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 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;105:37683768--8585

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%

PCMZLPCMZL

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%

PCFCL, PCFCL, follicular patternfollicular pattern

PCFCL, PCFCL, mixed patternmixed pattern

PCFCL, PCFCL, diffuse patterndiffuse pattern

PCFCL,PCFCL,

SpindleSpindle--cell variantcell variant

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

DLBCL DLBCL legleg--typetype

DLBCL legDLBCL leg--type,type,

leg or nonleg or non--leg locationleg location

PCBCL, Stanford Experience, n = 138

Follicle Center Lymphoma

(n=80)

Marginal Zone Lymphoma

(n=49)

Diffuse Large Cell Lymphoma-leg type

(n=9)Age median 52(17-88) 48(15 -80) 70(41-90)

% Male/Female 69/31 61/39 66/34

% Generalized 26 20 33

DSS, 5-year 95% 100% 33%

RFS, 5-year 48% 38% 17%

Sites for localized disease

H/N 53%

Arm 12%

Torso 27%

H/N 31%

Arms 34%

Torso 26%

Leg 5

Arm 1

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 patientsWillemze, Willemze, CurrCurr Op Op OncolOncol, 2006, 2006

Differential gene expression patterns, Differential gene expression patterns, PCFCL vs. DLBCL legPCFCL vs. DLBCL leg--type type HoefnagelHoefnagel et al, Blood 2005et 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– Assessing clonality using the newer BIOMED-2 PCR methods can

increase sensitivity and specificity (Morales et al, ASH abstract #2623, 2007)

Clinical suspicion of CBCLClinical suspicion of CBCL

Morphology/Morphology/immunophenotyeimmunophenotye

Not diagnostic of CBCL, Not diagnostic of CBCL, clinical suspicion highclinical suspicion highCBCLCBCL

IGHIGH and and IGKIGK BIOMEDBIOMED--2 PCR, 2 PCR, preferably on > 1 sitepreferably on > 1 site

Follow clinically, periodic Follow clinically, periodic biopsies as indicatedbiopsies as indicatedCBCLCBCL

Utility of BIOMEDUtility of BIOMED--2 PCR 2 PCR ClonalityClonality Assays in CBCL DiagnosisAssays in CBCL Diagnosis

classic morphology +/classic morphology +/--light chain restriction light chain restriction

PCR+PCR+ PCRPCR--

Skin biopsySkin biopsy

MZMZ--type CBCL, type CBCL, atypical presentation, atypical presentation, epidermotropicepidermotropic pattern, pattern, misdiagnosed as CTCLmisdiagnosed as CTCL

Blood 2007 110:479Blood 2007 110:479--484484

TNMB/staging system for MF/SS or nonTNMB/staging system for MF/SS or non--skin skin NHLsNHLs is is notnot applicableapplicable

Blood 2007;110: 479Blood 2007;110: 479--484484

Purely anatomic;Purely anatomic;

No stage No stage groupings;groupings;

1 system for all cut 1 system for all cut lymphomas;lymphomas;

To help To help describe/track describe/track dzdz, , improve improve management & management & communicationcommunication

Proposed T Classification

• Extent and distribution of primary cutaneous involvement

T1 solitary skin involvement

T2 regional skin involvement

T3 generalized skin involvement

Circular area (vs. square) may be more biologic and relevant to RT calculations

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

Proposed T-Classification

T1 solitary skin lesions:

T1a solitary lesion < 5 cm diameter

T1b solitary lesion > 5 cm diameter

Intended for single discrete tumor without morphologic appearance of coalescence (merging of >1 lesion)

Document body region involved, any special morphologic features such as ulceration (body region chart)

AAA BBB

Fig. 2Fig. 2Fig. 2

CD30+ ALCL, CD30+ ALCL, << 5 cm, 5 cm, T1aT1a NK/TNK/T--cell, > 5 cm, cell, > 5 cm, T1bT1b

Blood 2007;110:479Blood 2007;110:479--484484

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 nonBody regions in non--MF/SS TMF/SS T--classificationclassification

Proposed T-Classification

T2 regional skin involvement categoriesMultiple lesions limited to 1 body region or 2 contiguous body regions

T2a all dz encompassing in a < 15 cm diameter circular area

T2b all dz encompassing in a > 15, < 30 cm diameter circular area

T2c all dz encompassing in a > 30 cm diameter circular area

Intended to describe skin presentations where the tumors are confined in 1 or 2 contiguous body regions, whereas “T3” is intended for skin presentations that are more generalized

