NON-HODGKINS LYMPHOMA

outline

DEFINITION/DESCRIPTION BEHAVIOUR NHL vs HL EPIDEMIOLOGY CLASSIFICATION NATURAL HISTORY ETIOLOGY PATHOGENISIS/FORMATION OF MALIGNANT B-CELLS CLINICAL FEATURES ORAL MANIFESTATIONS HISTOLOGIC FEATURES PROGNOSTIC INDICATORS PROGNOSIS THERAPY/TREATMENT SIDE-EFFECT OF MEDICATIONS & THEIR MANAGEMENTS FOLLOW-UP CONCLUSION

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 , but can involve both the lymphoid nodes & organs and extranodal sites. NHL s vary in clinical behaviour , morphologic appearance , immunologic and molecular phenotype. The various types represent neoplastic lympoid cells arrested at various stages of normal differentiation.

Behavior

Indolent these lymphomas grow slowly. The majority of NHLs are considered indolent. Indolent lymphomas are generally considered incurable with chemotherapy and/or radiation therapy. Aggressive these lymphomas have a rapid growth pattern. This is the second most common form of NHL and are curable with chemotherapy. Very Aggressive these lymphomas grow very rapidly. They account for a small proportion of NHLs and can be treated with chemotherapy. Unless treated rapidly, these lymphomas can be life threatening. Treatment generally depends on the aggressiveness of the disease (indolent, aggressive, or very aggressive) Current ICD-9-CM diagnosis code range 200.0_ 200.8_ and 202.0_ 202.9_

Hodgkin's Lymphoma VS
Age

Non-Hodgkin's Lymphomas
Average age is about 67.

Average age is 27.7 with two age peaks, the major one between 15 and 24 with a lesser peak after age 55.

Chance of getting in all people over an entire lifetime Occurrence Location

Men 0.23% Women 0.20%

Men 2.12% Women 1.79%

About 15% of all lymphomas 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.

About 85% of all lymphomas 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. B-Lymphocytes, T-Lymphocytes or Natural Killer (NK) Cells depending on the subtype Less likely than HL to have systemic ("B") symptoms (27%) at the time of diagnosis. 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.

Affected Lymph Cells Symptoms

B-Lymphocytes characterized by the Reed-Sternberg Cell More likely than NHL (40%) to have systemic ("B") symptoms (such as fever and night sweats) at the time of diagnosis. 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 spread outward to the chest wall and areas around the heart and lungs.

Progression

EPIDEMIOLOGY

NHLs are the 5th most common cases of cancers in US (estimated incidence of 63,600 cases in 2001) Follicular centre cell lymphomas are the 2nd most common subtype (40% of NHL) Since 1950 , the incidence of NHL has steadily increased at approx 4% per yr. Gender The overall incidence of lymphoma is slightly higher in men than women. Age the median age at presentation for all subtypes of NHL is 65 75yrs. M>F More often clinically disseminated at diagnosis B-cell-70% ; T-cell-30%

Race Incidence varies by race, with whites at higher risk than blacks and Asian-Americans. Most histologies, particularly low-grade small lymphocytic and follicular lymphomas, are more common in whites than blacks. Prevalence of non-Hodgkins lymphoma (NHL) subgroups throughout Africa, particularly among persons with HIV/AIDS, is unknown. Geography Certain endemic geographical factors appear to influence the development of NHL in specific areas. Burkitts lymphoma in Africa : BK is more common in Africa. Disease site Malignant lymphomas are a heterogeneous group of neoplasms that usually arise or present in lymphoid tissues, such as lymph nodes, spleen, and bone marrow, thymus , tonsils ; stomach , skin and small intestine ,epidural involvement , paranasal sinuses , bulky retroperitoneal lymph nodes , , testicles , bone and almost any tissue.

The most frequent sites for extranodal lymphomas, which constitute about 26% of all lymphomas, are the stomach, skin, oral cavity and pharynx, small intestine, and CNS. Survival Prognosis is better in the young. The potential for cure varies among the different histologic subtypes and is directly related to stage at presentation and response to initial therapy. Survival Rates vary widely by cell type and staging.
1 Year Survival Rate: 77%
5 Year Survival Rate: 56% 10 Year Survival Rate: 42%

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)

Proposed WHO classification

Most widely used classification. Recognizes 3 major categories of lymphoid malignancies based on morphology and cell lineage: a) B-cell neoplasm b) T-cell/natural killer (NK) cell neoplasms . c) Hodgkin lymphoma o Both a&b are each divided into i) precursor neoplasm & , ii)well mature differentiated neoplasm.

