management updates in cbcl - stanford...
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Management Updates in CBCL
Youn H. KimDepartment of Dermatology
Multidisciplinary Cutaneous Lymphoma GroupStanford Comprehensive Cancer Center
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Disclosure of Conflicts of Interest
Youn H. Kim, M.D.
Management Updates in CBCL
Investigator in clinical trials supported by Transgene
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Management Update in CBCL
Handout will be available next week at web site:cutaneouslymphoma.stanford.edu
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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
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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%
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PCMZLPCMZL
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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%
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PCFCL, PCFCL, follicular patternfollicular pattern
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PCFCL, PCFCL, mixed patternmixed pattern
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PCFCL, PCFCL, diffuse patterndiffuse pattern
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PCFCL,PCFCL,
SpindleSpindle--cell variantcell variant
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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
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DLBCL DLBCL legleg--typetype
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DLBCL legDLBCL leg--type,type,
leg or nonleg or non--leg locationleg location
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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
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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
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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)
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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
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MZMZ--type CBCL, type CBCL, atypical presentation, atypical presentation, epidermotropicepidermotropic pattern, pattern, misdiagnosed as CTCLmisdiagnosed as CTCL
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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Updates in Management
• NCCN practice guidelines for CBCL, work in progress
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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
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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
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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)
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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)
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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
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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)
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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)
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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
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• Zürich, PCMZL, before and after TG1042 treatment:
TG1042.01: Efficacy results
at baseline visitafter 2 cycles = 6 injections
at day 29 visit
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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
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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
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PBS treated A20-bearing mice
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Days post-inoculation
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or S
ize
(cm
2)
CpG treated A20-bearing mice
0
1
2
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4
5
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7
8
0 10 20 30 40 50 60 70
Days post-inoculation
Tum
or S
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Radiation treated A20-bearing mice
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0 10 20 30 40 50 60 70
Days post-inoculation
Tum
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CpG and Radiation treated in A20-bearing mice
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0/7 2/9
1/9 8/10
Treatment of Lymphoma with the Combination of Radiotherapy and Intratumoral Injection of CpG
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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
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Screening Week #7
RT+CpG immunization site on chest
CBCL, MZCBCL, MZ--type (failed type (failed rituximabrituximab, CHOP, RT), CHOP, RT)
Evaluation SiteEvaluation Site
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In situ vaccination with CpGSummary• Potential for efficacy
• Well-tolerated with acceptable toxicity– Grade 1-2 injection site reaction, flu-like symptoms
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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
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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!)