Morphology can be either discrete/separate or clustered/grouped/coalescent

Document body region(s) involved

CC

AA

BB

Fig. 3Fig. 3Fig. 3

CD30+ ALCLCD30+ ALCL

FCLFCL

DLBCL, legDLBCL, leg

Blood 2007;110:479Blood 2007;110:479--484484

T2a, T2a,

RegionalRegional

<<15 cm circular area15 cm circular area

BB

CCAA

Fig. 4Fig. 4Fig. 4

DLBCLDLBCL--legleg

FCLFCL

FCLFCL

T2b, T2b,

Regional, Regional,

>15 cm, >15 cm, <<30 cm30 cm

Blood Blood 2007;110:2007;110:479479--484484

AAA

CCC

Fig. 5Fig. 5Fig. 5

BBB

T2c,T2c,

Regional,Regional,

> 30 cm> 30 cmDLBCLDLBCL--legleg

FCLFCL

DLBCLDLBCL--legleg--typetype

Blood Blood 2007;110:2007;110:479479--484484

Proposed T-Classification

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

T3a multiple lesions involving 2 non-contiguous body regions

T3b multiple lesions involving > 3 body regions

T3 designation is intended for skin presentations that are more generalized than T2 (regional categories) with either extensive (3 or more regions) or distant (2 non-contiguous regions) skin involvement

Morphology can be either discrete/separate or clustered/grouped/coalescent

Document body region(s) involved

AAA BBBFig. 6Fig. 6Fig. 6

T3aT3a, 2 non, 2 non--contiguous regions, FCLcontiguous regions, FCL T3bT3b, , >> 3 regions, CD30+ ALCL3 regions, CD30+ ALCL

Blood 2007;110:479Blood 2007;110:479--484484

ISCL/EORTC Recommendations for Staging Evaluation in Cutaneous Lymphomas other than MF/SS, Blood 2007;110:479Blood 2007;110:479--484484

• Complete history/ROS and physical examination

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

• Imaging studies– CT chest, abdomen & pelvis w/ contrast alone or with whole body

FDG-PET; include CT or U/S of neck if indicated– Whole body integrated PET/CT (alternative to contrast-enhanced CT)

LNs > 1.0 cm in short axis and /or have significantly increased PETactivity 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, Blood 2007;110:479Blood 2007;110:479--484484

• 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

• Additional studies as clinically indicated

Updates in Management

• NCCN practice guidelines for CBCL, work in progress

IndolentIndolent(MZL/FCL)(MZL/FCL)

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

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

GeneralizedGeneralized(T3)(T3)

SolitarySolitary(T1)(T1)

MultipleMultiple(T2(T2--3)3)

•• ObservationObservation•• RTRT•• ExcisionExcision•• Topical Topical txtx

-- NM, NM, imiqimiq, , retinoidretinoid

•• Clinical TrialsClinical Trials

•• ObservationObservation•• RT for RT for sxsx+ lesions+ lesions•• Topical Topical txtx

-- NM, NM, imiqimiq, retinoid, retinoid•• BiologicsBiologics

-- RituximabRituximab, IFN, , IFN, retinoidsretinoids

•• Chemotherapy:Chemotherapy:Single or CombinationSingle or Combination

•• Clinical TrialsClinical Trials

•• RT (caution)RT (caution)•• RR--CHOP CHOP ++ IFRTIFRT•• Clinical TrialsClinical Trials

•• RR--CHOP CHOP ++ IFRTIFRT•• Clinical TrialsClinical Trials

Management of PCBCLManagement of PCBCL

Rituximab, 2007 marked 10th anniversary of FDA approval

• Chimeric anti-CD20 MAb (IgG1)

• MOA via ADCC, CDC, apoptosis

• May synergize or add to activity of chemotherapy

• Minimal toxicity

• Well established effectiveness in nodal BCL (375 mg/m2 q wk x 4)

• Limited publication in cutaneous BCLs, though great responses are seen

• Role of maintenance therapy in CBCL is unknown (?375 mg/m2 q 12wks x 2 yrs)

• Rituximab resistance, innate and acquired

– Strategies to overcome resistance

B cell

CD 20

Beyond rituximab, new MAb in clinical studies

• Novel anti-CD20 MAbs– Higher affinity for FcγRIIIa– Lower immunogenecity (fully human or humanized)

• Targets other than CD20– Anti-CD22 MAb (epratuzumab)– Anti-CD40 MAb (SGN40, HCD122)– Anti-CD80 MAb (galiximab)– Anti-HLA-DR MAb (apolizumab)– Anti-idiotype MAb

• Immunoconjugates– I-131 tositumomab (Bexxar), Y-90 ibritumomab tiuxetan (Zevalin)

Cutaneous B-cell LymphomaOther emerging new/novel therapies

• Gene delivery-based immunotherapy– Adenovirus-interferon-γ gene transfer (TG1042, Transgene)

• Vaccination strategies– In situ vaccination using intra-tumoral CpG + low-dose RT

• Inhibition of signal transduction pathways– Tyrosine kinase inhibitors (R406 - Syk kinase inhibitor)– Protein kinase C inhibitors (enzastaurin – PKC β inhibitor)

