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

2. Lymphomas Tumors of The Lymphoid Tissue 4% of all cancers
Mostly ‘solid’ tumors … but
may occasionally have an additional leukemic component !

3. Simplified schema of Hematopoetic Cancers
WBC
Acute and chronic
Myeloid ‘Leukemias’
RBC
Myeloid
Platelets
Hematopoetic Stem Cell
B Cells
Lymphomas
Hodgkins (30%)
Non Hodgkins (70%)
Lymphoid
T cells

5. NHL: Incidence 56,000 cases /year. 25,000 deaths per year
Incidence rose
Better diagnosis, aging population and HIV
4% of all cancers
85% are B cell type and 15% are T cell type

6. 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

7. 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

8. NHL: Etiology and Pathogenesis Environmental Factors
Inconsistent and contradictory studies
Higher risk associated with several occupations: Farmers, agricultural workers chemists
Causal relationship not established

9. NHL: Classification(s)
Lukes and Collins (1970s)
NCI working formulation (1980s)
R.E.A.L Classification: Revised European American Classification (1990s)
WHO classification, 2000

10. 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

11. NCI Working Formulation
Low 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

12. NHL : Classification (contd).
Low grade /Indolent NHL
Are INCURABLE
Intermediate /High Grade
Are more “Aggressive” but potentially CURABLE!

13. NHL : WHO Classification (most common subtypes)
B Cell Neoplasms
Precursor B Cell Neoplasms:
Lymphoblastic Lymphoma/ALL
Mature B Cell Neoplasms:
CLL/SLL
MALT
Diffuse Lg B Cell
Mantle Cell
Burkitts Lymphoma/Leukemia
Plasma cell Myeloma
Uncertain Malignant Potential:
PostTransplant Lymphoprolif.dis
T Cell and NK Cell
Precursor T cell Neoplasms
Lymphoblastic lymphoma/Leukemia
Mature T Cell Neoplasms
Primary T cell lymphoma (NOS)
Angio immuno blastic lymphoma
Mycosis Fungoides/Sezary
Anaplastic LCL,primary systemic type

14. 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

15. NHL : Diagnosis and Staging procedures
H & P
CBC, Chemistry, LDH
Excisional LN biopsy, also send for immunophenotyping (flow cytometry) and cytogenetics

16. 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

17. 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)

18. HD: Ann Arbor Staging SytemII
III I IV

19. 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

20. NHL: Two Commonest subtypes
Diffuse Large Cell
Lymphoma
Follicular Lymphoma

21. 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

22. Diffuse Large Cell NHL International 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 yr survival
Score 0-1= low risk %
Score 2 = Low Intermed %
Score 3 = High Intermed %
Score 4-5= High risk %
(Shipp et al Blood 1994:83:1165)

23. 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)

24. ‘CHOP’Chemotherapy CHOP regimen was developed >20 years ago!
Several attempts to improve upon its efficacy by adding drugs or increasing dose failed

25. 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)

26. 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)

27. 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.

28. NHL Therapy: RITUXIMAB Targeted 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

29. NHL Targeted Therapy: Radioimmunotherapy (Ibritumomab-Y90)
Conjugating Radio isotopes to anti CD 20 Antibody has further enhaunces its activity
Myelosupression
Secondary Myelodysplasia

30. INDOLENT LYMPHOMAS Follicular 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

31. Indolent lymphomas Follicular 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.

32. Other Important Non 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

33. Conclusions NON 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

34. THANK YOU!