Advances in Management of NHL

8/8/2019 Advances in Management of NHL

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Presented byDr/ Nelly Mohamed Abd El Razek

Advances inManagement of NHL


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Review


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Definition

Lymphoma is defined as Cancer that begins in cells of the

immune system. There are two basic categories of

lymphomas. One kind is Hodgkin lymphoma, which ismarked by the presence of a type of cell called the Reed-

Sternberg cell. The other category is non-Hodgkin

lymphomas (NHLs), which includes a large, diverse groupof cancers of immune system cells.


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patho phesiologyNHL represents a progressive clonal expansion of B cells or T cells

and/or natural killer (NK) cells arising from the accumulation of

genetic lesions that affect proto-oncogenes or tumor suppressor genes,

resulting in cell immortalization. These oncogenes can be activated bychromosomal translocations (ie, the genetic hallmark of lymphoid

malignancies), or tumor suppressor loci can be inactivated by

chromosomal deletion or mutation. In addition, the genome of certain

lymphoma subtypes can be altered with the introduction of exogenous

genes by various oncogenic viruses.


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I ncidence

Middle East Cancer Consortium (MECC) registries,

multiyear averages showed very high standardized

incidence rates (ASRs) for lymphoma among Egyptians(16.3/100.000 person). These rates exceeded the United

States Surveillance Epidemiology and End Results (US

SEER) incidence rate (15.3/100.000 person) considered

one of the highest in the world as well as the rates of the

other MECC studied populations.


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possible explanations for the higher NHL rate inEgypt may be the high prevalence of HCV

infection, HHV8 infections, other types of infections, or adverse environmental exposuresand pollution .


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Classification

U pd a ted REAL/WHO Cl a ssific a tionB-cell neoplasmsPrecursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/ lymphoblastic lymphoma (LBL).

Peripheral B-cell neoplasms.B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.

B-cell prolymphocytic leukemia.Lymphoplasmacytic lymphoma/immunocytoma .

Mantle cell lymphoma.Follicular lymphoma.Extra nodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type.Nodal marginal zone B-cell lymphoma ( monocytoid B-cells).Splenic marginal zone lymphoma ( villous lymphocytes).

Hairy cell leukemia.Plasmacytoma/plasma cell myeloma.Diffuse large B-cell lymphoma.Burkitt lymphoma.


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T -cell and putative NK-cell neoplasms

Peripheral T-cell and NK-cell neoplasms.T-cell chronic lymphocytic leukemia/prolymphocytic leukemia.T-cell granular lymphocytic leukemia.Mycosis fungoides/Szary syndrome.

Peripheral T-cell lymphoma, not otherwise characterized.Hepatosplenic gamma/delta T-cell lymphoma.Subcutaneous panniculitis-like T-cell lymphoma.Angioimmunoblastic T-cell lymphoma.Extra nodal T-/NK-cell lymphoma, nasal type.

Enteropathy-type intestinal T-cell lymphoma.Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).Anaplastic large cell lymphoma, primary systemic type.Anaplastic large cell lymphoma, primary cutaneous type.Aggressive NK-cell leukemia


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H odgkin lymphoma

Nodular lymphocytepredominant Hodgkinlymphoma.

Classical Hodgkin lymphoma.Nodular sclerosis Hodgkin lymphoma.Lymphocyte-rich classical Hodgkin lymphoma.Mixed-cellularity Hodgkin lymphoma.

Lymphocyte-depleted Hodgkin lymphoma


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M odific ation of REAL Cl assific ation of Lym pho pr olife ra tiveDise ases

P lasma cell disorders .Bone.Extramedullary.

Monoclonal gammopathy of undetermined significance.Plasmacytoma.Multiple myeloma.Amyloidosis.

H odgkin lymphoma .Nodular sclerosis Hodgkin lymphoma.Lymphocyte-rich classical Hodgkin lymphoma.Mixed-cellularity Hodgkin lymphoma.Lymphocyte-depleted Hodgkin lymphoma.

