Dr Opeyemi Idaewor

7/28/2019 Dr Opeyemi Idaewor

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NON-HODGKINS

LYMPHOMA


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OUTLINE DEFINITION/DESCRIPTION

BEHAVIOUR NHL vs HL EPIDEMIOLOGY CLASSIFICATION NATURAL HISTORY

ETIOLOGY PATHOGENISIS/FORMATION OF MALIGNANT B-CELLS CLINICAL FEATURES ORAL MANIFESTATIONS HISTOLOGIC FEATURES PROGNOSIS/PROGNOSTIC FACTORS THERAPY/TREATMENT SIDE-EFFECT OF MEDICATIONS & THEIR MANAGEMENTS FOLLOW-UP CONCLUSION


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DEFINITION/DESCRIPTION Lymphomas are malignancies of lymphoid cells Lymphomas can be divided on the basis of

pathologic features into HL and NHL. NHL are a heterogenous group of proliferative

malignancies (B-cell and T-cell neoplasms ) that

arises primarily in the lymphoid nodes , can involve both the lymphoid nodes & organs andextranodal sites.

NHL s vary in clinical behaviour , morphologicappearance , immunologic and molecular

phenotype. The various types represent neoplastic lympoid

cells arrested at various stages of normaldifferentiation.


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Non-Hodgkins Lymphoma

Non-Hodgkins lymphomas (NHL) are aheterogeneous group of malignant lymphomas.There are many different subtypes, every few yearsthe classification is updated. Today, morphology,

immunophenotype, molecular, cytogenetics, andother techniques are used for diagnosis.

Treatment generally depends on the aggressivenessof the disease (indolent, aggressive, or very

aggressive) Current ICD-9-CM diagnosis code range 200.0_

200.8_ and 202.0_ 202.9_


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Behavior Indolent these lymphomas grow slowly. The

majority of NHLs are considered indolent.Indolent lymphomas are generally consideredincurable with chemotherapy and/or radiationtherapy.

Aggressive these lymphomas have a rapidgrowth pattern. This is the second most commonform of NHL and are curable with chemotherapy.

Very Aggressive these lymphomas grow veryrapidly. They account for a small proportion ofNHLs and can be treated with chemotherapy.Unless treated rapidly, these lymphomas can belife threatening.


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Hodgkin's Lymphoma

VS

Non-Hodgkin's Lymphomas

Age Average age is 27.7 with two age peaks, the major one

between 15 and 24 with a lesser peak after age 55. Average age is about 67.

Chance of getting in

all people over an

entire lifetime

Men 0.23%

Women 0.20%

Men 2.12%

Women 1.79%

Occurrence About 15% of all lymphomas About 85% of all lymphomas

Location The disease occurs most often in lymph nodes above the

collar bone. In Hodgkin's it is also more likely to appear

in the chest cavity between the lungs (the mediastinum),

particularly in younger patients.

Only about 15% to 20% of cases are found in areas below

the diaphragm.

Disease occurs outside the nodes in about 4% of cases.

In NHL it is more likely to appear in the nodes in the

abdomen (called the mesenteric nodes).

The disease occurs in the chest cavity in less than

40% of patients. (An exception, lymphoblastic

lymphoma, which is seen most often in young

people, is likely to first appear in the chest.)

Disease occurs outside the nodes in about 23% of

patients. Slow-growing lymphomas are common in

the liver and bone marrow.

Affected Lymph

CellsB-Lymphocytes

characterized by the Reed-Sternberg Cell

B-Lymphocytes, T-Lymphocytes or Natural Killer

(NK) Cells depending on the subtype

Symptoms More likely than NHL (40%) to have systemic ("B")

symptoms (such as fever and night sweats) at the time ofdiagnosis.

Less likely than HL to have systemic ("B")

symptoms (27%) at the time of diagnosis.

Progression Less likely than NHL to be diagnosed in stage IV (10%).

Hodgkin's disease usually progresses in an orderly way

from one lymph node region to the next. This process

may be slow, particularly in younger people, or very

aggressive. The disease typically spreads downward

from the initial site. If it spreads below the diaphragm, it

usually reaches the spleen first; the disease then may

spread to the liver and bone marrow. If the disease starts

in the nodes in the middle of the chest, it may spreadoutward to the chest wall and areas around the heart and

lungs.

More likely than HD to be diagnosed in stage IV

(36%) but this will vary by NHL subtype.

