Douglas E. Gladstone, MD - 61st Annual Scientific Meeting

Classification Diagnostic Tools andTreatment of Non‐Hodgkin LymphomaAmerican Society of Cytopathology59 th Annual Scientific Meeting2011Douglas E. Gladstone, MDClinical Director IPOPAssociate Professor of OncologySidney Kimmel Comprehensive Cancer Centerat Johns Hopkins

• NoneDisclosures

Characteristics and GradeLow GradeIndolentHigh GradeAggressiveRelatively long survival Short survival withouttherapyNondestructive growth Destructive growthNo cellular atypia Cellular atypiaRespect privileged Invade privileged sitessitesRegulatory influences AutonomousFail to grow in culture Immortalized in culture

Goal of this Talk•To request a new NHL classification systembased on cancer biology•Three malignant conditions:•Diffuse large B cell•Mantle Cell• Chronic Lymphocytic Leukemia

Diffuse Large B cell lymphomaIs there an important clinicalsubdivision?

Diffuse Large B cell Lymphoma• Classification based on histology and IHC•Germinal center (GCB)•Activated B‐cell (ABC)

GC DLBCL & ABC DLBCL by IHCHans et al, Blood 2004

GC vs ABCClinical OutcomesAlizedah AA et, Nature 2000

Rituximab & GC vs ABCrituximab improves survival of both subtypesFu, K et al 2008, JCO

GC vs ABC subsetCORAL Trial of RICE v DHAP•Which salvage regimen is the best?RAR‐ICE x 3SD/POD → OffCD20+ DLBCLRelapsed/RefractoryN→DOMIZER‐DHAP x 3A BS EC AT MPR/CR →RANDOMR x 6IZObsEN=249•Place of immunotherapy post transplantation?

Coral: COllaborative trial inRelapsed Aggressive LymphomaGC vs ABC•Patients treated with GC DLBCL have anmarginally improved outcome when treatedwith R‐DHAP Thieblemont et 2011 JCOGisselbrecht et al, 2010 JCO

Low Grade LymphomasAre there an important clinicalsubdivisions?

Mantle Cell Lymphoma• DiagnosisJust another low grade lymphoma?• Flow Cytometry: CD5+, CD20+, CD23‐• Genetics– cyclin D1 positive– BCL‐1 positive– T(11,14)• Relatively short survival (high grade paradigm)• Incurable with chemotherapy (low gradeparadigm)

Immunoglobulin Heavy ChainVariable Region Mutational Status• Somatic hypermutation (SHM) of Ig• Diversification: turning a naïve B cell to ahigh‐affinity antibody producer• SHM is thought to occur in the germinalcenter after antigen stimulation• often dependent on T cells

Mantle Cell LymphomaImmunoglobulin Heavy Chain Variable Region Mutational Status• IGHV mutational status in MCL is oftenUNMUTATED• This may explain the variable clinicaloutcomes in these patientsAgathangelidis et al, 2011 Sem Cancer Bio

Chronic Lymphocytic Leukemia• Stage Rai0: lymphocytosis (L)I: (L) + nodesII: (L) + spleen or liverIII: (L) + anemiaIV: (L) + low PLT• Flow Cytometry– CD 5+, CD20+, CD 23+

Chronic Lymphocytic LeukemiaPrognosis: Background• Clinical correlates• Stage• WBC doubling time• Marrow histology

Chronic Lymphocytic Leukemia• Interphase FISHPrognosis: Background• Immunoglobulin variable region heavy chain (IGHV)mutational status• CD38• ZAP 70

IGHV Mutational Status isPrognostic in del(13q) CLL• Studied 79 patientsHopkins Experience• 196 cases of CLL (2004‐2010)• 79 (40%) had FISH and IGHV• Follow‐up 4.5 (range: 0‐22) yearsGladstone et al, 2011 Leuk Lymphoma

79 patientsIGHV Mutational Status isPrognostic in del(13q) CLLHopkins Experience38 (48%)Unmutated41 (52%)Mutated13 (34%)del(13q) only34 (83%)del(13q) only• Unmutated IGHV sequences occur 50% of thetime• The majority of patients with del (13q) onlydisease will have a mutated sequenceGladstone et al, 2011 Leuk Lymphoma

IGHV Mutational Status is Prognosticin del(13q) CLLProgression to Advanced DiseaseGladstone et al, 2011 Leuk Lymphoma

IGHV Mutational Status is Prognosticin del(13q) CLLLikelihood of Receiving TreatmentGladstone et al, 2011 Leuk Lymphoma

IGHV Mutational Status is Prognosticin del(13q) CLLOverall SurvivalGladstone et al, 2011 Leuk Lymphoma

IGHV Mutational Status is Prognosticin del(17p)/del (11q) CLL• Studied 66 patientsHopkins Experience• Screened 159 cases of CLL with a resultant IGHVsequence (2006‐2011)• 66 (41%) del(11q)/del(17p)• Follow‐up 3.1 (range: 0.1‐19.4) yearsUnpublished data

IGHV Mutational Status is Prognosticin del(17p)/del (11q) CLLHopkins Experience66 high riskpatients50 (76%)Unmutated16 (24%)Mutated• In high‐risk cytogenetic groups an UnmutatedIGHV sequence is much more frequentUnpublished data

IGHV Mutational Status is Prognosticin del(17p)/del (11q) CLLUnpublished Data

IGVH Mutational Status andthe CLL Cancer StemCD19CLL with chromosomal aberrations and known IGVHmutational statusPatient #1Mutated ‐13qPatient #2Unmutated ‐13q‐11q+12CD34Unmutated CLL: verysmall 34 + 19 pos/dimpopulationMutated CLL: notpresent34 + 19 pos

Where we are

Leukemia and Lymphoma• Cancer of white blood cells– Lymphoma• When they get caught up in the lymph nodes– Leukemia• When they freely circulate in the blood stream

Where I Hope We Go

Classification Based on the Originof the Cancer Stem Cell• Unmutated CLL• Unmutated MCL•Mutated CLL•Mutated MCL•GC DLBCLPre‐GerminalGerminalunnamedPostGerminal•Pre B cell ALL• Burkitts•DLBCL• MultipleMyeloma