lymphomas

VARUN. M M-PHARM(PHARMACOLOGY) I YR II SEM

ALL

CLL
nave

Lymphomas

MM

B-lymphocytes Plasma cells T-lymphocytes

Lymphoid progenitor

AML
Hematopoietic stem cell Myeloid progenitor

Myeloproliferative disorders
Neutrophils Eosinophils Basophils Monocytes Platelets

Red cells

Epidemiology of lymphomas
5th most frequently diagnosed cancer in both sexes
males > females incidence
NHL increasing
Hodgkin lymphoma stable

Lymphoma classification(2001 WHO)

Lymphomas are heterogeneous groups of malignancies

that arise from malignant transformation of immune cells of lymphoid tissue. B-cell neoplasms
precursor mature
NonHodgkin Lymphomas

T-cell & NK-cell neoplasms

precursor
mature

Hodgkin lymphoma
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A practical way to think of lymphoma

Category Survival of untreated patients Years Curability To treat or not to treat

NonHodgkin lymphoma

Indolent

Generally not curable

Generally defer Rx if asymptomatic

Aggressive

Months

Curable in some
Curable in some Curable in most

Treat

Very aggressive Hodgkin lymphoma All types

Weeks

Treat

Variable months to years

Treat

Hodgkin lymphoma

Thomas Hodgkin (1798-1866)

Classical Hodgkin Lymphoma

hodgkins lymphoma
Thomas Hodgkins first described this mysterious

disease of the lymph system in 1932. Hodgkins lymphoma is the clonal malignant lymphoid disease of transformed lymphocytes. Malignant cells of HL are Reed Sternberg cells Patients with Hodgkins disease are categorized into four prognostic groups ( IPI). Early favorable Early unfavorable Advanced favorable Advanced unfavorable
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ETIOLOGY
Genetic alterations Infection - EBV Antigen stimulation Immunosuppressant's like HIV infected, solid-organ

transplantation recipients, congenital immunosupression. Risk is increased in people with ataxia and telangiectasia.

Hodgkin lymphoma pathophysiology

cell of origin: germinal centre B-cell transcriptional process are disrupted (Gene re-arrangements)

Prevent B- cell marker expression & production of immunoglobin messenger ribonucleic acid.

Failure to express immunoglobin apoptosis.

Increased immunoglobin survival and proliferation are favoured.

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Reed- sternberg cells over expresses nuclear factor- kB.

The normal cellular consequences of failure to express immunoglobin apoptotic pathways, cell survival and proliferation. Infections with EBV , viral and bacterial infections increases the expression of nuclear factor- kB.

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A possible model of pathogenesis

transforming event(s) EBV? loss of apoptosis

cytokines

germinal centre B cell

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RS cell inflammatory response

Reed-Sternberg cell

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B-cell development
stem cell lymphoid progenitor
progenitor-B

CLL

mature naive B-cell

germinal center B-cell

memory B-cell

MM
pre-B immature B-cell

ALL DLBCL, FL, HL

plasma cell

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Hodgkin lymphoma Histologic subtypes

Classical Hodgkin lymphoma II. Nodular lymphocyte- predominant Hodgkins disease. Classical Hodgkin lymphoma common subtypes
I.
nodular sclerosis (most common subtype) mixed cellularity lymphocyte-rich lymphocyte depleted

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Cotswold's staging classification of hodgkins lymphoma

Stage I Stage II Stage III Stage IV

A: absence of B symptoms B: fever, night sweats, weight loss

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International prognostic factors project score

Risk Factors :
Serum albumin (<4 g/dL) Hemoglobin (<10.5 g/dL)

Male gender
Stage IV disease Age (45 years) WBC count (15000/mm3) Lymphocytopenia (< 600 /mm3)

Number of Factors 0 1 2 3 4
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Freedom from progression 844 773 672 603 514 425

Overall Survival 892 902 812 783 614 565

TREATMENT FOR EARLY- STAGE FAVORABLE DISEASE

Patients with early-stage favorable disease have stage IA or stage

IIA disease and no adverse risk factors ( extra nodal disease, bulky disease, three or more sites of nodal involvement, or an erythrocyte sedimentation rate of 50). According to NCCN guidelines: (i) Two cycles of Stanford V regimen ( doxarubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin and prednisone) or (ii) Four cycles of the ABVD ( doxorubicin, Adriamycin, bleomycin, vinblastine, and dacarbazine ) regimen followed by radiation. With this approach, 5 year progression- free and overall survival > 90 % can be achieved.
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TREATMENT FOR EARLY- STAGE UNFAVORABLE DISEASE

Patients with early-stage favorable disease have

stage IA or stage IIA disease and with adverse risk factors ( extra nodal disease, bulky disease, three or more sites of nodal involvement, or an erythrocyte sedimentation rate of > 50). Mechlorethamine, vincristine, procarbazine, and prednisone are one of the first highly effective drugs to treat Hodgkins lymphoma.