The Non-Hodgkin's lymphomas are less predictable

in their course than Hodgkin's and they are more

apt to spread.


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EPIDEMIOLOGY

NHLs are the 5th most common cases of cancers inUS (estimated incidence of 63,600 cases in 2001)

Follicular centre cell lymphomas are the 2nd mostcommon subtype (40% of NHL)

Since 1950 , the incidence of NHL has steadilyincreased at approx 4% per yr. Gender The overallincidence of lymphoma is slightly higher in menthan women.

Age Except for high-grade lymphoblastic and smallnoncleaved cell lymphomas, which are the mostcommon types of NHL seen in children and youngadults, the median age at presentation for all

subtypes of NHL is 65-70 yrs.


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Race Incidence varies by race, with whites athigher risk than blacks and Asian-Americans.

Incidence is increasing

NHL>HD

More often clinically disseminated at diagnosis

B-cell-70% ; T-cell-30%

Prevalence of non-Hodgkins lymphoma (NHL)subgroups throughout Africa, particularlyamong persons with HIV/AIDS, is unknown.

Geography Certain endemic geographicalfactors appear to influence the development ofNHL in specific areas.

Burkitts lymphoma is most common in Africa.


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Disease site Malignant lymphomas are aheterogeneous group of neoplasms that usuallyarise or present in lymphoid tissues, such as

lymph nodes, spleen, and bone marrow, Lymphatic tissues which include : thymus ,

spleen , tonsils , Lymph tissues are found in stomach , skin and

small intestine They may arise in almost any tissue. The most frequent sites for extranodal

lymphomas, which constitute about 26% of alllymphomas, are the stomach, skin, oral cavityand pharynx, small intestine, and CNS.

There may be Epidural involvement , paranasalsinuses , bulky retroperitoneal lymph nodes ,bone marrow , testicles , bone


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Survival The 5-year relative survival rate ofpatients with NHL increased from 28% between1950 and 1954 to 49% between 1979 and 1985.

These improvements in survival occurredmainly in young adults and children.

The potential for cure varies among the differenthistologic subtypes and is directly related tostage at presentation and response to initial

therapy.

Survival Rates

vary widely by cell type and staging.

1 Year Survival Rate: 77%




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CLASSIFICATION

There is a lack of a uniform classification hampers NHL treatment.

Classifications available include:

-the International Working formulatn(1982)-Rappaport classification obsolete

- Revised European-American

Lymphoma (REAL classification)-Updated WHO REAL / WHO

classification (2001)

See figure in this page :


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Proposed WHO classification

Most widely used classification. Recognizes 3 major categories of lymphoid

malignancies based on morphology and celllineage:

a) B-cell neoplasmb) T-cell/natural killer (NK) cell

neoplasms .c) Hodgkin lymphoma

o Both a&b are each divided into i) precursorneoplasm & , ii)well mature differentiatedneoplasm.


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WHO/REAL Classification of Lymphoid Neoplasms

B-Cell Neoplasms

Precursor B-cell neoplasm

Precursor B-lymphoblastic leukemia/lymphoma

(precursor B-acute lymphoblastic leukemia)

Mature (peripheral) B-neoplasms

B-cell chronic lymphocytic leukemia / small lymphocyticlymphoma

B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma

Splenic marginal zone B-cell lymphoma

(+ villous lymphocytes)*

Hairy cell leukemia

Plasma cell myeloma/plasmacytoma

Extranodal marginal zone B-cell lymphoma of MALT typeNodal marginal zone B-cell lymphoma

(+ monocytoid B cells)*

Follicular lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphoma

Mediastinal large B-cell lymphoma

Primary effusion lymphoma

Burkitts lymphoma/Burkitt cell leukemia

T and NK-Cell Neoplasms

Precursor T-cell neoplasmPrecursor T-lymphoblastic leukemia/lymphoma

(precursor T-acute lymphoblastic leukemia

Formerly known as lymphoplasmacytoid lymphoma orimmunocytomaII Entities formally grouped under the heading large granularlymphocyte

leukemia of T- and NK-cell types* Provisional entities in the REAL classification

Mature (peripheral) T neoplasmsT-cell chronic lymphocytic leukemia / small

lymphocytic lymphomaT-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaII

Aggressive NK leukemiaAdult T-cell lymphoma/leukemia (HTLV-1+)