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 lymphocytic lymphoma 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 type Nodal 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 neoplasm Precursor T-lymphoblastic leukemia/lymphoma (precursor T-acute lymphoblastic leukemia
Mature (peripheral) T neoplasms T-cell chronic lymphocytic leukemia / small lymphocytic lymphoma T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemiaII Aggressive NK leukemia Adult 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

Formerly known as lymphoplasmacytoid lymphoma or immunocytoma II Entities formally grouped under the heading large granular lymphocyte leukemia of T- and NK-cell types * Provisional entities in the REAL classification

Frequency of NHL Subtypes in Adults

Mantle cell (6%)

Peripheral T-cell (6%)

Indolent (35%) Other subtypes with a frequency 2% (9%)

Composite lymphomas (13%)

Armitage et al. J Clin Oncol. 1998;16:27802795.

Diffuse large B-cell (31%)

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

Formation of NHLs
The types of non- Hodgkins lymphoma reflect the developmental stages of lymphocytes. Each type of lymphoma can be viewed as a lymphocyte arrested at a certain stage of development and transformed into a malignant cell. 85% B cell origin, the rest T or null cell.

B CELL DIFFERENTIATION Ig

Cell Surface Markers CD19 CALLA (CD10) CD20 CD38

Precursor B Cell Leukemias CLL, B Cell Lymphomas Waldenstrms, Myeloma

A B lymphocyte

immunoblast

small cleaved

large cleaved

small noncleaved

large noncleaved

G H

T lymphocyte

small lymphocyte

plasma cell

ETIOLOGY
Genetic abnormalities e.g non-random chromosomal & molecular rearrangement , ,most common chr. Abnormality being t(14;18) (q32:q21) translocation found in 85% of follicular lymphomas. DNA repair defects Ataxia telangiectasia xeroderma pigmentosum Familial pattern plays minimal role co-existence of multiple breast cancer , ovarian cancer, sarcomas and lymphomas in a family suggest abnormality in tumour suppressor genesImmune suppression congenital (ataxia telengiectasia , Wiskott-Aldrich syndrome, common variable hypogammaglobulineamia, organ transplant (cyclosporine) AIDS increasing age Connective tissue disorder : - sjogren syndrome, rheumatoid arthritis, chronic lymphocystic thyroiditis , & systemic lupus erythematosus (SLE).

Chronic inflammation and antigenic stimulation

Etiology of NHL

Viral causes

Helicobacter pylori inflammation, stomach Chlamydia psittaci inflammation, ocular adnexal tissues Sjgrens syndrome

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 patients with HIV infection, multicentric Castlemans disease. Environmental factors : chemicals pesticides & herbicides (e.g organophosphates, chlorophenols) , solvents and organic chemicals (e.g benzene , carbon tetrachloride) , and wood preservatives. Hence , workers in plastic , petroleum, rubber and synthetic industries have a slightly increases risk of NHL.

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

CLINICAL FEATURES contd

Intestinal lymphoma ( abdominal pain, anemia, dysphagia); CNS ( headache, cranial nerve palsies, spinal cord compression) Skin, Testis; Thyroid; Lung Bone marrow (low grade): Pancytopenia
So ,

Systemic symptoms like fever , night sweats , weight loss (systemic B symptoms) remission in pxts with low-grade lymphomas Hepatosplenomegaly Fever CytopeniasExtranodal :

Organ-specific symptoms like , e.g shortness of breath , chest pain , cough , abdominal pain & distension, bone pains may indicate the sites involved.

Clinical Features

Lymphadenopathy may fluctuate or spontaneously remit, especially in lowgrade lymphomas. B symptoms more common in high-grade lymphomas. Hematogenous spread 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.

Neurological symptomsCNS involvement may occur with aggressive lymphomas ; e.g intra-ocular lymphoma , menigeal and diffuse involvement (Lymphomatous meningitis). CNS prophylaxis (discussed later) is used to ameliorate neurological symptoms. neurological paraneoplastic syndrome (a term used for very rare collection of symptoms which can occur in lymphoma , more commonly , NHL and include walking and balance problem , change in movement of the eye (cerebellar degeneration), personality disorder in encephalitis. Primary central nervous system lymphoma.

