Transcript Lymphomas - Lafayette Medical Education Foundation

Non Hodgkins
Lymphoma
M. Mahmood Khan, MD
Hematology-Oncology
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
WBC
Acute and chronic
RBC
Myeloid
Hematopoetic
Stem Cell
Platelets
Myeloid
‘Leukemias’
B Cells
Lymphomas
Lymphoid
Hodgkins (30%)
T cells
Non Hodgkins (70%)
NHL: Incidence
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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 Pathogenesis
Environmental 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 Formulation
Low Grade
Intermediate
High grade
•Small
Lymphocytic
(SLL)
•Follicular small
•Follicular Large
•Large cell
immunoblastic
•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 Neoplasms
• T Cell and NK Cell
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:
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
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PostTransplant Lymphoprolif.dis
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).
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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
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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
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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 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 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)
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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
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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: RITUXIMAB
Targeted therapy or Immunotherapy
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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)
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Conjugating Radio
isotopes to anti CD 20
Antibody has further
enhaunces its activity
• Myelosupression
• Secondary
Myelodysplasia
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
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.
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
Conclusions
NON HODGKINS LYMPHOMA
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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!