Extranodal NK/T-cell lymphoma, nasal type#

Enteropathy-like T-cell lymphoma**

Hepatosplenic T-cell lymphoma*

Subcutaneous panniculitis-like T-cell lymphoma*

Mycosis fungoides/Szary syndrome

Anaplastic large cell lymphoma, T/null cell,

primary cutaneous type

Peripheral T-cell lymphoma, not otherwise characterized

Angioimmunoblastic T-cell lymphoma

Anaplastic large cell lymphoma, T/null cell,

primary systemic type

Hodgkins Lymphoma (Hodgkins Disease)

Nodular lymphocyte predominance Hodgkins lymphoma

Classic Hodgkins lymphoma

Nodular sclerosis Hodgkins lymphoma (grades 1 and 2)

Lymphocyte-rich classic Hodgkins lymphoma

Mixed cellularity Hodgkins lymphoma

Lymphocyte depletion Hodgkins lymphoma

Not described in REAL classification Includes the so-called Burkitt-like lymphomas

** Formerly known as intestinal T-cell lymphoma# Formerly know as angiocentric lymphoma


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Indolent (35%)

Diffuse large

B-cell (31%)Armitage et al. J Clin Oncol. 1998;16:2780

2795.

Mantle cell (6%)

Peripheral T-cell (6%)

Other subtypes with a

frequency 2% (9%)

Frequency of NHL Subtypes in Adults

Composite

lymphomas (13%)


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Types of Lymphoma

Indolent (low grade) Life expectancy in years, untreated

85-90% present in Stage III or IV

Incurable

Intermediate

Aggressive (high grade) Life expectancy in weeks, untreated

Potentially curable


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Etiology of NHL Chronic inflammation and antigenic stimulation Helicobacter pylori inflammation, stomach

Chlamydia psittaci inflammation, ocular adnexaltissues

Sjgrens syndrome Viral causes EBV and Burkitts lymphoma

HTLV-I and T cell leukemia-lymphoma

HTLV-V and cutaneous T cell lymphoma Hepatitis C

KSHV - in body cavitybased lymphomas in patientswith HIV infection, multicentric Castlemans disease.


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ETIOLOGY contd

Environmental factors :-

chemicals pesticides & herbicides (e.g

organophosphates, chlorophenols) ,solvents and organic chemicals (e.gbenzene , carbon tetrachloride) , andwood preservatives.

Hence , workers in plastic , petroleum,rubber and synthetic industries have aslightly increases risk of NHL.


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Etiology of NHL Immune suppression

congenital (ataxia telengiectasia , Wiskott-Aldrich syndrome,common variable hypogammaglobulineamia,

organ transplant (cyclosporine) AIDS

increasing age

Connective tissue disorder :

- sjogren syndrome, rheumatoidarthritis, chronic lymphocysticthyroiditis , & systemic lupuserythematosus (SLE).


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CLINICAL FEATURES contd Systemic symptoms like fever , night sweats , weight loss

(systemic B symptoms) remission in pxts with low-gradelymphomas

Hepatosplenomegaly Fever Night sweats Cytopenias B symptoms more common in high-grade lymphomas. Organ-specific symptoms like , e.g shortness of breath ,

chest pain , cough , abdominal pain & distension, bone

pains may indicate the sites involved. Hematogenousspread of disease, with no predictable pattern. Classic lymphoma: arises in lymph node or bone marrow. Extranodal primary more common in high-grade

lymphoma. Waldeyers ring involvement frequent in GI lymphomas.


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CLINICAL FEATURES contd Neurological symptoms-

CNS involvement may occur with aggressive lymphomas ;e.g intra-ocular lymphoma ,

menigeal and diffuse involvement (Lymphomatousmeningitis).

CNS prophylaxis (discussed later) is used to ameliorate

neurological symptoms.

neurological paraneoplastic syndrome (a term used for veryrare collection of symptoms which can occur in lymphoma ,more commonly , NHL and include walking and balance

problem , change in movement of the eye (cerebellardegeneration), personality disorder in encephalitis)

Primary central nervous system lymphoma.