NHL PXT

BURKITS LYMP

Gut obstruction Ascites SVC obstruction

Compression syndrome:

Oral manifestations Maybe a manifestation of systemic disease. Oral lesions are xterised by swellings which may rapidly grow and then ulcerate ; in some cases, then become very large , fungating , necrotic, and foulsmelling. Pain is a variable feature. When underlying bone is involved , tooth mobility and pain may develop.

Histologic features

Histologic pattern is described as either nodular or diffuse. In the nodular pattern , large clusters of cells are seen. The diffuse pattern produces a monotonous distribution of cells with no evidence of nodularity 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.

Making the diagnosis

nodular (follicular) diffuse

Indolent

Aggressive

small cell

large cell

Types ofNon-Hodgkins Lymphoma

Small lymphocytic

Immunoblastic

Follicular Lymphoma

Mantle cell

Large Cell

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 additional studies, such as immunophenotyping and genotyping, should be considered. Initial diagnostic evaluation of patients with lymphoproliferative 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 upper extremity veins in superior vena cava syndrome; breast masses; hepatosplenomegaly, bowel obstruction, renal mass, and testicular or ovarian mass;

focal neurologic signs, such as plexopathy, spinal cord compression, nerve root infiltration, and meningeal involvement; skin lesions. Biopsy of peripheral lymphadenopathy .Excisional biopsy of node is preferred to show nodal architecture (follicular vs diffuse). fine needle aspiration biopsy can be useful to confirm disease where biopsy is difficult ,eg. lung, liver or to document relapse but only after diagnosis has been established by node biopsy Chest x-ray (mediastinal or hilar adenopathy, pleural effusions,parenchymal

lesions)

CT scan of the chest (mediastinal, hilar, or parenchymal pulmonary disease) 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 or alkaline phosphatase is elevated Lymphagiogram.

CBC with differential and platelet count (peripheral blood lymphocytosis 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 in some cases. General chemistry panel, b2-microglobulin are recommended HIV serology in patients with diffuse large cell, immunoblastic, and small noncleaved histologies; HTLV-1 serology in patients with cutaneous T-cell lymphoma, especially if they have hypercalcemia Cytogenetic and molecular analyses of lymph node, bone marrow, and peripheral blood (selected cases). 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 nasopharyngeal involvement; (2) high-grade lymphoblastic lymphoma and small noncleaved cell lymphomas (Burkitts and non-Burkitts types); (3) HIV-related lymphoma; and (4) primary CNS lymphoma

 Perform 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) Order for : ultrasound of opposite testis in patients with a testicular primary Spinal MRI scan for epidural disease when clinically indicated (useful in

the evaluation of suspected spinal cord compression)

PET (FDG-glucose) scanning is gaining wider acceptance as a potential diagnostic approach for staging at diagnosis and relapse. Immunohistochemistry to confirm cells are lymphoid

LCA (leukocyte common antigen) Monoclonal staining with Igk or Igl

Flow cytometry:
CD 19, CD20 for B cell lymphomas

CD 3, CD 4, CD8 for T cell lymphomas 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

Staging is the process of finding out how far the cancer has spread. This is very important because the treatment and the patient's outlook for survival depend on the exact type and stage 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.

Ann Arbor Staging

Stage I : Involvement of single LN region (I) or extra lymphatic site (IAE ) Stage II : Two or more LN regions involved (II) or an extra lymphatic site and lymph node regions on the same side of diaphragm Stage III : Involvement of lymph node regions on both sides of diaphragm, with (IIIE) or without (III) localized extra lymphatic involvement or involvement of the spleen (IIS) or both (IISE) Stage IV : Involvement outside LN areas (Liver, bone marrow)

A : Absence of B symptoms B : B symptoms present

Determining prognosis across NHL subtypes

Prognostic indicators The initial evaluation of NHL helps to establish the correct diagnosis and extent of disease. Prognostic models have been developed for predicting outcome in patients and include the International Prognostic Index (IPI) for aggressive lymphoma and the Follicular Lymphoma International Prognostic Index (FLIPI) for follicular lymphoma. the updated versionsthe Revised International Prognostic Index (R-IPI) and FLIPIhave yet to be universally adopted. Age-adjusted International Prognostic Index (aaIPI)

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 previously listed characteristics present in a patient with aggressive NHL. Scores range from 0 to 5. See figure in this page:

International Prognostic Index (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 function normally 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 body outside of lymph nodes PS (performance status complete normal daily activities?) : Needs a lot of help with daily Serum LDH is high

International Prognostic Index (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

Therapy
the most important therapeutic modality is chemotherapy , especially for intermediate- and highgrade NHL. Surgery is useful in selected situations, such as GI lymphoma, particularly if the disease is localized or if there is a risk of perforation. Orchiectomy is part of the initial management of testicular lymphoma. Radiation therapy plays a more limited role in the treatment 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 planned treatment.

