biologics

• Rituximab, IFN, retinoids– Chemotherapy

• Single-agent or combination– Observation

Rituximab

• Chimeric monoclonal antibody

• Binds specifically to CD20

• Induces apoptosis

• Activates CDC and ADCC

• May synergize or add to activity of chemotherapy

• Minimal toxicity

• Well established effectiveness in nodal BCL

• Limited publication in cutaneous BCLs

B cell

CD 20

Courtesy of Dr. Steve HorwitzCourtesy of Dr. Steve Horwitz

Aggressive CBCL (DLBCL leg-type, other)

• Solitary (T1)– RT– CHOP or Rituximab + CHOP

(R-CHOP) +/- IFRT

• Multiple lesions (T2-3)– CHOP or R-CHOP +/- IFRT

Observation without treatment is not recommendedObservation without treatment is not recommended

Cutaneous B-cell LymphomaEmerging new therapies

Gene delivery-based immunotherapyAdenovirus-interferon-γ gene transfer (TG1042, Transgene)

Dummer et al, Blood 2004;104:1631-1638• Intratumoral injection of non-replicating adenovirus vector

with human IFN-γ cDNA insert (Ad IFN-γ) ⇒ Gene transfer and expression of IFN-γ cDNA confirmed by

RT-PCR⇒ Injected tumors show detectable transgene-derived IFN-γ

mRNA, profound immune activation, up-regulation of IFN-γ-inducible genes

⇒ Sustained production and serum levels of IFN-γ

Adenovirus-interferon-γ gene transfer

• Anti-tumor activity of INF-γ– Immune-stimulatory effects

• Inhibits Th2 cytokine production by tumor cells• Boosts in IL-12 secretion by APC• Enhances cell-mediated cytoxicity (macrophage, NK-cell)• Augments tumor antigen-specific CD8+ T-cell activity

– Antiproliferative effects– Modulation of gene activity

• Encouraging phase I/II results in CBCL– 5/5 local responses (3 CR 2 PR)– 3/3 global responses (2 CR 1 PR)– Well-tolerated (injection site and flu-like reactions)

Phase II Clinical Trial of Intra-Tumoral Administration of TG1042 (Ad IFN-γ) in Patients with Relapsing Primary Cutaneous B-cell Lymphoma

• MZL, FCL (DLBCL leg-type excluded)

• Intra-tumoral injection (max 6 tumors) q wk x 3, off 4th wk (1 cycle), up to 4 cycles

• Measure local and systemic/global responses

• Participating centers – Europe: U Zürich, Nantes, Créteil, Montpellier– US: MD Anderson, Stanford, NW, MSKCC (pending)

Cutaneous B-cell LymphomaEmerging new therapies

+++++++++CpG-C

+++++++CpG-B

--++++CpG-A

IFN-αIFN-γpDC

ActivationB-Cell

ActivationCytokine ProductionODN

type

Novel in situ vaccination with CpG, a TLR9 agonist

Three classes of CpG ODNs with differential Immune activity

B cell

Adaptive Immunity

TLR9

Increased Ab secretion

Innate Immunity

}Increased sensitivity to antigen

T cell

IL-6

IFN-α, γ

IL-10

TNF-αIL-12 (IL15?)

IFN-γ, IP-10, TRAIL

Other cytokines / chemokines: IP-10, MIP-1a/b, MCP-1, IL-8

Increased MHC

++

++

++

++

++

++

++

DC

NK cell, monocytes

CpG

CTL

Antigen-specific T Cells

TLR9

CpG Bridges Innate Immunity and Adaptive Immunity

Radiation

Phase I/II Study of Intratumoral Injection of CPG 7909, A TLR9 Agonist, Combined with Local Radiation in Low-Grade B-cell Lymphoma and Mycosis FungoidesIn situ vaccination strategy

CpG Youn KimYoun KimAnjali MoralesAnjali MoralesWei AiWei AiRichard HoppeRichard HoppeRon LevyRon LevyStanford Univ.Stanford Univ.NIH LPPGNIH LPPG

