Introduction to Low Grade Lymphomas Gena Piliotis.
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Transcript of Introduction to Low Grade Lymphomas Gena Piliotis.
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