Introduction to Low Grade Lymphomas

Gena PiliotisGena Piliotis

Objectives

Classification of Low Grade LymphomasClassification of Low Grade Lymphomas How to diagnoseHow to diagnose PrognosisPrognosis Treatment optionsTreatment options

Classification

WHO – 2007WHO – 2007

Mature B cellMature B cell Low Grade - Mostly nodalLow Grade - Mostly nodal

Mature T cellMature T cell Low Grade - Mostly Skin Low Grade - Mostly Skin

B Cell Low Grade NHLB Cell Low Grade NHL

B Cell Low Grade Lymphomas

Follicular LymphomaFollicular Lymphoma Grade I, II, IIIGrade I, II, III

Marginal ZoneMarginal Zone Splenic (with villous lymphs)Splenic (with villous lymphs) Extranodal / MALT Extranodal / MALT

• (mucosal associated lymphoid tissue)(mucosal associated lymphoid tissue) Nodal/DisseminatedNodal/Disseminated

Mantle Cell LymphomaMantle Cell Lymphoma Lymphoplasmacytic Lymphoma / WaldenstromsLymphoplasmacytic Lymphoma / Waldenstroms Hairy Cell LeukemiaHairy Cell Leukemia

General Principals All CD 19/20 +All CD 19/20 + All surface immunoglubulin +All surface immunoglubulin + All can have prolonged asymptomatic phaseAll can have prolonged asymptomatic phase Watch and Wait first line therapyWatch and Wait first line therapy Not curableNot curable Median survival 5-10+ yearsMedian survival 5-10+ years Multiple Treatment options availableMultiple Treatment options available Pattern of diminishing returnsPattern of diminishing returns

Immunohistochemistry

1919 2020 SIgSIg 55 1010 2323 2525 4343 103103 FMFMC7C7

FollFoll ++ ++ ++ -- ++ ++ -- -- -- --

MargMarg ++ ++ ++ -- -- -- -- -- -- --

MantlMantl ++ ++ ++ ++ -- -- +/-+/- -- -- ++

HairyHairy ++ ++ +/-+/- -- -- -- ++++ -- ++++ ++

SLLSLL ++ ++ ++ ++ -- ++ -- ++ -- --

LympLymp ++ ++ ++++ -- -- -- -- ++ -- --

Stage – Ann Arbor I - I - Involvement of a single lymph node region or a single Involvement of a single lymph node region or a single

extranodal site.extranodal site.

II -II -Involvement of two or more lymph nodes on the same Involvement of two or more lymph nodes on the same side of the diaphragm or localized involvement of an extra side of the diaphragm or localized involvement of an extra lymphatic organ or site and one or more lymph nodes on lymphatic organ or site and one or more lymph nodes on the same side of the diaphragm.the same side of the diaphragm.

III - III - Involvement of lymph node regions on both sides of Involvement of lymph node regions on both sides of

the diaphragm that may also be accompanied by the diaphragm that may also be accompanied by involvement of the spleen or by localized involvement of an involvement of the spleen or by localized involvement of an extra lymphatic organ or site or both.extra lymphatic organ or site or both.

IV - IV - Diffused or disseminated involvement of one or more Diffused or disseminated involvement of one or more extra lymphatic organs or tissues, with or without extra lymphatic organs or tissues, with or without associated lymph node involvement.associated lymph node involvement.

B - B SymptomsB - B Symptoms E - extranodalE - extranodal

Follicular Lymphoma Most CommonMost Common

25 % of all NHL25 % of all NHL Variable clinical pattern / prognosisVariable clinical pattern / prognosis

Median survival 7-10 yrsMedian survival 7-10 yrs ImmunophenotypeImmunophenotype

CD 19, 20, 10, bcl2, t(14;18)CD 19, 20, 10, bcl2, t(14;18) Histological GradeHistological Grade FLIPI – new international Scoring SystemFLIPI – new international Scoring System

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Kadin, M. ASH Image Bank 2003;2003:100691

Figure 1. Low power view of lymph node showing uniform nodular pattern of neoplastic follicles

Follicular Histologic Grades Based on number of Large cells / hpfBased on number of Large cells / hpf

Grade IGrade I 0-5 centroblasts / hpf0-5 centroblasts / hpf

Grade IIGrade II 6-156-15

Grade IIIGrade III >15>15 IIIa vs IIIbIIIa vs IIIb ? More like DLBCL?? More like DLBCL?

