Advances in

Management of NHL

Presented by
Dr/ Nelly Mohamed Abd El Razek
Review
 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 is
marked 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 group
of cancers of immune system cells.
 pathophesiology
 NHL 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 by
chromosomal 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.
 Incidence

 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.
 possible explanations for the higher NHL rate in
Egypt may be the high prevalence of HCV
infection, HHV8 infections, other types of
infections, or adverse environmental exposures
and pollution.
 Classification
Updated REAL/WHO Classification
B-cell neoplasms
 Precursor 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.
 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/Sézary 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
 Hodgkin lymphoma

 Nodular lymphocyte–predominant Hodgkin

lymphoma.
 Classical Hodgkin lymphoma.
 Nodular sclerosis Hodgkin lymphoma.
 Lymphocyte-rich classical Hodgkin lymphoma.
 Mixed-cellularity Hodgkin lymphoma.
 Lymphocyte-depleted Hodgkin lymphoma
Modification of REAL Classification of Lymphoproliferative Diseases
 Plasma cell disorders.
 Bone.
 Extramedullary.
 Monoclonal gammopathy of undetermined significance.
 Plasmacytoma.
 Multiple myeloma.
 Amyloidosis.
 Hodgkin lymphoma.
 Nodular sclerosis Hodgkin lymphoma.
 Lymphocyte-rich classical Hodgkin lymphoma.
 Mixed-cellularity Hodgkin lymphoma.
 Lymphocyte-depleted Hodgkin lymphoma.
 Indolent lymphoma/leukemia.
 Follicular lymphoma (follicular small-cleaved cell [grade 1], follicular mixed small-cleaved, and
large cell [grade 2], and diffuse small-cleaved cell).
 Chronic lymphocytic leukemia/small lymphocytic lymphoma.
 Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
 Extra nodal marginal zone B-cell lymphoma (MALT lymphoma).
 Aggressive 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/Sézary syndrome.
 T-cell granular lymphocytic leukemia.
 Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+).
 Nodular lymphocyte–predominant 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 lymphoma
 Lymphomatoid 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
 Staging
The Ann Arbor staging system
 Stage I
Stage I NHL means involvement of a single lymph node region (I) or localized involvement
of a single extra lymphatic organ or site (IE).
 Stage 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 lymphatic organ
or site and its regional lymph nodes with or without other lymph node regions on the
same side of the diaphragm (IIE).  [Note: The number of lymph node regions involved
may be indicated by a subscript (e.g., II3).
 Stage 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 lymphatic
organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIS+E).
 Stage IV
Stage IV NHL means disseminated (multifocal) involvement of one or more extralymphatic
sites with or without associated lymph node involvement or isolated extra lymphatic
organ involvement with distant (nonregional) nodal involvement.
Diagnosis of NHL
 Traditional Methods for diagnosis of NHL
Clinical laboratory 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 Coomb’s test, or hypogamma

globulinemia.
 Lymph node biopsy/fine-needle aspiration

 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.
 Bone marrow aspiration/trephine biopsy

BM aspirations are carried out principally to permit cytological

assessment but also for immunophenotypic, cytogenetic,
molecular genetic and other specialized investigations. A
trephine biopsy, which is carried out in the same procedure,
may permit a diagnosis of NHL, particularly low-grade
lymphoma in which the marrow is often infiltrated. In patients
with NHL, examination of a trephine bone marrow biopsy is an
important part of the staging procedure, and it is useful for
assessing the response to treatment and re-staging when
patients relapse after treatment.
 Immunophenotyping
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.
The fluorescent in situ hybridization technique
(FISH)
 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.
 The polymerase chain reaction (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.
 Imaging
 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.
PET scanning of lymphoma is useful for

 Staging
 Restaging
 Assessing response to therapy
 Guiding biopsy
 Molecular Methods
 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..
 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.
Treatment of NHL
 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 therapy

 High dose chemotherapy followed by autologous (auto) blood

or marrow transplantation (BMT)
 Chemotherapy
 The treatment of aggressive NHL took a significant step forward in
the 1970s with the introduction of curative combination
chemotherapy regimens, primarily (CHOP). Second-generation and
third-generation combination chemotherapy regimens, such as m-
BACOD, ProMACE-CytaBOM ,and MACOP-B, have since been
developed in the hopes of increasing survival rates.
 None have produced superior results , and they have been associated
with greater toxicity and costs. CHOP remains the treatment of choice
in most patients with aggressive forms of NHL. Treatment with first-
generation therapies such as CHOP produces long-term remissions in
45% to 55% of patients , and efforts are being made to further
improve outcomes.
 Researches are focusing on dose-intensification strategies to improve
the outcomes with CHOP and other chemotherapy regimens
Using granulocyte colony-stimulating factor (G-CSF) as an
adjunct 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.
 Radiation therapy
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 Therapy

 Stereotactic Radiotherapy
 Image-Guided Radiation Therapy (IGRT)
 Biological therapy
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 patient’s immune system to
more successfully fight the disease. Substances
that may be used include:
 Interferon

 Monoclonal antibodies
 Interferon

Produced by the white blood cells, this

hormone-like protein helps the immune system
fight infections. Some research has suggested
that treating a patient with artificially created
 interferon can cause certain types of NHL to
shrink or stop expanding.
 Monoclonal antibodies
 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.
 Radioimmunotherapy
 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 131I-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.
High dose chemotherapy followed by autologous
(auto) blood or marrow transplantation (BMT)

Another standard treatment is high dose chemotherapy followed

by autologous (auto) blood or marrow transplantation (BMT).
Although response rates are better than with conventional
chemotherapy, auto BMT has not lead to an overall improvement
in survival because patients continue to relapse.

An alternative to using the patient’s 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.
 There are several other approaches to immunomodulatory therapy

being tested by US NCI-funded centers. For example, therapeutic

vaccines 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.