Advances in Management of NHL
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Transcript of 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.