Current up-front treatment regimens for aggressive lymphomas

Regimen CHOP BACOP M-BACOD ProMACE/MOP P MACOP-B

Drugs Cyclophosphamide, Doxorubicin, Vincristine, Prednisone Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine. Prednisone Methotrexate, Leucovorin, Bleomycin, Cyclophosphamide, Vincristine, Dexamethasone Prednisone, Methotrexate, Leucovin, Doxorubicin, Cyclophosphamide, Etoposide Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin, Prednisone, Trimethoprim-sulfamethoxazole

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

Management

Low grade: Asymptomatic : No treatment ; Radiotherapy for localised disease (Stage 1); Chemotherapy: mainstay is Chlorambucil; Initial response good , but repeated relapses, median survival 610 yrs;
Newer: Fludarabine, 2-CdA (Chlorodeoxyadenosine)

Monoclonal antibody: Rituximab SCT/BMT

Aggressive ( high / intermediate grade): Chemotherapy: mainstay CHOP -every 3 weeks, at least 6 cycles Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine, Prednisolone

High risk cases with poor prognostic factors or relapse : High dose chemotherapy combined with autologous BMT / SCT Monoclonal antibody

With CNS involvement / leukemic relapse : Similar to

ALL

RX of Relapsed NHL

ESHAP (etoposide, cisplatin, cytarabine, and methylprednisone) DHAP (dexamethasone, cisplatin, and cytarabine) ICE (etoposide, carboplatin, and ifosfamide

Treatment of HIV-related lymphomas

Most lymphomas seen in patients who have HIV infection are of high-grade histology (immunoblastic and small noncleaved cell) and advanced stage at presentation. Extranodal disease is common, with unusual sites of presentation, 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, many patients are unable to tolerate aggressive chemotherapy regimens.

Treatment of HIV-related lymphomas , chemotherapy (contd)

Attenuated-dose regimens (such as CHOP or m-BACOD, with 50% reduction of the doxorubicin and cyclophosphamide doses plus growth factor support) are well tolerated, although hematologic toxicity remains a problem in some patients. A subgroup of patients without adverse prognostic factors achieve durable remissions when treated aggressively. CNS prophylaxis with intrathecal chemotherapy is necessary to prevent meningeal dissemination.

CNS prophylaxis Risk factors for CNS disease include histology (high-grade small noncleaved and lymphoblastic NHL) and special sites of involvement by diffuse aggressive NHL (bone marrow, testis, paranasal sinus, nasopharyngeal, and epidural). Methotrexate (12-15 mg) or cytarabine (Ara-C; 25 mg/m) can be used for intrathecal therapy

A conceptual depiction of the cell cycle phases that all cellsnormal and neoplasticmust traverse before and during cell division.

The percentages given represent the approximate percentage of time spent in each phase by a typical malignant cell The duration of G1, however, can vary markedly. Many of the effective anticancer drugs exert their action on cells traversing the cell cycle and are called cell cycle-specific (CCS) drugs. A second group of agents called cell cycle-nonspecific (CCNS) drugs can sterilize tumor cells whether they are cycling or resting in the G0 compartment. CCNS drugs can kill both G0 and cycling cells (although cycling cells are more sensitive). In general, CCS drugs are most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are proliferating or are in the growth fraction. CCNS drugs (many of which bind to cellular DNA and damage these macromolecules) are particularly useful in low growth fraction solid tumors as well as in high growth fraction tumors

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

Cyclophosphamide 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 microsomal system to 4-Hydroxycyclophamide and Aldophosphamide. 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 synthesis. Major Side effects: 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

Doxorubicin (ADRIAMYCIN) inhibit DNA and RNA synthesis Acute leukemia, Hodgkin's disease, non Hodgkin's lymphomas (BACOP regimen), CA of breast & ovary, small cell CA of lung, sarcomas, best available agent for metastatic thyroid CA I.V. Cardiac toxicity - Doxorubicin mainly affects the heart muscles, leading to tiredness or breathing trouble when climbing stairs or walking, swelling of the feet .

