Non Hodgkins Lymphoma M. Mahmood Khan, MD Hematology-Oncology 12/5/03

Non HodgkinsLymphoma

M. Mahmood Khan, MD

Hematology-Oncology

12/5/03

Lymphomas

• Tumors of The Lymphoid Tissue

• 4% of all cancers

• Mostly ‘solid’ tumors … but

may occasionally have an additional leukemic component !

Simplified schema of Hematopoetic Cancers

Hematopoetic Stem Cell

Myeloid

Lymphoid

Acute and chronic

Myeloid ‘Leukemias’

LymphomasHodgkins (30%)

Non Hodgkins (70%)

WBC

RBC

Platelets

B Cells

T cells

NHL: Incidence

• 56,000 cases /year.

• 25,000 deaths per year

• Incidence rose 1973- 1998

• Better diagnosis, aging population and HIV

• 4% of all cancers

• 85% are B cell type and 15% are T cell type

NHL: Etiol. & Pathogenesis (contd).

• Viruses:HTLV 1 : associated with Adult T cell Leukemia/Lymphoma

EBV : Burkitts Lymphoma, esp in endemic form (95%),

PTLD, some AIDS associated NHL and all AIDS associated

primary CNS lymphoma

HHV8 : Kaposi’s Sarcoma and primary effusion lymphoma

• Helicobacter Pylori: MALT lymphoma

NHL : Pathogenesis (contd).

Chromosomal translocations

• t(8:14) seen in Burkitts Lymphoma

• t(14:18) >80% of follicular NHL,

leads to over expression of ‘anti apoptotic gene’ bcl-2

• t(11:14) seen in almost all Mantle Cell lymphomas

NHL: Etiology and PathogenesisEnvironmental Factors

• Inconsistent and contradictory studies

• Higher risk associated with several occupations: Farmers, agricultural workers chemists

• Causal relationship not established

NHL: Classification(s)

• Lukes and Collins (1970s)

• NCI working formulation (1980s)

• R.E.A.L Classification: Revised European American Classification (1990s)

• WHO classification, 2000

NHL Classification (contd).

NCI WORKING FORMULATION• Clinically very useful and practical• Divides lymphomas into : 1. Low grade 2. Intermediate grade and 3. High grade NHL

• Based on morphology (Architecture and Cell size)• Examples: Diffuse Large cell NHL Follicular small cell NHL

NCI Working FormulationLow Grade Intermediate High grade

•Small Lymphocytic (SLL)

•Follicular Large •Large cell immunoblastic

•Follicular small •Diffuse small cleaved

•Diffuse mixed small and large

•Lymphoblastic

•Follicular mixed, small and large

•Diffuse Large Cell • Diffuse Small non cleaved

NHL : Classification (contd).

• Low grade /Indolent NHL

Are INCURABLE

• Intermediate /High Grade

Are more “Aggressive” but potentially CURABLE!

NHL : WHO Classification(most common subtypes)

• B Cell NeoplasmsPrecursor B Cell Neoplasms:• Lymphoblastic Lymphoma/ALLMature B Cell Neoplasms:• CLL/SLL• MALT• Diffuse Lg B Cell• Mantle Cell• Burkitts Lymphoma/Leukemia• Plasma cell MyelomaUncertain Malignant Potential:• PostTransplant Lymphoprolif.dis

• T Cell and NK CellPrecursor T cell Neoplasms• Lymphoblastic

lymphoma/LeukemiaMature T Cell Neoplasms• Primary T cell lymphoma

(NOS)• Angio immuno blastic

lymphoma• Mycosis Fungoides/Sezary• Anaplastic LCL,primary

systemic type

NHL : Clinical Presentation

• Indolent types: Present typically at advanced stage, with L.N., spleen or marrow disease

• Aggressive NHL: Present as enlarging mass in nodal, or extra nodal areas. H&N, liver, GI, skin, marrow and bone are more common extra nodal sites.

• Lymphadenopathy in NHL is typically non tender, firm or rubbery

• ‘B’ symptoms : Fever, drenching nite sweats or Wt. Loss >10% in 6 months

NHL : Diagnosis and Staging procedures

• H & P• CBC, Chemistry, LDH• Excisional LN biopsy,

also send for immunophenotyping (flow cytometry) and cytogenetics

NHL: Diagnosis & Staging procedures (contd).

• CT scan of chest, abdomen and pelvis• PET scan• Bone Marrow Biopsy• Lumbar Puncture if CNS symptoms or aggressive lymphoma with bone marrow

involvement

Stages of NHL Ann Arbor Staging System

• I : 1 L.N. site (or one extra nodal site, IE)• II : 2 or more L.N. sites (same side of diaphragm)• III: Involvement above and below diaphragm• IV: Diffuse or disseminated involvement of 1 or

more extralymphatic tissues or organs• (A= Absence of systemic symptoms, B= Presence

of B symptoms)