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TREATMENT FOR ADVANCED- STAGE DISEASE

DRUG MOPP Mechlorethamine Vincristine Procarbazine Prednisone Repeat every 21 days ABVD Adriamycin Bleomycin Vinblastine Dacarbazine
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Dosage (mg//m2) 6 1.4 100 40

Route IV IV Oral Oral

Days 1,8 1,8 1-14 1-14

25 10 6 375

IV IV IV IV

1, 15 1, 15 1, 15 1, 15

Repeat 28 days

Relative frequencies of different lymphomas

Non-Hodgkin Lymphomas

Diffuse large B-cell Hodgkin lymphoma NHL Follicular Other NHL

~85% of NHL are B-lineage

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Non-hodgkins lymphoma
Non-Hodgkins lymphomas (NHL) are a heterogeneous

group of malignant lymphomas. There are many different subtypes, every few years the classification is updated. Today, morphology, immunophenotype, molecular, cytogenetic, and other techniques are used for diagnosis. Treatment generally depends on the aggressiveness of the disease (indolent, aggressive, or very aggressive)

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Follicular Lymphoma
Mbr (major breakpoint region, 150 bp) Bcl2 Chromosome 18

C JH Double strand DNA break by RAG1/2

Chromosome 14

Translocation takes place in B cell precursors.

Bcl2

t(14;18) translocation

Transformation takes place during B cell activation in GC. E C 3E

bcl2 23

Unregulation of Bcl2 expression by IgH enhancers

Over-expression of Bcl-2 may prevent the apoptosis of germinal center B cells

Plasma cells

Germinal center
activation

Germinal center

apoptosis Memory cells

Germinal center IgH-Bcl2 activation

Germinal center

follicular lymphoma Most follicular lymphoma Ig V regions contain somatic hypermutation. 24 Apoptosis inhibited

Burkitts Lymphoma
breakpoints myc Chromosome 8

*** V(D)J

C
E S

IgH Chromosome 14, 80% IgChromosome 2

Class switch recombination

Somatic hypermutation

Igchromosome 22

3E myc S C C t(8:14) 3E myc E 25 S C C

Hodgkin Lymphoma
Classical HL (NS, MC, LR, LD) Nodular lymphocyte Predominant (NLPHL) Indolent

Non Hodgkin Lymphoma

Aggressive Highly Aggressive

B cell Follicular SLL/CLL Marginal zone LP (WM)

T/NK cell Mycosis fungoides Sezary syndrome Primary cut ALCL

B cell DLBCL FLg3 and tFL Mantle cell Primary effusion

T/NK cell ALCL Angioimmunoblastic Subq panniculitis-like Blastic NK Extnanodal NK/T nasal Enteropathy-type Hepatosplenic PTCL nos

B cell Pre-B lymphoblastic Burkitt

T/NK cell Pre-T lymphoblastic

Multiple 26Myeloma

FL Treatment
Mostly radiation. Chemotherapy Prednisone Purine analogs fludarbine, cladribine, Rutiximab CHOP cyclophosphamide, Hydroxydaurubicin, Oncovin, Prednisone. CHOP + R.

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Other types
Radio immunotherapy. I- tositumomab (Bexxar) Y- Ibritumomab tiuxetan (Zevalin) mostly in relapsed conditions. Hematopoietic stem cell transplantation.

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Radioimmunotherapy with Y-90 Zevalin

Monoclonal antibody

Ibritumomab Murine monoclonal antibody parent of Rituximab

Tiuxetan Conjugated to antibody, forming strong urea-type bond Stable retention of YBeta 90
radiation

Chelator
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Y-90 radionuclide

Conclusion
Discussed Hodgkins Disease Discussed Non-Hodgkins Lymphoma Discussed Classification Systems Discussed Treatment Options

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Thank You
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