Lymphoma Symptoms


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Lymphoma Symptoms

(Hodgkin's Disease = HL, or a form of Non-Hodgkin's Lymphoma = NHL):

Lymph node swelling, often in the upper body area but it can be in almost any node or

related organ. The node is usually NOT painful as opposed to infected lymph nodes

which are common and can be painful

(HL, NHL)

A lack of energy, general fatigue. (HL, NHL)

Weight loss - usually at least 10% over a short time (HL, NHL)

Fevers which can come and go. This can be accompanied by chills or a feeling of

temperature swings (HL, NHL)

Night sweats - unexplained sweating at night, often drenching (more often HL than

NHL)

Itching - itching without an apparent cause or rash, sometimes deep in the skin rather

than on the surface, sometimes on different parts of the body (more often HL than

NHL)

Less Often:Some people have lower back pain that is unexplained (may be caused by expanding

lymph nodes pressing on nerves). (HL, NHL)

Lymph nodes are possibly painful after alcohol consumption. (HL)

What now?

A good percentage of diagnoses are made during routine tests, x-rays, or even while

pregnant. This is how difficult it is to diagnose lymphoma based on external symptoms

alone


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NHL PXT BURKITS LYMP


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Oral manifestations

Maybe a manifestation of systemicdisease.

Oral lesions are xterised by swellings

which may rapidly grow and then ulcerate; in some cases, then becomevlarge ,fungating , necrotic, and foul-smelling.

Pain is a variable feature. When underlying bone is involved , tooth

mobility and pain may develop.


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Histologic features

Histologic pattern is described as either nodularor diffuse.

In the nodular pattern , large clusters of cells areseen.

The diffuse pattern produces a monotonousdistribution of cells with no evidence ofnodularity or germinal centre formation.

The diffuse pattern produces an entire

effacement of normal lymph node architecture. The nodular pattern is seen more often in adults

than in children.


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Making the diagnosis

nodular (follicular) diffuse

small cell large cell

Indolent Aggressive


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Small lymphocytic Immunoblastic

Mantle cell Large Cell

Types of Non-Hodgkins Lymphoma

Screening and diagnosis


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Screening and diagnosis No effective methods are available for screening or identifying

populations at high risk for the development of NHL. A definitive diagnosis can be made only by biopsy of pathologic

lymph nodes or tumor tissue. A formal review by an expert hematopathologist for additionalstudies, such as immunophenotyping and genotyping, should beconsidered.

Initial diagnostic evaluation of patients withlymphoproliferative malignancy should include:

Careful history (night sweats, weight loss, fever; neurologic,musculoskeletal, or GI symptoms)

Physical examination (lymph nodes, including submental,infraclavicular, epitrochlear, iliac, femoral, and popliteal nodes;

pericardial rub, pleural effusion, distended neck and/or upperextremity veins in superior vena cava syndrome; breast masses;


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CT scan of the abdomen and pelvis (enlarged lymph nodes


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CT scan of the abdomen and pelvis (enlarged lymph nodes,splenomegaly, filling defects in liver and spleen)

Bilateral bone marrow biopsy

Gallium scan (optional/selected cases)

Bone scan (selected cases) if musculoskeletal symptoms are present oralkaline phosphatase is elevated

CBC with differential and platelet count (peripheral bloodlymphocytosis with circulating malignant cells is common in low-grade

lymphomas). Bone marrow and peripheral blood involvement may be present, and

the distinction between leukemia and lymphoma is difficult to make insome cases.

General chemistry panel, b2-microglobulin are recommended

HIV serology in patients with diffuse large cell, immunoblastic, andsmall noncleaved histologies; HTLV-1 serology in patients withcutaneous T-cell lymphoma, especially if they have hypercalcemia

Cytogenetic and molecular analyses of lymph node, bone marrow, and

peripheral blood (selected cases)


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Perform examination of CSF (lumbar puncture)

and strongly consider CNS prophylaxis in patients with:

(1) diffuse aggressive NHL with bone marrow, epidural,

testicular, paranasal sinus, or nasopharyngealinvolvement;

(2) high-grade lymphoblastic lymphoma and smallnoncleaved cell lymphomas (Burkitts and non-Burkitts

types); (3) HIV-related lymphoma; and

(4) primary CNS lymphoma

Perform Upper GI series with small bowel follow-through in patients with :

head and neck involvement (tonsil, base of tongue,nasopharynx)

and those with a GI primary lymphoma (e.g MALT)


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Order for : ultrasound of opposite testis in patients with a testicular

primary

Spinal MRI scan for epidural disease when clinicallyindicated (useful in the evaluation of suspected spinal cordcompression)

PET (FDG-glucose) scanning is gaining wider acceptance asa potential diagnostic approach for staging at diagnosis and

relapse. Immunohistochemistry Flow cytometry: Chromosome changes

14;18 translocation in follicular lymphoma bcl-2 oncogene

t(8;14), t(2;8), t(8;22) in Burkitts lymphoma c-myc oncogene

t(11;14) in mantle cell lymphoma

cyclin D1 gene

Staging of non Hodgkin lymphoma


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Staging of non-Hodgkin lymphoma Staging is the process of finding out how far the cancer has

spread. This is very importantbecause the treatment and thepatient's outlook for survival depend on the exact type andstage of the cancer.