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Kadin, M. ASH Image Bank 2003;2003:100691

Figure 6. follicular lymphoma 1/3 with predominance of centrocytes

International Scoring Systems

IPIIPI Age >60Age >60 Elevated LDHElevated LDH Stage III/IVStage III/IV ECOG >2ECOG >2 > 1 extranodal > 1 extranodal

sitessites

FLIPIFLIPI Age > 60Age > 60 Elevated LDHElevated LDH Stage III/IVStage III/IV > 4 nodal sites > 4 nodal sites Hb < 120Hb < 120

Prognosis - FLIPI 0-1 risk factors0-1 risk factors

5 yr OS = 90.6 %5 yr OS = 90.6 % 10 yr OS = 71 %10 yr OS = 71 %

2 risk factors2 risk factors 5 yr OS = 77.6 %5 yr OS = 77.6 % 10 yr OS = 51 %10 yr OS = 51 %

>= 3 risk factors>= 3 risk factors 5 yr OS = 52.5 %5 yr OS = 52.5 % 10 yr OS = 36 %10 yr OS = 36 %

Treatment Options

Limited Stage I/IILimited Stage I/II

Radiation 3000 – 4000 cGyRadiation 3000 – 4000 cGy40-50 % long term remission40-50 % long term remissionRare to relapse at site of radiationRare to relapse at site of radiation

Treatment Options Advanced Stage DiseaseAdvanced Stage Disease

Watch and WaitWatch and Wait

First lineFirst lineAlkalator based chemoAlkalator based chemo• Chlorambucil, CVPChlorambucil, CVP

Combination therapy with RituxanCombination therapy with Rituxan– Marcus et al, Blood 2005Marcus et al, Blood 2005

• RCVP vs CVP– 32 vs 15 mos PFSRCVP vs CVP– 32 vs 15 mos PFS• Improvements in over all survivalImprovements in over all survival

Add Rituxan to first lineAdd Rituxan to first line

Other Treatment Options

Purine Analogues – FludarabinePurine Analogues – Fludarabine No difference in OS vs CVP first lineNo difference in OS vs CVP first line Minor difference in PFSMinor difference in PFS Less salvageableLess salvageable Use for Second lineUse for Second line

Anthracyclines – CHOPAnthracyclines – CHOP No difference in OS vs CVP first lineNo difference in OS vs CVP first line

Better RR but more toxicBetter RR but more toxic Can only use onceCan only use once ? Transformed patients? Transformed patients Use for Third lineUse for Third line

Other Treatment Options

Maintenance RituximabMaintenance Rituximab Double PFSDouble PFS Emerging evidence to improved OSEmerging evidence to improved OS Multiple regimens in literatureMultiple regimens in literature

375 mg/m375 mg/m2 2 q 3 mos x 2 yearsq 3 mos x 2 years Data mainly from second line regimensData mainly from second line regimens CCO fundingCCO funding

Post first line combo immunochemotherapyPost first line combo immunochemotherapy Within 6 months of chemoWithin 6 months of chemo Q 3 months x 2 yearQ 3 months x 2 year Currently only funded onceCurrently only funded once

Other Treatment Options

InterferonInterferon Consolidative after high dose chemoConsolidative after high dose chemo Need high doses, possible improved PFSNeed high doses, possible improved PFS Side Effects prohibitSide Effects prohibit

Radioimmune Conjugates (anti CD 20)Radioimmune Conjugates (anti CD 20) Bexxar (I-131) Zevalin (Y-90)Bexxar (I-131) Zevalin (Y-90) >= 3>= 3rdrd line line Can respond in Rituxan FailuresCan respond in Rituxan Failures Bystander effectBystander effect Can have better PFS than prior regimenCan have better PFS than prior regimen

Other Treatment Options Autologous Stem Cell transplantAutologous Stem Cell transplant

Not standard of careNot standard of care May improve PFS – but not cureMay improve PFS – but not cure

Allogeneic Stem Cell transplantAllogeneic Stem Cell transplant Possible curative therapyPossible curative therapy Still experimentalStill experimental

Consider if young and high risk diseaseConsider if young and high risk disease FLIPI highFLIPI high Relapsed < 1 yr after first lineRelapsed < 1 yr after first line

Follicular Grade III

? More like DLBCL?? More like DLBCL? Anthracycline up frontAnthracycline up front Grade IIIaGrade IIIa

> 15 centroblasts / hpf> 15 centroblasts / hpf centrocytes still presentcentrocytes still present

Grade IIIbGrade IIIb sheets of centroblastssheets of centroblasts

If behaving more aggressively treat like DLBCLIf behaving more aggressively treat like DLBCL

Marginal Zone Lymphoma 8-10 % of NHL8-10 % of NHL Can be associated with Hepatitis CCan be associated with Hepatitis C ImmunophenotypeImmunophenotype