I ndolent lymphoma/leukemia .

Follicular lymphoma (follicular small-cleaved cell [grade 1], follicular mixed small-cleaved, and largecell [grade 2], and diffuse small-cleaved cell).Chronic lymphocytic leukemia/small lymphocytic lymphoma.Lymphoplasmacytic lymphoma (Waldenstrm macroglobulinemia).Extra nodal marginal zone B-cell lymphoma (MALT lymphoma).


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A ggressive lymphoma/leukemia.Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma).Splenic marginal zone lymphoma (Splenic lymphoma with villous lymphocytes).Hairy cell leukemia.

Mycosis fungoides/Szary syndrome.T-cell granular lymphocytic leukemia.Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+).Nodular lymphocytepredominant Hodgkin lymphoma.Diffuse large cell lymphoma (includes diffuse mixed-cell, diffuse large cell, immunoblastic, and T-cell rich large B-cell lymphoma).

Distinguish:Mediastinal large B-cell lymphoma.Follicular large cell lymphoma (grade 3).Anaplastic large cell lymphoma (CD30+).

Extra nodal NK-/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphomaLymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma).Angioimmunoblastic T-cell lymphoma.Peripheral T-cell lymphoma, unspecified.

Subcutaneous panniculitis-like T-cell lymphoma.Hepatosplenic T-cell lymphoma.

Enteropathy-type T-cell lymphoma.Intravascular large B-cell lymphoma

Burkitt lymphoma/Burkitt cell leukemia/Burkitt-like lymphoma.

Precursor B-cell or T-cell lymphoblastic lymphoma/leukemia.Primary central nervous system (CNS) lymphoma.Adult T-cell leukemia/lymphoma (HTLV 1+).Mantle cell lymphoma.Polymorphic post transplantation lymphoproliferative disorder (PTLD).AIDS-related lymphoma.True histiocytic lymphoma.Primary effusion lymphoma.B-cell or T-cell prolymphocytic leukemia


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S t a ging

The Ann Arbor staging systemS tage I

Stage I NHL means involvement of a single lymph node region (I) or localized involvementof a single extra lymphatic organ or site (IE).

S tage II

Stage II NHL means involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extra lymphaticorgan or site and its regional lymph nodes with or without other lymph node regions onthe same side of the diaphragm (IIE). [Note: The number of lymph node regionsinvolved may be indicated by a subscript (e.g., II 3).S tage III

Stage III NHL means involvement of lymph node regions on both sides of the diaphragm(III) that may also be accompanied by localized involvement of an extra lymphaticorgan or site (IIIE), by involvement of the spleen (IIIS), or both (IIIS+E).S tage IV

Stage IV NHL means disseminated (multifocal) involvement of one or more extralymphaticsites with or without associated lymph node involvement or isolated extra lymphaticorgan involvement with distant (nonregional) nodal involvement.


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Di a gnosis of NHL

N1


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Slide 13

N1 NELLY, 12/25/2008


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T ra dition al M ethods fo r di a gnosis of NHLClinic a l l ab ora tor y testing

Complete blood counts (CBCs) are within their specific reference

ranges early in the disease. As the disease progresses, the CBC will

show anemia, thrombocytopenia, leukopenia, or pancytopenia, which

are seen secondary to bone marrow infiltration. Also possible is a

lymphocytosis with circulating malignant cells and a thrombocytosis .

Blood chemistries show an elevated LDH due to an increase in tumor

burden and abnormal liver function tests that occur secondary to

hepatic involvement.

monoclonal gammopathy, positive Coombs test, or hypogamma

globulinemia.


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Lym ph node bio psy/fine-needle as pi ra tion

FNA cytology is an accurate, rapid, economic, minimally-invasive,

and reliable procedure. There are some disadvantages. One

disadvantage is that in some situations the needle cannot remove the

amount of tissue needed for a diagnosis.