Tests used to gather information for staging (Staging Workup)

Physical exam

CBC, chemistries, urinalysis

CT scans of chest, abdomen and pelvis

Bone marrow biopsy and aspirate

(Lumbar puncture)

AIDS lymphoma T cell lymphoblastic lymphoma

High grade lymphoma with positive marrow

Staging laparotomy and lymphangiogram are not indicated in

non-Hodgkins lymphoma.

Staging


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Staging

Stage I : Involvement of single LN region (I) or extralymphatic site (IAE )

Stage II : Two or more LN regions involved (II) or anextra lymphatic site and lymph node regions on thesame side of diaphragm

Stage III : Involvement of lymph node regions on both

sides of diaphragm, with (IIIE

) or without (III) localizedextra lymphatic involvement or involvement of thespleen (IIS) or both (IISE)

Stage IV : Involvement outside LN areas (Liver, bonemarrow)

A: Absence of B symptomsB : B symptoms present


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Non Hodgkins lymphoma

Incidence is increasing

NHL>HD

Median age of presentation is 65-70 yrs

M>F

More often clinically disseminated at diagnosis

B-cell-70% ; T-cell-30%


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Stage IV: Multifocal involvement of one or moreextranodal organs or tissues

with or without associated lymph node or isolatedextralymphatic

organ involvement Designations (applicable to any stage)

A: No symptoms.

B: Fever, drenching night sweats, unexplainedweight loss (>10% body

weight) during the previous 6 months. X: Bulky disease (lymphoid node or extranodal

tissue >10 cm in any dimension). E: Involvement of an extranodal site that is

contiguous or proximal to the known nodal site.

See figure on this page:


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Determining prognosis across


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Determining prognosis acrossNHL subtypes

Prognostic indicators

The initial evaluation of NHL helps to establish thecorrect diagnosis and extent of disease.

Prognostic models have been developed for

predicting outcome in patients on the basis oas andinclude the International Prognostic Index (IPI) foraggressive lymphoma and the Follicular LymphomaInternational Prognostic Index (FLIPI) for follicularlymphoma.

Age-adjusted International Prognostic Index (aaIPI)

the updated versionsthe Revised InternationalPrognostic Index (R-IPI) and FLIPIhave yet to be

universally adopted.


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International Prognostic Index

(IPI) Five adverse prognostic risk factors for IPI 1. Age >60 years 2. Ann Arbor stage III/IV 3. >1 extranodal site 4. Serum lactate dehydrogenase (LDH) level

>normal 5. Eastern Cooperative Oncology Group (ECOG)

performance status 2

One point is assigned to each of the previouslylisted characteristics present in a patient withaggressive NHL. Scores range from 0 to 5.

See figure in this page:


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(IPI) , contd. Good prognostic factors

Age 60 or

Stage I or II

No lymphoma outside of

lymph nodes, or lymphoma in only 1 area

outside of lymph nodes

PS: Able to functionnormally

activities Serum LDH is normal

Poor prognostic factors below Age above 60

Stage III or IV

Lymphoma is in more

than 1 organ of the bodyoutside of lymph nodes

PS (performance status complete normal dailyactivities?) : Needs a lot

of help with daily Serum LDH is high



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(IPI) , contd Each poor prognostic factor is assigned 1 point. People with no

poor prognostic factors would have a score of 0, while those with all of the poor

prognostic factors would have a

score of 5.

The index divides people with lymphomas into 4 risk groups:

Low (0 or 1 poor prognostic factors)

Low intermediate (2 poor prognostic factors)

High intermediate (3 poor prognostic factors)

High (4 or 5 poor prognostic factors)

Prognosis

Low grade : Median survival 10 yrs

High Grade:

Increasing age, advanced stage, concomitant disease, raised

LDH,T- cell phenotype : Poor prognosis

h


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Therapythe most important therapeutic modality is

chemotherapy , especially for intermediate- and high-grade NHL.