+ CD 19, 20, SIg+ CD 19, 20, SIg - CD 10, 5, 23- CD 10, 5, 23

SubtypesSubtypes Splenic Lymphoma with/without villous Splenic Lymphoma with/without villous

lymphocyteslymphocytes Extranodal / MALT Extranodal / MALT Nodal with/without monocytoid lymphsNodal with/without monocytoid lymphs

Subtypes Marginal Zone Lymphoma

PFS OS

Splenic Marginal Zone

Rare – 1% NHLRare – 1% NHL Spleen and Bone Marrow involvedSpleen and Bone Marrow involved Hepatitis CHepatitis C Autoimmune CytopeniasAutoimmune Cytopenias

Indolent Disease Indolent Disease Median Survival 8-10 yrsMedian Survival 8-10 yrs

Survival of Splenic Survival of Splenic Marginal zone PatientsMarginal zone Patients

Survival of Splenic Survival of Splenic Marginal zone who Marginal zone who achieve CR vs those achieve CR vs those who don’twho don’t

Figure 2. Survival of patients who obtained complete response (CR) and non- complete response (nCR)

Figure 1. OS and FFS of the whole series

Splenic Marginal Zone Treatment Watch and WaitWatch and Wait

First LineFirst Line SplenectomySplenectomy

Second LineSecond Line Treat like FollicularTreat like Follicular

Extranodal / MALT Mucosal Associated Lymphoid TissueMucosal Associated Lymphoid Tissue 5 % of NHL5 % of NHL

Breast, lung, orbit, GI, GU, Skin, H&NBreast, lung, orbit, GI, GU, Skin, H&N Most common in StomachMost common in Stomach

Chronic antigenic stimulationChronic antigenic stimulation H pyloriH pylori Hepatitis CHepatitis C ChlamydiaChlamydia Borrelia Borrelia

Gastric MALT - Staging

I - I - Tumour confined to GI tract Tumour confined to GI tract single or multiple lesionssingle or multiple lesions

• Endoscopic UltrasoundEndoscopic Ultrasound–Mucosal vs MuscularisMucosal vs Muscularis

II - Tumour extending into abdomenII - Tumour extending into abdomen• IIII11 local perigastric nodes local perigastric nodes• IIII22 distant nodes distant nodes

IIE – Penetrating serosa into adjacent IIE – Penetrating serosa into adjacent organs organs

IV - DisseminatedIV - Disseminated

Gastric Malt

Prognosis Prognosis Indolent DiseaseIndolent Disease Tends to stay localized to stomachTends to stay localized to stomach 5 yr OS 80-90%5 yr OS 80-90%

Figure 4

Figure 5

Gastric Malt - Treatment Localized to StomachLocalized to Stomach

Hpylori eradication aloneHpylori eradication alone60-85 % remissions60-85 % remissionsMay take up to 18 mosMay take up to 18 mos• Need repeated endoscopiesNeed repeated endoscopies

Can consider if low grade lesions confined Can consider if low grade lesions confined to the mucosato the mucosa

Should be offered to all patients in Should be offered to all patients in combinationcombination

H pylori Eradication

Amoxicillin 1gm bid x 10 daysAmoxicillin 1gm bid x 10 days Clarithromycin 250 mg bid x 10 daysClarithromycin 250 mg bid x 10 days Omeprazole 20 mg bid x 10 daysOmeprazole 20 mg bid x 10 days

oror

Bismuth 302 mg qid x 14 daysBismuth 302 mg qid x 14 days Metronidazole 50 mg tid x 14 daysMetronidazole 50 mg tid x 14 days Tetracycline 50 mg qid x 14 daysTetracycline 50 mg qid x 14 days Omeprazole 20 mg bid x 14 daysOmeprazole 20 mg bid x 14 days

Gastric MALT – Treatment

RadiationRadiation 300 cGy in 15 fractions300 cGy in 15 fractions

ChemotherapyChemotherapy If radiation refractoryIf radiation refractory Or disseminatedOr disseminated Treat like follicularTreat like follicular

Non Gastric Extranodal MALT

LocalizedLocalized 2400 cGy in 12 – 3600 cGy in 182400 cGy in 12 – 3600 cGy in 18

DisseminatedDisseminated Treat like FollicularTreat like Follicular

Nodal Marginal +/- monocytoid lymphs

Rare – 1-2 % NHLRare – 1-2 % NHL Prognosis is poorest among subtypesPrognosis is poorest among subtypes

Median Survival 5 yrsMedian Survival 5 yrs Treatment OptionsTreatment Options

Like Follicular LymphomaLike Follicular Lymphoma

Nodal Marginal Zone Lymphoma

Mantle Cell Lymphoma

Behaves like both aggressive and indolentBehaves like both aggressive and indolent Not curable, but aggressive courseNot curable, but aggressive course