Although NHL are conventionally diagnosed and graded on biopsy

specimens, it may be useful to be able to not only diagnose but also

grade these cases on Fine needle aspiration cytology (FNAC) smears.This modality may assist clinicians in management of cases of NHLs,

especially in centres working within the constraints of limited

availability or non availability of ancillary techniques.


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I mmuno phenoty ping

Immunophenotyping has become a fundamental step in

the diagnosis of lymph nodal and extra lymph nodal

proliferative disorders. It helps distinguish reactive from

neoplastic lymphoid infiltrates, lymphoid from

nonlymphoid malignancies, and specific lymphoid

neoplasms . In recent years, FCM has proven useful in the

evaluation of mainly lymph node lymph proliferative

disorders on samples obtained by surgical specimens or

fine-needle cytometry.


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T he fluo r escent in situ hy br idiz ation technique (F IS H)

This technique is used for the detection of target molecules with a system of coupled

antibodies and fluorochromes.

A reciprocal t (14;18)(q32;q21) translocation is the hallmark cytogenetic abnormality

for FL, resulting in fusion of the immunoglobulin heavy-chain (IgH) and BCL-2genes.

Several methods, including conventional cytogenetics, PCR analysis, and Southern blot

analysis, can be used to demonstrate this rearrangement, but they are of limited value. A

newly developed long-range PCR amplification method may have greater efficiency in

detecting IgH/BCL-2 rearrangements that occur outside the mbr and mcr regions;

however, it is technically demanding, and it is not performed routinely.Interphase FISH is a desirable alternative, because it is fast and convenient for

detecting specific chromosomal translocations associated with different subtypes of

NHL at the cellular level. It is particularly advantageous in evaluating cytologic

material, because it requires only a small number of cells.


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T he polyme ra se ch a in r eaction (PCR)

It is a technique widely used in molecular biology. It

derives its name from one of its key components, a DNA

polymerase used to amplify a piece of DNA by in vitro

enzymatic replication.

It allows early diagnosis of lymphomas, and is already

being used routinely. PCR assays can be performed

directly on genomic DNA samples to detect translocation-

specific malignant cells at a sensitivity which is at least

10,000 fold higher than other methods.


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I ma ging Position emission tomography (PET) scan with the

glucose analogue 2-(F-18)-fluoro-2-deoxy-D glucose

(18F-FDG) has emerged as a clinical method for staging

and monitoring responses to treatment in a variety of

cancers.

Conventional imaging deals with alterations of normal

anatomy and enlargement of masses, whereas PET is a

biochemical tool that allows to look at changes in

metabolism. Even look at changes in gene expression.


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PET scanning of lymphoma is useful for

Staging

RestagingAssessing response to therapyGuiding biopsy


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M olecul ar M ethods

Recently, the novel technology of "gene chips" or DNA

microarrays has greatly enhanced the efficiency of

analyzing expression of many genes simultaneously at the

RNA level. Understanding the relationship of lymphoid

neoplasms to their normal counterparts and the genetic

events that lead to malignant transformation in lymphoid

cells are essential for physicians caring for patients with

lymphoma, since these are the basis of modern

classification, diagnosis, and prognosis prediction. .


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Gene expression profiling using complementary DNA (cDNA)microarrays has the potential to improve current lymphoma

classification schemes by establishing a molecular diagnosis of

these malignancies. The use of this technology led to the

discovery of biologically and clinically distinct subtypes of

diffuse large B-cell lymphoma (DLBCL).

Gene expression data can also be used to formulate powerful

mathematical algorithms that predict the clinical outcome in

patients with DLBCL and mantle cell lymphoma.