Surgery is useful in selected situations, such as GIlymphoma, particularly if the disease is localized or if

there is a risk of perforation. Orchiectomy is part ofthe initial management of testicular lymphoma.

Radiation therapy plays a more limited role in thetreatment of NHL but is useful in localized disease and

for palliation. A careful general evaluation of the patient is necessary

to assess any contraindications to the plannedtreatment.


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Regimen Drugs

CHOP Cyclophosphamide, Doxorubicin, Vincristine,

Prednisone

BACOP Bleomycin, Doxorubicin, Cyclophosphamide,

Vincristine. Prednisone

M-BACOD Methotrexate, Leucovorin, Bleomycin,

Cyclophosphamide, Vincristine, Dexamethasone

ProMACE/MOP

P

Prednisone, Methotrexate, Leucovin, Doxorubicin,

Cyclophosphamide, Etoposide

MACOP-B Methotrexate, Leucovorin, Doxorubicin,Cyclophosphamide, Vincristine, Bleomycin,

Prednisone, Trimethoprim-sulfamethoxazole

Current up-front treatment regimens for aggressive lymphomas

(Used at various doses, with, or without radiation)

Management


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ManagementLow grade:

Asymptomatic : No treatment ;

Radiotherapyfor localised disease (Stage 1); Chemotherapy: mainstay is

Chlorambucil; Initial response good , but repeatedrelapses, median survival 6-10 yrs; Newer: Fludarabine, 2-CdA (Chlorodeoxyadenosine)

Monoclonal antibody: RituximabSCT/BMT

Aggressive( high / intermediate grade):

Chemotherapy: mainstayCHOP -every 3 weeks, atleast 6 cycles Cyclophosphamide,Doxorubicin Hydrochloride,Vincristine,

Prednisolone

Treatment of HIV-related


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Treatment of HIV related

lymphomas Most lymphomas seen in patients who have HIV

infection are of high-grade histology (immunoblasticand small noncleaved cell) and advanced stage atpresentation.

Extranodal disease is common, with unusual sites ofpresentation, including the rectum, CNS, and multiple

soft-tissue masses. Some patients present with primary CNS lymphoma. Poor-risk factors include high LDH, large tumor bulk,

extranodal disease, and low CD4 counts (< 100

cells/L). Chemotherapy Because of their increased risk for opportunistic

infections and impaired hematologic reserve, manypatients are unable to tolerate aggressive chemotherapy

regimens.

Treatment of HIV-related


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Treatment of HIV relatedlymphomas , chemotherapy

(contd) Attenuated-dose regimens (such as CHOP or m-BACOD, with 50% reduction of the doxorubicin andcyclophosphamide doses plus growth factor

support) are well tolerated, although hematologictoxicity remains a problem in some patients.

A subgroup of patients without adverse prognosticfactors achieve durable remissions when treated

aggressively. CNS prophylaxis with intrathecal chemotherapy is

necessary to prevent meningeal dissemination. (Fora more detailed discussion of HIV-related NHL.


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CNS prophylaxis

Risk factors for CNS disease includehistology (high-grade small noncleavedand lymphoblastic NHL) and special sitesof involvement (bone marrow, testis,

paranasal sinus, nasopharyngeal, andepidural) by diffuse aggressive NHL.

Methotrexate (12-15 mg) or cytarabine

(Ara-C; 25 mg/m) can be used forintrathecal therapy

A conceptual depiction of the cell cycle phases


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A conceptual depiction of the cell cycle phases

that all cellsnormal and neoplasticmust

traverse before and during cell division.


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CLASSIFICATION OF ANTI-TUMOUR AGENTS

IN NHL TREATMENT Cell Cycle-Specific (CCS)

Agents

Antimetabolites

Cytarabine Fludarabine

Methotrexate

Antitumor antibiotic

Bleomycin

Epipodophyllotoxins Etoposide

Vinca alkaloids Vincristine Vinblastine

Cell Cycle-Nonspecific(CCNS) Agents Alkylating agents

Cyclophosphamide

Anthracyclines Doxorubicin

Platinum analogs

Cisplatin

Carboplatin

CyclophosphamideC l h h id i lk l i I i id l d


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Cyclophosphamide is an alkylating agent. It is a widely used as

a DNA crosslinking and cytotoxic chemotherapeutic agent. It is given orally as well as intravenously with efficacy. It is inactive in parent form, and must be activated to cytotoxic form by liver