More extranodal disease / organ More extranodal disease / organ involvementinvolvement

Blastic PhaseBlastic Phase

Mantle Cell

ImmunophenotypeImmunophenotype + CD 19, 20, 5, 43, FMC7, SIg (IgM/D)+ CD 19, 20, 5, 43, FMC7, SIg (IgM/D) - CD 10, 23- CD 10, 23 t (11:14)t (11:14) Cylcin D1 over-expression / bcl-2 +Cylcin D1 over-expression / bcl-2 +

PrognosisPrognosis Low IPI – Low IPI – 5 yr OS 50%5 yr OS 50% High IPI – High IPI – 5 yr OS 0 %5 yr OS 0 %

Mantle Cell - Treatment Watch and WaitWatch and Wait

Clinical TrialsClinical Trials

Auto SCT has been disappointingAuto SCT has been disappointing

Treat like FollicularTreat like Follicular

Consider Allo SCT if young and high riskConsider Allo SCT if young and high risk

Hairy Cell Leukemia

Rare - <1% of all NHLRare - <1% of all NHL Pancytopenia / SplenomegallyPancytopenia / Splenomegally Circulating atypical cellsCirculating atypical cells ““Dry Tap” – bone marrow fibrosisDry Tap” – bone marrow fibrosis

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Kadin, M. ASH Image Bank 2003;2003:100609

Figure 8. Hairy cell leukemia, peripheral blood - Wright-Giemsa stain - Mononuclear cells with surface membrane projections

Hairy Cell Leukemia ImmunophenotypeImmunophenotype

+ CD 19, 20, 25, 103, FMC7, SIg+ CD 19, 20, 25, 103, FMC7, SIg- CD 10, 5, 23- CD 10, 5, 23

StagingStaging No standard stagingNo standard staging Age > 50 / nodal involvementAge > 50 / nodal involvement

PrognosisPrognosis Favourable, very indolent diseaseFavourable, very indolent disease 5 yr OS > 90 %5 yr OS > 90 %

Hairy Cell - Treatment

Watch and WaitWatch and Wait Hb >100 g/L Neuts > 1.0 Plts > 50Hb >100 g/L Neuts > 1.0 Plts > 50

First Line First Line 2CDA / cladrabine2CDA / cladrabine

7 day continuous / 5 day pulse7 day continuous / 5 day pulseRR >80 %RR >80 %12 yr PFS 54% / OS 87%12 yr PFS 54% / OS 87%

Hairy Cell - Treatment

Second LineSecond Line 2CDA2CDA

RR > 50%RR > 50%

Third LineThird Line SplenectomeySplenectomey InterferonInterferon RituxanRituxan

Lymphoplasmacytic Lymphoma

Rare – 1% NHLRare – 1% NHL Nodal / Spleen / Bone Marrow involvedNodal / Spleen / Bone Marrow involved Monclonal protein – IgMMonclonal protein – IgM HyperviscosityHyperviscosity Autoimmune ComplicationsAutoimmune Complications

AIHA, ITP, vasculitis, cryoglobulinsAIHA, ITP, vasculitis, cryoglobulins

Lymphoplasmacytic

ImmunophenotypeImmunophenotype + CD 19, 20, 22, 38, 79a, SIg (IgM)+ CD 19, 20, 22, 38, 79a, SIg (IgM) - CD 23, 10, 5- CD 23, 10, 5

MorphologyMorphology Mature lymphocytesMature lymphocytes Plasmacytoid featuresPlasmacytoid features

Lymphoplasmacytic Staging Staging

Use Ann Arbor – but not as helpfulUse Ann Arbor – but not as helpful

Poor Prognostic FeaturesPoor Prognostic Features Age > 60Age > 60 MaleMale Hb <110Hb <110 IgM > 40IgM > 40 High Beta 2 microglobulinHigh Beta 2 microglobulin Low albumenLow albumen

Lymphoplasmacytic

Scoring Prognosis (1 point each)Scoring Prognosis (1 point each) Age >65Age >65 Albumen <40Albumen <40 At least 1 cytopeniaAt least 1 cytopenia At least 2 cytopeniaAt least 2 cytopenia

Low Low (0/1)(0/1) 5yr OS 83%5yr OS 83% Interm Interm (2)(2) 5yr OS 62%5yr OS 62% High High (3/4)(3/4) 5yr OS 25%5yr OS 25%

Lymphoplasmacytic Watch and WaitWatch and Wait

First lineFirst line Like FollicularLike Follicular

Plasma exchangePlasma exchange HyperviscocityHyperviscocity NeuropathyNeuropathy

Autologous Stem Cell TransplantAutologous Stem Cell Transplant Allogenic Stem Cell TransplantAllogenic Stem Cell Transplant