ADVANCES IN

LYMPHOMA

INTRODUCTION
Lymphomas encompass a group of lympho proliferative malignant diseases that
originate from T- and B cells in the lymphatic system.
Non-Hodgkin lymphoma involves a heterogeneous group of over 40
lymphoproliferative malignancies with diverse patterns of behaviours and responses
to treatments.
OBJECTIVE
To provide an overview of lymphomas
Recent changes in work up
Generalized approach to management of lymphomas
Newer drugs in lymphoma.
Currently, several NHL classification schemas exist, reflecting the growing
understanding of the complex diversity of the NHL subtypes. The Working
Formulation, 1982, classified and grouped lymphomas by morphology and clinical
behavior (ie, low, intermediate, or high grade). In the 1990s, the Revised EuropeanAmerican Lymphoma (REAL) classification attempted to apply immunophenotypic
and genetic features in identifying distinct clinicopathologic NHL entities. The World
Health Organization (WHO) classification further elaborates upon the REAL
approach. This classification divides NHL into those of B-cell origin and those of Tcell and natural killer (NK)cell origin.

Lymph node is anatomically divided into cortex and medulla, in cortex are follicles,
which nare further divided into the germinal center (GC), the mantle zone, and the
surrounding marginal zone. B cells that have successfully rearranged their IG genes
in the bone marrow move to peripheral lymphoid organs as nave B cells. Only GC B
cells with high affinity for the antigen will be positively selected to exit the GC and
further differentiate into plasma cells or memory B cells, whereas low-affinity clones
are eliminated by apoptosis.

PREVALENCE OF LYMPHOMA IN JIPMER:

A descriptive cross-sectional study wherein 1010 cases of lymphnode biopsies from
PMER(January 2007 to June 2012 )were reviewed.
Neoplastic lesions were more common comprising 53% (535 cases) and included 32.1% (324
cases) of non-Hodgkin lymphoma, 12.4% (125 cases) of Hodgkin lymphoma and 8.5% (86
cases) of metastatic lesions. The non-neoplastic lesions were 47% (475 cases), which included
21.6% (218 cases) of non-specific reactive lymphoid hyperplasia, 6.8% (69 cases) of other
reactive or specific lymphoid hyperplasia, 18% (182 cases) of tuberculous lymphadenitis, 0.6%
(6 cases) of other granulomatous lesions.
Among 324 cases of NHL, T-cell lymphoma - 38% (123 cases) and B-cell lymphoma 54% (175
cases) with DLBCL being the most common, 29.3% (95 cases).
Other subtypes of B cell lymphomas were, 6.8% (22 cases) of follicular lymphoma (FL), 1.85%
(6 cases) of burkitt lymphoma, 0.3% (1 case) of lymphoplasmacytic lymphoma (LPL), 2.8% (9

cases) of marginal zone lymphoma (MZL), 4% (13 cases) of mantle cell lymphoma (MCL), 3.7%
(12 cases) of chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL).
T-cell NHLs were 10.5% (34 cases) of anaplastic large cell lymphoma (ALCL), 17.3% (56 cases)
of PTCL-NOS, 1.85% (6 cases) of angioimmunoblastic T-cell lymphoma (AITL), 0.9% (3 cases)
of adult T-cell lymphoma/leukemia (ATLL) and 7.4% (24 cases) of precursor T-lymphoblastic
lymphoma.

Newer agents causing non Hodgkin lymphoma were established like borrelia,
campylobacter, simian virus 40, silicone breast implants.

Simplified World Health Organization Classification of Non-Hodgkin's Lymphoma by Clinical

Behavior
Indolent
B Cell
Follicular lymphoma (grades I and II)
Chronic lymphocytic leukemia / small lymphocytic lymphoma
Marginal zone: extranodal, mucosa-associated lymphoid tissue
(MALT), nodal, splenic
Plasma cell myeloma
Plasmacytoma
Hairy cell leukemia
T Cell
Mycosis fungoides
Szary syndrome
Aggressive
B Cell

Diffuse large B cell lymphoma and variants

Follicular lymphoma (grade III)
Mantle cell*
T Cell
Peripheral T cell
Anaplastic large cell
Highly Aggressive
Burkitt's lymphoma
Precursor B/T lymphoblastic