Experimental Design

Necrosis Apoptosis

DC

Intratumoral CpG

XRT

T cellDC

DCs migrate to LN

Well-established tumor

Day 0

Tumor Inoculation

(107)

Days 19, 20, 21, 24, and 26

Intratumor CpG (100µg/mouse)

Measure tumor sizeDays 17 and 18 XRT

Necrosis Apoptosis

Well-established tumor

PBS treated A20-bearing m ice

012

3456

78

0 10 20 30 40 50 60 70

Days post-inoculation

Tum

or S

ize

(cm

2)

CpG treated A20-bearing mice

0

1

2

3

4

5

6

7

8

0 10 20 30 40 50 60 70

Days post-inoculation

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ize

(cm

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Radiation treated A20-bearing m ice

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0 10 20 30 40 50 60 70

Days post-inoculation

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CpG and Radiation treated in A20-bearing mice

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1/9 8/10

Treatment of Lymphoma with the Combination of Radiotherapy and Intratumoral Injection of CpG

CpG injection, Days 1 & 2, then weekly x 8

Radiotherapy Days 1 & 2 (2 Gy x 2)

Intratumoral CpG + local RT in CTCLIntratumoral CpG + local RT in CTCL

Expect reduction of radiated tumorExpect reduction of radiated tumor

Assess clinical response of non-Assess clinical response of non-radiated MF lesionsradiated MF lesions

Pre-, during, and post-treatment Pre-, during, and post-treatment blood and tissue studiesblood and tissue studies

Assess clinical responseAssess clinical responseDays 1, 2Days 1, 2

RT 2 Gy x 2RT 2 Gy x 2

In situ vaccination with CpGSummary• Potential for efficacy

• Well-tolerated with acceptable toxicity– Grade 1-2 injection site reaction, flu-like symptoms

IndolentIndolent(MZL/FCL)(MZL/FCL)

AggressiveAggressive(DLBCL leg-type)(DLBCL leg-type)

Solitary / RegionalSolitary / Regional(T1-2)(T1-2)

GeneralizedGeneralized(T3)(T3)

SolitarySolitary(T1)(T1)

MultipleMultiple(T2-3)(T2-3)

• RTRT• ExcisionExcision

• ObservationObservation• RT for sx+ lesionsRT for sx+ lesions• Topical tx Topical tx

- NM, imiq, retinoid- NM, imiq, retinoid• BiologicsBiologics

- Rituximab, IFN, - Rituximab, IFN, retinoidsretinoids

• Chemotherapy:Chemotherapy:Single or CombinationSingle or Combination

• Clinical TrialsClinical Trials

• RT (caution)RT (caution)• R-CHOP R-CHOP ++ IFRT IFRT

• R-CHOP R-CHOP ++ IFRT IFRT• Clinical TrialsClinical Trials

Management of PCBCLManagement of PCBCL

Multidisciplinary Cutaneous Lymphoma Clinic/ProgramMultidisciplinary Cutaneous Lymphoma Clinic/ProgramYoun Kim, Director, Youn Kim, Director, DermatologyDermatologyRichard Hoppe, Co-Director, Richard Hoppe, Co-Director, Radiation OncologyRadiation OncologyRanjana Advani, Sunil Reddy, Ranjana Advani, Sunil Reddy, Medical OncologyMedical OncologySabine Kohler, Uma Sundrum, Sabine Kohler, Uma Sundrum, DermatopathologyDermatopathologySunil Reddy, Anjali Varma-Morales, Sunil Reddy, Anjali Varma-Morales, Cutaneous LymphomaCutaneous Lymphoma FellowsFellowsNatalie Viakhireva, Natalie Viakhireva, Physician AssistantPhysician AssistantKatherine Sutherland, Katherine Sutherland, Research Assistant/Trials AdministratorResearch Assistant/Trials AdministratorStefanie Farmer, Stefanie Farmer, Trials CoordinatorTrials CoordinatorDermatology ResidentsDermatology Residents

Web Site: Web Site: cutaneouslymphoma.stanford.educutaneouslymphoma.stanford.edu