CYT450 liver microsomaal system to 4-Hydroxycyclophamide andAldophosphamide. 4-Hydroxycyclophamide and Aldophosphamide are delivered to the dividing

normal and tumor cells. Aldophosphamide is converted into acrolein and phosphoramide mustard. They crosslink DNAs resulting in inhibition of DNA synthesisMajor Side effects

3. Nausea and vomiting, decrease in PBL count, depression of blood cell counts,bleeding ,alopecia (hair loss) , skin pigmentation, pulmonary fibrosis

Bleomycin (BLENOXANE)

fragment DNA chains and inhibit repair Germ cell tumors of testes and ovary, e.g., testicular carcinoma (can be curative

when used with vinblastine & cisplatin), squamous cell carcinoma Given I.V. or I.M. Mucosocutaneous reactions and pulmonary fibrosis, bone marrow depression much less than other

antineoplastics


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Doxorubicin (ADRIAMYCIN)

inhibit DNA and RNA synthesis

Acute leukemia, Hodgkin's disease, nonHodgkin's lymphomas (BACOP regimen), CAof breast & ovary, small cell CA of lung,

sarcomas, best available agentfor metastatic thyroid CA

I.V. Cardiac toxicity, Doxorubicin mainlyaffects the heart muscles, leading totiredness or breathing trouble whenclimbing stairs orwalking, swelling of the feet.


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Methotrexate (Antimetabolites) Mechanism of action

inhibits formation ofFH4 (tetrahydrofolate)from folic acid byinhibiting the enzyme

,dihydrofolatereductase (DHFR);

since FH4 transfersmethyl groups

essential to DNAsynthesis and henceDNA synthesis blocked.

Side effect and route of

administration bone marrow depression, intestinal lesions

and interferencewith embryogenesis. Drug interaction: aspirin and

sulfonamidesdisplacemethotrexate fromplasma proteins.

Orally effective as wellas given I.V


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Vincristine

(MOA)

Cytotoxic:

Inhibitionofmitotic spindle

formation bybinding to tubulin.

M-phase of the cell

cycle. Antimitotic drug

(natural product)

Side-effects

Bone marrowdepression,

epithelial

ulceration, GI disturbances,

neurotoxicity

IV

Targeted therapy of NHL


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Targeted therapy of NHL The biotechnology revolution has led to the

development of targeted therapies for NHL,

including Immunotherapy : monoclonal antibody ,unconjugated antibodies, e.g rituximab.

radioimmunotherapy, e.g tositumomab, Y2B8(yttrium 90)

and immunotoxins, e.g DAB-389-IL2 , anti-tac(fv)-pe38 , both targeting CD-25(IL-2) present onT-celllymphomas , a subset of indolent B-celllymphomas and HL.

Stem Cell Transplantation (SCT) Allogenenic (a donor) Autologous SCT Bone Marrow Transplant

Autologous stem cell transplant


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Autologous stem cell transplant In an autologous stem cell transplant, the patients own stem

cells are removed from his or her bone marrow or peripheralblood.

They are collected on several occasions in the weeks beforetreatment. The cells are frozen and stored while the person gets

treatment (high-dose chemotherapy and/or radiation) andare then reinfused into the patients blood.

This is the most common type of transplant used to treat NHLIt may be hard to get a stem cell sample that is free of lymphoma

cells.

Allogeneic stem cell transplant In an allogeneic stem cell transplant, the stem cells come

from someone else. The donors tissue type (also known as the HLA type) needs to match

the patients tissue type as closely as possible to help prevent the risk of major

problems with the transplant.

Allogeneic stem cell transplant, contd.


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Usually this donor is a brother or sister if they have thesame tissue type as the patiient or HLA-matched,unrelated donor .

The stem cells for an allogeneic SCT are usually collectedfrom a donors bone marrow or peripheral (circulating)

blood on several occasions. In some cases, the source ofthe stem cells may be blood collected from an umbilicalcord (the cord that attaches a baby to the placenta) after ababy is born. This blood is rich in stem cells.

Regardless of the source, the stem cells are then frozenand stored until they are needed for the transplant.

