HIV RELATED LYMPHOMAHIV RELATED LYMPHOMA

Dr Martin RowlandsDr Martin RowlandsNorth Manchester General HospitalNorth Manchester General Hospital

First description of high grade NHL in 90 First description of high grade NHL in 90 homosexual men with AIDS in 1984.homosexual men with AIDS in 1984.

Aggressive B cell lymphoma classified as AIDS Aggressive B cell lymphoma classified as AIDS defining illness in 1985.defining illness in 1985.

Lymphoma second most common cancer Lymphoma second most common cancer associated with HIV infection.associated with HIV infection.

Relative risk of developing lymphoma within 3 Relative risk of developing lymphoma within 3 years of HIV diagnosis is increased by 165 fold years of HIV diagnosis is increased by 165 fold compared with people without HIV infection.compared with people without HIV infection.

Risk 652 fold for diffuse immunoblastic lymphomas.Risk 652 fold for diffuse immunoblastic lymphomas.

3600 fold for primary CNS lymphomas.3600 fold for primary CNS lymphomas.

1000 fold for Burkitt lymphomas.1000 fold for Burkitt lymphomas.

113 fold for intermediate grade Non Hodgkins 113 fold for intermediate grade Non Hodgkins lymphomas.lymphomas.

14 fold for low grade Non Hodgkins lymphomas.14 fold for low grade Non Hodgkins lymphomas.

Risk of Hodgkins Disease increased 5 to 15 fold Risk of Hodgkins Disease increased 5 to 15 fold (x10).(x10).

SPECTRUM OF HIV ASSOCIATED LYMPHOMASSPECTRUM OF HIV ASSOCIATED LYMPHOMAS

1.Lymphomas also occurring in immunocompetent:1.Lymphomas also occurring in immunocompetent:

Burkitt lymphoma: Classical Burkitt lymphoma: Classical

Plasmacytoid differentiation.Plasmacytoid differentiation.

Diffuse large B cell lymphoma: CentroblasticDiffuse large B cell lymphoma: Centroblastic ImmunoblasticImmunoblastic

Extranodal marginal zone lymphomasExtranodal marginal zone lymphomas

Peripheral T cell lymphomas :AnaplasticPeripheral T cell lymphomas :Anaplastic NOSNOS

Classical Hodgkins lymphoma.Classical Hodgkins lymphoma.

LYMPHOMAS SPECIFIC TO HIV INFECTION.LYMPHOMAS SPECIFIC TO HIV INFECTION.

Primary effusion lymphomas : Effusion onlyPrimary effusion lymphomas : Effusion only

Solid extracavitatorySolid extracavitatory

Plasmablastic lymphomas : Oral cavityPlasmablastic lymphomas : Oral cavity

SystemicSystemic

OTHER: Multicentric Castlemans Disease (plasma cell Multicentric Castlemans Disease (plasma cell

variant).variant).

CD4 ( T helper ) cell is specifically infected and lysed CD4 ( T helper ) cell is specifically infected and lysed by HIV.by HIV.

CD4 count is used as a measure of CD4 count is used as a measure of immunocompetence.immunocompetence.

Normal CD4 count 500-1500 x 10Normal CD4 count 500-1500 x 106 6 / L./ L. HAART usually started when CD4 < 350HAART usually started when CD4 < 350 Increasing opportunistic infections and malignancies Increasing opportunistic infections and malignancies

as CD4 as CD4

count falls ( particularly <100)count falls ( particularly <100)

HIV viral load measure ( PCR) of HIV viraemia.HIV viral load measure ( PCR) of HIV viraemia.

Usual aim of HAART is undetectable viral load and Usual aim of HAART is undetectable viral load and increase in CD4 count.increase in CD4 count.

OVERVIEW OF LYMPHOMAGENESISOVERVIEW OF LYMPHOMAGENESIS

Defect of immune surveillance i.e reduced CD4 Defect of immune surveillance i.e reduced CD4 count. This is a particular feature of DLBC and count. This is a particular feature of DLBC and Primary CNS lymphomas whose incidence increases Primary CNS lymphomas whose incidence increases as CD4 count falls.as CD4 count falls.

The incidence of Burkitt lymphoma and Hodgkins The incidence of Burkitt lymphoma and Hodgkins disease is little affected by CD4 count.disease is little affected by CD4 count.