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Treatment of NHL


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The treatment of NHL varies greatly depending on tumor stage,

phenotype (B, T or NK/null-cell), histology (ie, whether low,intermediate, or highgrade), symptoms, performance status,

patient's age, and comorbidities. Several types of treatment are

used against NHL, including:

Chemotherapy

Radiation therapy

Biological therapyHigh dose chemotherapy followed by autologous (auto) blood

or marrow transplantation (BMT)


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Using granulocyte colony-stimulating factor (G-CSF) as anadjunct to chemotherapy is an effective way of decreasing

the risk of febrile neutropenia and infection associated

with myelosuppressive regimens. Reports indicate that G-

CSF reduces the incidence of chemotherapy-induced

neutropenia, febrile neutropenia, and infections in elderly

patients with NHL. This has made chemotherapy dose

intensification possible.


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Radi a tion the rap y

Precise high-energy radiation is used to destroy cancer cells and

shrink tumors. NHL is usually treated with external beam

radiation. Several special types of external beam therapy are

available:Three-Dimensional Conformal Radiation Therapy (3D-CRT)

Intensity Modulated Radiation Therapy (IMRT)

Neutron Beam TherapyStereotactic Radiotherapy

Image-Guided Radiation Therapy (IGRT)


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B iologic a l the rap y

This method uses substances naturally produced

by the immune system to kill lymphoma cells

and slow the growth of the cancer cells. It also

helps activation of the patients immune system to

more successfully fight the disease. Substances

that may be used include:Interferon

Monoclonal antibodies


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I nte r fer on

Produced by the white blood cells, this

hormone-like protein helps the immune system

fight infections. Some research has suggestedthat treating a patient with artificially

created interferon can cause certain types of

NHL to shrink or stop expanding.


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M onoclon al anti bodies

Antigens found solely on the cancer cell surface are

termed tumor-specific antigens and are desirable targets

for MAb therapy. The preferred absence of antigens on

normal cells and stem cells reduces toxic effects on

normal tissues and allows repopulation of depleted cells

after treatment. Other desirable antigenic characteristics

are a high density of tumor surface expression, stability of the antigen on the cell surface, and a biological function

necessary for tumor cell survival.


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Radioimmunothe rap y

Radioimmunotherapy (RIT) using radiolabeled anti-CD20 antibodies has

been explored most extensively in follicular lymphomas and follicular

lymphomas that have transformed to a higher grade. At present, two

radiolabeled anti-CD20 antibodies are approved by the U.S. Food and

Drug Administration for clinical use in the United States: tositumomab

and 131 I-tositumomab, and 90Y-ibritumomab tiuxetan. Therapeutic

regimen at radiation doses designed not to require stem cell support

(nonmyeloablative doses). However, a growing literature also exists on

the use of tositumomab and 131 I-tositumomab at myeloablative doses,

where considerable therapeutic activity has been demonstrated.


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High dose chemothe rap y followed b y autologous ( auto)blood o r marr ow t ra ns pl ant ation ( BMT )

Another standard treatment is high dose chemotherapy followed by

autologous (auto) blood or marrow transplantation (BMT).

Although response rates are better than with conventionalchemotherapy, auto BMT has not lead to an overall improvement

in survival because patients continue to relapse.

An alternative to using the patients cells for transplant is to use

cells from a matched donor. In addition to eliminating the problem

of tumor cells in the graft, cells from another person (called an allo

transplant) have been shown to have anti-tumor activity.


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There are several other approaches to immunomodulatory therapy

being tested by US NCI-funded centers. For example, therapeuticvaccines targeting the tumor-specific antibody (called an idiotype)

have demonstrated promising results against lymphomas. Additional

vaccine therapies being developed include those based on dendritic

cells, idiotype proteins engineered to produce a stronger immune

response, DNA, heat shock proteins, and gene-modified tumor cells. It

is hoped that these immunotherapeutic agents, used alone or in

combination, may someday allow effective treatment of lymphoid

malignancies and delay or even replace the need for conventional

cytotoxic therapies.

Documents

Advances in Management of NHL