The use of allogeneic transplants is limited in treatinglymphoma because they can have severe side effects


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Long-term side effects: Some complications and side effects can persist for a long

time

or may not occur until months or years after thetransplant. These include: Graft-versus-host disease (GVHD), which occurs only in

allogeneic transplants Infertility and premature menopausal symptoms in

female patients (caused by damage to the ovaries) Infertility in male patients Damage to the thyroid gland that can cause problems with

metabolism Cataracts (damage to the lens of the eye that can affect

vision) Damage to the lungs, causing shortness of breath Bone damage called aseptic necrosis (if damage is severe,

the patient may need to have part of the affected bone andthe joint replaced)

Possible development of leukemia several years later

Graft-versus-host disease (GVHD): This is one of the most serious complications of allogeneic (donor)


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This is one of the most serious complications of allogeneic (donor)stem cell transplants.

It occurs because the immune system of the patient is taken over bythat of the donor.

The donor immune system then may recognize the patients ownbody tissues as foreign and may react against them. Symptoms can include severe skin rashes, itching, mouth sores ,

nausea, and severe diarrhea. Liver damage (jaundice). The lungs mayalso be damaged.

The patient may also become easily fatigued and develop muscle

aches. GVHD is often described as either acute or chronic, based on how

soon after the transplant it begins. Sometimes GVHD can become disabling, and if its severe enough, it

can be life-threatening. Usually, immune-suppressing drugs can be used to help control

GVHD, On the positive side, the graft-versus-host disease also leads to graft-

versus-lymphoma activity. Any lymphoma cells remaining after thechemotherapy and radiation therapy are often killed by donorimmune cells since the lymphoma cells are seen as foreign by thedonors immune system as well. Mild graft-versus-host disease can bea good thing.

SIDE EFFECTS OF


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SIDE EFFECTS OF

CHEMOTHERAPYY

Hair loss Mouth sores Loss of appetite Nausea and vomiting Diarrhea Greater chance of infection (from low white

blood cell counts) Easy bruising or bleeding (from low platelet

counts) Fatigue (from low red blood cell counts)

Examples of Supportive Care


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Examples of Supportive Care

for Patients With NHL

Myelosuppression The primary adverse effect of many of the chemotherapyregimens used to treat NHL is myelosuppression.

Also, transplant recipients are at increased risk ofdeveloping secondary myelodysplasia and acute myeloid

leukemia, regardless of whether or not they received aradiation-containing conditioning regimen. Prophylactic treatment with antibiotics or colony-

stimulating factor may: decrease the incidence or duration of myelosuppression,

reduce treatment-related toxicity, and facilitate delivery of the planned chemotherapy. With the decline in the role of radiation as part of the initial

therapy for NHL, the risk of certain radiation-inducedcomplications has been reduced or eliminated.

VaccinationsP i i h CLL d h i i


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Patients with CLL and those receiving sometherapeutic agents(including bendamustine andofatumumab)

should avoid vaccinations, especially with liveviruses.

Inactivated influenza vaccine is recommendedannually, although patients who have received

rituximab generally do not respond to this vaccine forup to 9 months after treatment. Patients should receive the pneumococcal vaccine

every 5 years. Tumor lysis syndrome Although rare, TLS may occur during treatment of

advanced NHLs, most often with the first cycle of chemotherapy and

within the first 72 hours of therapy.

Tumor lysis syndrome contd


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Tumor lysis syndrome , cont d. It occurs when the breakdown of tumors exceeds the

bodys ability to excrete the excess metabolic by-

products. TLS can lead to kidney failure, arrhythmias, and, if

untreated, death. It is best managed if anticipated and preventive

measures are instituted prior to chemotherapy). Treatment includes rigorous hydration, management

of hyperuricemia, and frequent monitoring ofelectrolytes with aggressive correction if needed.

In patients at risk for TLS, the pharmacist shouldconsider eliminating medications that couldexacerbate the component conditions (e.g., thiazidediuretics, potassium supplements, potassium-sparing diuretics

Follow-up of long-term survivors


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p g Relapse

The most important risk to patients with NHL is relapse.

Patients with advanced low-grade NHL are at a constantrisk of relapse,

and late recurrence of disease may be seen, sometimes

after the patient has been in remission for more than adecade.

Physical examination at 2- to 3-month intervals

and follow-up CT scans at 4- to 12-month intervals arerecommended.

Secondary malignancies Long-term survivors are at

increased risk for second cancers.


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Reference

Non-Hodgkins lymphoma , Shaferstextbook of oral pathology , pg 246 252.


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THANK SIRs and MAs

, CONSULTANTS ,SNR REGISTRARS,REGISTRARS , AND MY FELLOW HOUSE-

OFFICERS, FOR LISTENING.

Documents

Dr Opeyemi Idaewor