Chronic immune stimulation either by HIV or other Chronic immune stimulation either by HIV or other pathogens. pathogens.

B cell dysregulation (Igs,cytokines)B cell dysregulation (Igs,cytokines)

Other viruses: EBV in DLBC,HD,Plasmablastic Other viruses: EBV in DLBC,HD,Plasmablastic lymphoma,Hodgkins disease.lymphoma,Hodgkins disease.

HHV-8 in Primary effusion lymphoma and HHV-8 in Primary effusion lymphoma and Castlemans disease.Castlemans disease.

(Lymphomas seen with particularly low CD4 counts).(Lymphomas seen with particularly low CD4 counts).

THE EFFECT OF HAARTTHE EFFECT OF HAART

Significant reduction in the incidence of DLBC Significant reduction in the incidence of DLBC (immunoblastic) and Primary CNS lymphoma since (immunoblastic) and Primary CNS lymphoma since the introduction of effective HAART.the introduction of effective HAART.

No change / proportional increase in incidence of No change / proportional increase in incidence of Burkitt lymphoma and Hodgkins disease which are Burkitt lymphoma and Hodgkins disease which are largely unrelated to CD4 count.largely unrelated to CD4 count.

Differential Diagnoses:Differential Diagnoses:

Tuberculosis.Tuberculosis.

Other malignancies.Other malignancies.

Immune reconstitution syndromes.Immune reconstitution syndromes.

Toxoplasmosis.Toxoplasmosis.

Features of clinical presentation in HIV lymphoma.Features of clinical presentation in HIV lymphoma.

Usually present at advanced stage with B Usually present at advanced stage with B symptoms.symptoms.

Extranodal disease common i.e. G.I.tractExtranodal disease common i.e. G.I.tract

Marrow and meningeal involvement more common.Marrow and meningeal involvement more common.

Both Hodgkins and Non Hodgkins lymphomas Both Hodgkins and Non Hodgkins lymphomas behave with more aggressive course.behave with more aggressive course.

PRETREATMENT INVESTIGATIONS:PRETREATMENT INVESTIGATIONS: FBC, Renal and liver function, LDH, urate, IgGS.FBC, Renal and liver function, LDH, urate, IgGS. Histology review.Histology review. Marrow aspirate+trephine (cytogenetics, Marrow aspirate+trephine (cytogenetics,

immunology)immunology) CD4 , HIV viral load.CD4 , HIV viral load. CT Scans. (MR Brain)CT Scans. (MR Brain) (PET scan )(PET scan ) Echo / LVEFEcho / LVEF

CMV,Hep B+C,Toxoplasma serologyCMV,Hep B+C,Toxoplasma serology MAI screen.MAI screen.

LP for CSF cytology +/- intrathecal Rx. (DLBC ,LP for CSF cytology +/- intrathecal Rx. (DLBC ,

Burkitt,Plasmablastic).Burkitt,Plasmablastic).

TREATMENT (general)TREATMENT (general)

HAART (avoid AZT,didanosine)HAART (avoid AZT,didanosine) HydrationHydration Allopurinol / Rasburicase.Allopurinol / Rasburicase.

Septrin / DapsoneSeptrin / Dapsone AciclovirAciclovir FluconazoleFluconazole Azithromycin ( CD4 count <100)Azithromycin ( CD4 count <100)

NutritionNutrition CMV PCR monitoring. ( CD4 count <100)CMV PCR monitoring. ( CD4 count <100) Growth factor support.Growth factor support.

Complicating Factors:Complicating Factors:

Co-Infections:Co-Infections:

Hepatitis BHepatitis B

Hepatitis CHepatitis C

TuberculosisTuberculosis

Mycobacterium avium intracellulare (MAI)Mycobacterium avium intracellulare (MAI)

Pneumocystis.Pneumocystis.

Psychological / SocialPsychological / Social

““Double diagnosis” at presentationDouble diagnosis” at presentation

Family issuesFamily issues

Drug abuse.Drug abuse.

DLBC NHLDLBC NHL Pre HAART poor outcomes .Median survival 5-Pre HAART poor outcomes .Median survival 5-

6mnths.6mnths.