Cutaneous B-cell Lymphoma (CBCL)Emerging 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-Lesional Administration of TG1042 (Ad IFN-γ) in Patients with Relapsing Primary CBCL

• MZL, FCL (DLBCL leg-type excluded)

• Intra-tumoral injection (max 6 tumors) d1, d8, d15 (off d22) = 1 cycle, up to 4 cycles– 5 x 1010 vp pf TG 1042 per lesion each treatment

• Study endpoints– Primary efficacy: local response (response of injected/treated lesions)– Secondary efficacy: global/systemic response, DOR, TTP, QOL– Safety

• Participating centers – Europe: Zürich, Nantes, Créteil, Montpellier, Belgrade– US: Stanford, Chicago (NW), Houston (MD Anderson)

Phase II Clinical Trial of Intra-Lesional Administration of TG1042 (Ad IFN-γ) in Patients with Relapsing Primary CBCL

Preliminary results

• 9 pts enrolled, 8 pts treated (only 4 completed study thus far)

• Interim efficacy results– 4 local clinical responses (2 CR, 2 PR)– 1 distant, systemic response (CR after only 2 cycles)– 4 pending response data

• Interim safety data– Mostly Gr 1-2 injection site, flu-like symptoms– No sig. laboratory AEs– No SAEs

• Zürich, PCMZL, before and after TG1042 treatment:

TG1042.01: Efficacy results

at baseline visitafter 2 cycles = 6 injections

at day 29 visit

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 mice

012345678

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

Tum

or S

ize

(cm

2)

Radiation treated A20-bearing mice

012345678

0 10 20 30 40 50 60 70

Days post-inoculation

Tum

or S

ize

(cm

2)

CpG and Radiation treated in A20-bearing mice

012345678

0 10 20 30 40 50 60 70

Days post-inoculation

Tum

or S

ize

(cm

2)

0/7 2/9

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)

IntratumoralIntratumoral CpGCpG + local RT in CBCL+ local RT in CBCL

Expect reduction of radiated tumorExpect reduction of radiated tumor

Assess clinical response of nonAssess clinical response of non--radiated CBCL lesionsradiated CBCL lesions

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

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

RT 2 RT 2 GyGy x 2x 2

Screening Week #7

RT+CpG immunization site on chest

CBCL, MZCBCL, MZ--type (failed type (failed rituximabrituximab, CHOP, RT), CHOP, RT)

Evaluation SiteEvaluation Site

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(DLBCL leg--type)type)

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

GeneralizedGeneralized(T3)(T3)

SolitarySolitary(T1)(T1)

MultipleMultiple(T2(T2--3)3)

•• ObservationObservation•• RTRT•• ExcisionExcision•• Clinical TrialsClinical Trials

•• ObservationObservation•• RT for RT for sxsx+ lesions+ lesions•• Topical Topical txtx

-- NM, NM, imiqimiq, retinoid, retinoid•• BiologicsBiologics

-- RituximabRituximab, IFN, , IFN, retinoidsretinoids

•• Chemotherapy:Chemotherapy:Single or CombinationSingle or Combination

•• Clinical TrialsClinical Trials

•• RT (caution)RT (caution)•• RR--CHOP CHOP ++ IFRTIFRT•• Clinical TrialsClinical Trials

•• RR--CHOP CHOP ++ IFRTIFRT•• Clinical TrialsClinical Trials

Management of PCBCLManagement of PCBCL

Stanford Multidisciplinary Cutaneous Lymphoma Clinic/ProgramStanford Multidisciplinary Cutaneous Lymphoma Clinic/ProgramYoun Kim, Director, Youn Kim, Director, DermatologyDermatologyRichard Hoppe, CoRichard Hoppe, Co--Director, Director, Radiation OncologyRadiation OncologyRanjana Advani, Sunil Reddy, Ranjana Advani, Sunil Reddy, Medical OncologyMedical OncologySabine Kohler, Uma Sabine Kohler, Uma SundrumSundrum, , DermatopathologyDermatopathologyAnjali VarmaAnjali Varma--Morales, Daniel Navi, Morales, Daniel Navi, Cutaneous LymphomaCutaneous Lymphoma FellowsFellowsNatalie Viakhireva, Natalie Viakhireva, Physician AssistantPhysician AssistantKatherine Sutherland, Katherine Sutherland, Clinical Trials Medical AssistantClinical Trials Medical AssistantEkk Phixitxonh, Ekk Phixitxonh, Trials AdministratorTrials AdministratorDermatology and Radiation Oncology ResidentsDermatology and Radiation Oncology Residents

Website: Website: cutaneouslymphoma.stanford.educutaneouslymphoma.stanford.edu (handouts here!)(handouts here!)