Methotrexate (Antimetabolites

Mechanism of action inhibits formation of FH4 (tetrahydrofolate) from folic acid by inhibiting the enzyme ,dihydrofolate reductase (DHFR); since FH4 transfers methyl groups essential to DNA synthesis and hence DNA synthesis blocked. Side effect and route of administration bone marrow depression, intestinal lesions

Methotrexate , contd and interference with embryogenesis. Drug interaction: aspirin and sulfonamides displace methotrexate from plasma proteins. Orally effective as well as given I.V

Vincristine (MOA) Cytotoxic: Inhibition of mitotic spindle formation by binding to tubulin. M-phase of the cell cycle. Antimitotic drug (natural product) Side-effects Bone marrow depression, epithelial ulceration, GIdisturbances, Neurotoxicity IV

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-cell lymphomas , a subset of indolent B-cell lymphomas and HL. Stem Cell Transplantation (SCT) Allogenenic (a donor) Autologous SCT Bone Marrow Transplant

In an autologous stem cell transplant, the patients own stem cells are removed from his or her bone marrow or peripheral blood. They are collected on several occasions in the weeks before treatment. The cells are frozen and stored while the person gets treatment (high-dose chemotherapy and/or radiation) and are then reinfused into the patients blood. This is the most common type of transplant used to treat NHL It may be hard to get a stem cell sample that is free of lymphoma cells.

Autologous stem cell transplant

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. Usually this donor is a brother or sister if they have the same tissue type as the patient or HLA-matched, unrelated donor . The stem cells for an allogeneic SCT are usually collected from a donors bone marrow or peripheral (circulating) blood on several occasions. In some cases, the source of the stem cells may be blood collected from an umbilical cord (the cord that attaches a baby to the placenta) after a baby is born. This blood is rich in stem cells. Regardless of the source, the stem cells are then frozen and stored until they are needed for the transplant. The use of allogeneic transplants is limited in treating lymphoma because they can have severe side effects

Possible side effects

Side effects from a stem cell transplant are generally divided into early and long-term effects. Early or short-term effects: The early complications and side effects are basically the same as those caused by any other type of high-dose chemotherapy , and can be severe. They are caused by damage to the bone marrow and other quickly growing tissues of the body and can include: Low blood cell counts (with fatigue and increased risks of infection and bleeding) Nausea and vomiting Loss of appetite, and mouth sores. Diarrhoea

Long-term side effects:

Some complications and side effects can persist for a long time or may not occur until months or years after the transplant. 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 and the 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) stem cell transplants. It occurs because the immune system of the patient is taken over by that of the donor. The donor immune system then may recognize the patients own body 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 may also 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 graftversus-lymphoma activity. Any lymphoma cells remaining after the chemotherapy and radiation therapy are often killed by donor immune cells since the lymphoma cells are seen as foreign by the donors immune system as well. Mild graft-versus-host disease can be a good thing.

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 for Patients With NHL

Myelosuppression
The primary adverse effect of many of the chemotherapy regimens used to treat NHL is myelosuppression. Also, transplant recipients are at increased risk of developing secondary myelodysplasia and acute myeloid leukemia, regardless of whether or not they received a radiation-containing conditioning regimen. Prophylactic treatment with antibiotics or colonystimulating 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-induced complications has been reduced or eliminated.

Vaccinations
Patients with CLL and those receiving some therapeutic agents(including bendamustine and ofatumumab) should avoid vaccinations, especially with live viruses. Inactivated influenza vaccine is recommended annually, although patients who have received rituximab generally do not respond to this vaccine for up 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. 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 of electrolytes with aggressive correction if needed. In patients at risk for TLS, the clinician should consider eliminating medications that could exacerbate the component conditions (e.g., thiazide diuretics, potassium supplements, potassium-sparing diuretics

Follow-up of long-term survivors Relapse

The most important risk to patients with NHL is relapse. Among patients with diffuse aggressive lymphomas, most recurrences are seen within the first 2 years after the completion of therapy, although later relapses may occur. Early detection of recurrent disease is important because these patients may be candidates h intervals and follow-up CT scans at 4- to 12-month intervals are recommended. for potentially curative lesion, high-dose therapy and stem-cell transplantation are recommended. and late recurrence of disease may be seen, sometimes after the patient has been in remission for more than a decade. Physical examination at 2- to 3-month

Secondary malignancies :Long-term survivors are at

increased risk for second cancers.

Reference

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

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