Management of Lymphoma*
Category

Early stage

Indolent Non-Hodgkin's

Aggressive Non-Hodgkin's

Lymphoma

Lymphoma

Radiation alone may be

Short-course chemotherapy

Short-course chemotherapy

curative in FL and some

(CHOP) + radiation for some

(ABVD) + radiation for most

other forms

patients

patients

Hodgkin's Lymphoma

Chemotherapy (CHOP) with

rituximab
Advanced

Observation

Chemotherapy (CHOP) with

Chemotherapy with ABVD for 6-8

Stage

Chemotherapy + rituximab

rituximab for B cell subtypes

cycles, then radiation to

for B cell subtypes

for 6-8 cycles

persistent bulky masses

Rituximab alone

CHOP-based regimen or
clinical trial for T cell
lymphomas

Relapsed

Different chemotherapy or

Autologous transplant for

Autologous transplant for eligible

monoclonal antibody

eligible chemosensitive

chemosensitive patients

therapy

patients

Clinical trial

Clinical trial

Clinical trial

Autologous transplant

Chemotherapy

Chemotherapy

WORK UP:
A large number of studies have definitively demonstrated that PET-CT is the most
sensitive of current imaging studies, and is highly specific, not only for response
assessment, but for pretreatment determination of disease localization. since it was
accepted as the standard for restaging, it was reasonable to accept it for
pretreatment staging
Few changes were made in evaluation
1. when to do bone marrow ?
2. when to do L.P ?
Previously bone marrow was done in almost all patients, but now , Bone marrow is
done in all lymphomas except :
In HL, stage1, 2A
DLBCL stage 1, 2A
Stage 4 disease
The above recommendations have come from the study by El-Galaly et al. (J Clin
Oncol 2012;30:4508-14.)
The involvement of bone marrow has prognostic implications:
CONCORDANT : presence same lymphoma cells in filtrating the marrow.
DISCORDANT : marrow showing different type of malignant cells.
E.g. DLBCL diagnosed by lymph node biopsy, showing follicular cells in marrow is
DISCORDANT,
If marrow shows diffuse large B cells, then it is CONCORDANT.
CSF analysis indications :
Not all lymphomas involve CNS, mostly aggressive lymphomas and extensive stage
lymphomas involve lymphomas, hence Lumbar puncture is indicated only in the
following conditions.
High grade lymphoma( Burkitt or lymphoblastic)
DLBCL with bone marrow involvement.

 Primary CNS lymphomas

Post transplant lymphoproliferative disorders
Testicular involvement
Involvement of nasopharyngeal and paranasal sinus
HIV related lymphomas.

Newer classification for lymphomas(LUGANO classification)

STAGING :
PET-CT for staging of FDG-avid lymphoma histologies
Treatment directed more by limited or advanced disease and prognostic/risk
factors
Elimination of bone marrow biopsies in Hodgkin and most diffuse large B-cell
NHL
Elimination of routine chest X-ray
A and B only used for HL
Elimination of X, but record largest mass diameter
RESPONSE ASSESSMENT :
PET-CT is the basis of response assessment for all FDG avid histologies
CR includes residual masses that are not FDG-avid
Interpretation of PET using 5-point scale
Increase of single node for progressive disease

TREATMENT COURSE IN GENERAL :

For limited stage disease 3 4 cycles of CHOP is given, for extensive disease, 6-8
cycles of CHOP is given.

If patient has relapse, then SALVAGE regimen is given, then consolidation phase is
given and will be taken up for Autologous Stem cell transplantation.
PROGNOSTIC SYSTEMS IN LYMPHOMAS :
R-IPI for most of lymphoma
FLIPI-1,2 for follicular lymphoma
MIPI for mantle cell lymphoma
ROLE OF PET SCAN :
PET has significantly affected the staging and the post chemo response rate.

PET scan is done for

Initial staging
Mid treatment staging (interim PET)
Post treatment staging
INDICATIONS OF PET SCAN :
Done in almost all lymphomas except PET non avid tumours.

DEAUVILLE criteria
1. No uptake
2. Uptake mediastinum
3. Uptake > mediastinum but liver
4. Uptake moderately > liver uptake, at any site
5. Markedly increased uptake at any site and new sites of disease.

A positive scan is usually interpreted as residual uptake with a

score of 4

Disadvantages of PET scan :

All PET positive sites has to be biopsied to confirm.
Marrow involvement cant be assessed
Difficult in HIV/AIDS

MANTLE CELL LYMPHOMA :

I st line therapy is HYPER- CVAD. (Rhyper-CVAD)
Bortezomib, Lenalidomide, Ibrutinib

T CELL NHL RELAPSE:

Romidepsin
Belinostat
Pralatrexate
Bendamustine
Brentuximab vedotin
Gemcitabine
Alemtuzumab
RADIOTHERAPY

 Purpose of radiotherapy in limited disease and extensive disease is different.

In limited disease, goal is to decrease the cycles of chemotherapy.
In extensive disease, goal is to decrease the relapse, only bulky site will be
given RT.

Antibiotics/ Antivirals in NHL :

MALTOMA

- H . Pylori eradication regimen

Ocular adnexal lymphoma doxycycline

Adult T cell NHL

- zidovudine

HODGKIN LYMPHOMA

Hodgkin's lymphoma (HL) is one of the commonest tumours amongst the non-AIDSdefining malignancies (non-ADM).