HAART era :HAART era : CHOP+Rituximab CR 58% CHOP+Rituximab CR 58%

CDE-R CR 70% CDE-R CR 70%

DA-EPOCH-R CR 73%DA-EPOCH-R CR 73%

Caution in use Rituximab at CD4 counts <50.Caution in use Rituximab at CD4 counts <50.

CNS prophylaxis required.CNS prophylaxis required.

In good performance relapsed patients HDT + PBSC In good performance relapsed patients HDT + PBSC is a viable option.is a viable option.

PRIMARY CNS LYMPHOMAPRIMARY CNS LYMPHOMA Typically occurs with marked immunosuppression Typically occurs with marked immunosuppression

CD4<50.CD4<50. Marked reduction in incidence post HAART.Marked reduction in incidence post HAART.

Always EBV positive DLBC NHL.Always EBV positive DLBC NHL. Commonly multifocal brain lesions.Commonly multifocal brain lesions.

High dose methotrexate ivHigh dose methotrexate iv Followed by brain XRT.Followed by brain XRT.

Poor prognosis survival months to 1-2 years.Poor prognosis survival months to 1-2 years.

BURKITT LYMPHOMABURKITT LYMPHOMA

Poor response to CHOP type chemotherapy.Poor response to CHOP type chemotherapy.

Very good results with :Very good results with : R-CODOX-M / R-IVAC x 4 Courses.R-CODOX-M / R-IVAC x 4 Courses. (R-HyperCVAD / R-HDMTX/Cytarabine x 6)(R-HyperCVAD / R-HDMTX/Cytarabine x 6) DA-EPOCH-RDA-EPOCH-R

CNS disease potentially curable.CNS disease potentially curable.

HODGKINS DISEASE.HODGKINS DISEASE. More aggressive histologies common.More aggressive histologies common. Usually advanced disease at presentation.Usually advanced disease at presentation. Bone marrow involvement approx.40%Bone marrow involvement approx.40%

Localised disease ( 1A ) ABVD x3 + XRT.Localised disease ( 1A ) ABVD x3 + XRT.

Advanced Disease ABVD X 6-8Advanced Disease ABVD X 6-8

Favourable outcome in Post HAART era.Favourable outcome in Post HAART era.

PLASMABLASTIC LYMPHOMAPLASMABLASTIC LYMPHOMA

Aggressive disease.Aggressive disease. Characteristically presents with oral cavity mass. Characteristically presents with oral cavity mass.

Systemic forms occur Systemic forms occur No standard treatmentNo standard treatment Poor responses to CHOP like treatments.Poor responses to CHOP like treatments. Increasing evidence of good responses to more Increasing evidence of good responses to more

intensive treatments such as: HyperCVAD / HD intensive treatments such as: HyperCVAD / HD MTX / CytarabineMTX / Cytarabine

CODOX-M / IVACCODOX-M / IVAC

EPOCHEPOCH

PRIMARY EFFUSION LYMPHOMAPRIMARY EFFUSION LYMPHOMA

Associated with HHV8 +/- EBVAssociated with HHV8 +/- EBV Usually presents with pleural,pericardial effusions Usually presents with pleural,pericardial effusions

or ascites without mass lesions.or ascites without mass lesions. May relapse with extrcavitatory form.May relapse with extrcavitatory form. No standard treatment.No standard treatment. CHOP type therapies +/- Rituximab if CD20 +ve.CHOP type therapies +/- Rituximab if CD20 +ve. Prognosis generally poor.Median survival Prognosis generally poor.Median survival

<6mnths.<6mnths.

MULTICENTRIC CASTLEMAN’S DISEASE.MULTICENTRIC CASTLEMAN’S DISEASE.

Commonly presents with Commonly presents with lymphadenopathy,effusions and marked lymphadenopathy,effusions and marked constitutional symptoms +/- haemolysis.constitutional symptoms +/- haemolysis.

SStandard treatment now Rituximab X 4tandard treatment now Rituximab X 4

Prone to relapse / progression to NHL.Prone to relapse / progression to NHL.

Commonly ( approx 30%) occur with Kaposi Commonly ( approx 30%) occur with Kaposi sarcomasarcoma

Use HHV-8 PCR to monitor for early relapse.Use HHV-8 PCR to monitor for early relapse.