HD: Ann Arbor Staging Sytem

I

I II III IV

NHL: Ann Arbor Staging System

• Suffix ‘A’ means absence of B symptoms• Suffix ‘B’ means presence of B symptoms• Suffix ‘E’ means extra nodal disease• Suffix ‘S’ means splenic involvement• Suffix ‘X’ means bulky disease• For example: Stage IIIB-S means disease

above and below the diaphragm, with B symptoms and Splenic involvement

NHL: Two Commonest subtypes

• Diffuse Large Cell

Lymphoma

• Follicular Lymphoma

NHL : Diffuse large cell Lymphoma

• Commonest subtype• Classified as ‘intermediate grade’ in WF• Heterogenous disease 40% are cured with standard CHOP therapy 40% respond initially but later relapse 20% are refractory to any therapy

IPI : International Prognostic Index is used to estimate prognosis in an individual patient

Diffuse Large Cell NHLInternational Prognostic Index

• 5 ‘risk factors’ should be identified in each pt. At the time of diagnosis

• 1) Age >60

• 2) LDH> normal

• 3)ECOG performance status 2-4

• Stage III or IV

• Two or more extranodal sites

Score/risk category 5 yr survival

Score 0-1= low risk 73%

Score 2 = Low Intermed 51%

Score 3 = High Intermed 43%

Score 4-5= High risk 26%

(Shipp et al Blood 1994:83:1165)

Therapy: Diffuse Large Cell Lymphoma

• Limited stage (I or II) Non bulky: Combination of abbreviated chemotherapy (3-4 cycles of

CHOP) and radiation

• Advanced Stage (III or IV) or bulky disease: Full 6-8 cycles of chemoRx with additional XRT to bulky

areas

• Chemotherapy regimen is CHOP: Cyclophosphamide, Hydroxydoxorubicin, Oncovin and Prednisone)

‘CHOP’Chemotherapy

• CHOP regimen was developed >20 years ago!

• Several attempts to improve upon its efficacy by adding drugs or increasing dose failed

Large Cell NHL/ Rx:

Improving upon ‘CHOP’

• 1138 pt, intergroup trial• Randomized comparison

of CHOP vs more intensive regimens:

- m-BACOD

- ProMACE-cytaBOM- MACOP-B

• Results: CHOP was as good as others and was less toxic

(Fisher RI, NewEng J Med 1993,328:1002)

NHL Rx: Improving upon ‘CHOP’(adding Rituximab)

• French group ‘GELA’• Randomized trial• 399 pts• Elderly (higher risk pts)• CHOP x 8 +/- Rituximab• Improved results with addition

of ‘Rituxaimab’ RR 63% 75% 2yr EFS 38%57% 2 yr OS 57%70%

(Coiffier B; N Eng J Med 2002:346:235)

Large Cell NHL

RX of Relapsed disease• Randomized trial (PARMA)

• n = 109

• ‘Chemosensitive relapses’

• Std.salvage chemo vs Hi dose chemo stem cell transplant

• Better 5yr EFS(46% vs 12%)

• Better 5 yr OS (53% vs 32%)

• Based on this study High dose chemotherapy followed by Autologous SCT has become the standard of care in relapsed large cell lymphoma.

NHL Therapy: RITUXIMABTargeted therapy or Immunotherapy

• Monoclonal anti CD 20 antibody

• CD 20 is a cell surface receptor present on all B lymphocytes

• Rituximab (Rituxan) binds to CD 20 and eventually leads to cell lysis

• Very well tolerated drug, infusion reactions are possible

NHL Targeted Therapy: Radioimmunotherapy (Ibritumomab-Y90)

• Conjugating Radio isotopes to anti CD 20 Antibody has further enhaunces its activity

• Myelosupression

• Secondary Myelodysplasia

INDOLENT LYMPHOMASFollicular Lymphoma

• Typically presents as advanced stage• Some patients are asymptomatic at

diagnosis• This disease is incurable so far• Watchful waiting is acceptable in

asymptomatic patients • Therapy is required for disease related

symptoms

Indolent lymphomasFollicular NHL

• Single agent oral ‘Chlorambucil’ is useful therapy esp in elderly patients

• More aggressive regimens: CVP, CHOP or Fludarabine.

• Multi drug combinations improve response rate but does not result in cure

• Rituximab has become an extremely useful drug in these paitents.

• Radioimmunotherapy is also useful.• High dose chemotherapy and transplantation has not

resulted in cure so far. Area of active research.

Other ImportantNon Hodgkins Lymphomas

• Mantle Cell Lymphoma: Extremely challenging disease, CHOP-R results in remissions but never cure, consider early transplantation.

• Gastric MALT Lymphoma: Represents exaggerated immunologic response to H Pylori. Initial therapy should be directed against Helicobacter Pylori (Flagyl,Amoxicillin,Omeprazole). 70% patients respond!

• Small Lymphocytic lymphoma and Chronic Lymphocytic Leukemia: are ‘one and same’ disease.

SLL is lymph node based and CLL is leukemic. Rx and prognoses are same

ConclusionsNON HODGKINS LYMPHOMA

• Extremely heterogenous group of disease• WHO classification is probably going to stay• Indolent NHL : Slow growing but incurable• Aggressive NHL: Faster growing but/therefore

potentially curable• Follicular NHL: Commonest indolent type• DLCL: Commonest aggressive type• Intl.Prog.Index (IPI): Valuable predictor of

outcome in an individual patient

THANK YOU!