There are five types of Hodgkin lymphoma classified by the World Health
Organization: nodular sclerosing, mixed cellularity (see the image below),
lymphocyte depleted, lymphocyte rich, and nodular lymphocyte-predominant.
Risk Factors for HL :
Age
Histology
ESR or B symptoms
Mediastinal mass*
Number of nodal sites
Extranodal lesions

General treatment principles include the following:

Radiation therapy

Induction chemotherapy

Salvage chemotherapy

Hematopoietic stem cell transplantation.

Guidelines are from the National Comprehensive Cancer Network (NCCN), European
Society for Medical Oncology (ESMO) and the International Harmonization Project.
The following induction regimens are given as initial treatment for Hodgkin lymphoma:

MOPP (mechlorethamine, vincristine, procarbazine, prednisone)

ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine)
Stanford V (doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide, prednisone)
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,
prednisone)
SALVAGE REGIMEN :

ICE (ifosfamide, carboplatin, etoposide)

DHAP (cisplatin, cytarabine, prednisone)
ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin)

TARGETED THERAPY :
These drugs interfere with specific pathways involved in cancer cell growth or
survival.
Some targeted therapies block growth signals from reaching cancer cells or
reduce the blood supply to cancer cells or stimulate the immune system to
recognize and attack the cancer cell.

 Depending on the specific target, targeted therapies may slow cancer cell
growth or increase cancer cell death.

TARGETED THERAPY :
Proteasome inhibitors:

Bortezomib

Histone deacetylase (HDAC) inhibitors :

Romidepsin - peripheral T-cell lymphoma.

Belinostat - peripheral T-cell lymphomas

Kinase inhibitors :
Ibrutinib : Mantle cell lymphoma
Idelalisib (PI3K inhibitor) - follicular lymphoma, SLL

NEWER THERAPIES :
Anti CD 20 MAB :
RITUXIMAB :
Rituximab eliminates CD20-positive cells mainly through three mechanisms:
complement-dependent cytotoxicity (CDC), Ab- dependent cellular cytotoxicity
(ADCC) and the induction of apoptosis.
IMMUNOTOXINS :
Brentuximab vedotin - Anaplastic large cell lymphoma (ALCL).
Moxetumomab pasudotox HCL

Pathway targeted

Drug name

Side effects

Used in

STK( splenic tyrosine

kinase)

Fostamatinib

HTN, diarrhoea, fatigue

DLBCL ,FL

BTK (Bruton tyrosine

kinase)

Ibrutinib

PI3K inhibitor

Idelalisib

PKC beta(protein kinase C)

Enzastaurin

neutropenia

DLBCL,

M-TOR inhibitors

Rapamycin,
temsirolimus,
everolimus,
deforolimus

pancytopenia

MCL, DLBCL,

IMiDs(Immunomodulating
drugs)

Lenalidomide

Painful lymphnode
enlargement

SLL, DLBCL,PTCL

RITUXIMAB :

diarrhoea

Fever, diarrhoea,

Mantle cell, SLL

SLL, relpased FL

Rituximab eliminates CD20-positive cells mainly through 3 mechanisms:

complement-dependent cytotoxicity (CDC), Ab- dependent cellular cytotoxicity
(ADCC) and the induction of apoptosis.

Newer monoclonal antibodies :

Anti CD- 20 : Rituximab, Ocrelizumab, Ofatumumab,Veltuzumab,
Tositumomab
Anti CD- 22 : Epratuzumab( follicular, DLBCL)- (Infusion related toxicitiy and
transient B-cell depletion)
Anti- CD 23 : Lumiliximab (CLL/SLL)-( Minimal infusion toxicity and mild
cytopenia)
Anti - CD 80 : Galiximab ( follicular NHL)-(Fatigue , nausea and headache ;
deranged LFT and decrease in serum phosphate levels)

Anti CD 52 : Alemtuzumab ( ATL)- (Cyopenias leading to anemia,

infections and bleeding due to depletion of platelets)

 Anti - CD 2 : Siplizumab (ATL)- (EBV related lymphoproliferative disease

due to depletion of T cells and NK cells)
Anti - CD 30 : Brentuximab( Hodgkins, ALCL)-(cytopenias, numbness and
tingling sensation of hands and feet)

NEWER APPROACHES TO OVERCOME DRUG RESISTANCE :

Similar to antibiotics, drug resistance has evolved in chemotherapeutic agents also.
Most common cause of drug resistance is MDR mediated efflux.
MDR inhibitors like verapamil, cyclosporine, valspodar can be used in conjunction
with chemo drugs.
Newer vaccines are under trail (BiovaxIDTM) for lymphomas, but none of them are
approved.