Lymphomas: Part II

Natural history Non-Hodgkin’s lymphoma (NHL) Non-Hodgkin’s lymphoma (NHL) is a term covering all lymphoproliferative system malignancies except Hodgkin's lymphoma . The disease is rare in subject under 30 years of age and incidence increase with age . Around two-thirds of all cases are diagnosed in people over 60 years . Natural history Lymphomas can be classified by degree of aggressiveness: 1-Low grade or indolent كسول lymphomas : in which patients may remaining asymptomatic for many years . (untreated survival, measured in years) . 2-High-grade lymphoma is an aggressive and often rapidly fatal condition . (untreated survival measured in months)

Etiology: Congenital and acquired immunodeficiency is the most clearly defined factor known to increase NHL risk.' Immunosuppressant drugs following transplantation lead to a significantly increased (30-50 times) risk of NHL. The risk of NHL in people infected with HIV is more than 100 times that of the general population. Infectious organisms such as Epstein-Barr virus, Helicobacter pylori and hepatitis C virus have all been thought to play a part in the development of NHL. There are data pointing to a number of occupational, dietary, environmental and other risk factors that may help to explain the rising incidence of NHL .

Symptoms NHL usually presents with a painless lump in a lymph node area (most commonly the neck, but also the axillae or groin) . Weight loss, fever and night sweats (known as B-symptoms ) present in about 20% of patients with non-Hodgkin's lymphoma . Patients without these symptoms are classified as category A (without symptoms). There may be upper abdominal pain from hepatosplenomegaly. Spread of the disease is haematogenously (via the blood ) and so extra nodal sites may be involved . Extra nodal involvement is more common in NHL than HL , with involvement of bone marrow, gut , lung, skin, brain,….. . Other features relate to the site of origin of an extra-nodal lymphoma . For example, Mesenteric or gastrointestinal involvement can cause nausea, vomiting, obstruction, abdominal pain, palpable abdominal mass, or gastrointestinal bleeding. Bone marrow involvement can cause symptoms related to anemia, neutropenia( reduction of neutrophils), or thrombocytopenia(low platelet count) . whereas lymphoma of the central nervous system may cause symptoms of raised intracranial pressure with vomiting, headache and fits .

Laboratory Finding : Laboratory examination may reveal anaemia, a raised ESR & a raised Plasma lactate dehydrogenase (LDH) level Diagnosis and Staging: The diagnosis of NHL is established by histological examination of lymph node biopsy sample . (or biopsy of involved extranodal tissue ) . The staging system for non-Hodgkin's lymphoma is the same as that used for Hodgkin's disease and its main use is to distinguish localized stage I and II disease from the disseminated stage III and IV disease

classification The most recent classification of lymphoma is the World Health Organization/revised European-American Lymphoma classification which is 1-Precusor B-cell neoplasm 2-Mature (peripheral) B-cell neoplasms 3-Precursor T-cell neoplasm 4-Mature (peripheral) T-cell and natural-killer neoplasms Diffuse Large B-Cell Lymphoma (DLBCL ), an aggressive lymphoma, represents around 30 % and B-cell follicular lymphoma , an indolent (non-aggressive) lymphoma represents around 22 % of all cases of lymphoma Both of them are within the second group (Mature (peripheral) B-cell neoplasms) All other types of lymphoma have a frequency of less than 10 %, therefore this lecture will focus on Diffuse Large B-Cell Lymphoma (DLBCL ) & follicular lymphoma.

A-Indolent NHL (Low grade ): Desired outcome : The primary treatment goals for non-Hodgkin's lymphoma are to relieve symptoms and, whenever possible, cure the patient of disease without causing unacceptable toxicity . Treatment A-Indolent NHL (Low grade ): Follicular lymphoma is the most common indolent lymphoma . Treatment strategies are summarized for follicular Lymphoma as an example of how to treat indolent lymphoma as follow: Low grade : Stag I/II -----▻ Radiation -----▻ Relapse Stage III/IV either: -asymptomatic -----▻ watch and wait . - symptomatic ----▻ chlorambucil ----▻ Relapse ----▻ Second line chemotherapy   Most patients relapse (median response duration is about 2 years), at least 20% of complete responders will remain in remission for about 10 years .

Early stage follicular lymphoma treatment Involved-field radiotherapy (Radiation to a single field ), when given alone, can cure early stage (I or II) follicular lymphoma and this remains the standard of care in this patient group Advanced Follicular Lymphoma(stage III/ IV): 1- Asymptomatic patients at diagnosis can be followed with " Watch and wait " policy in which therapy is delayed until the patient experiences systemic symptoms or disease progression such as rapidly progressive or bulky adenopathy, anemia, thrombocytopenia, or disease in threatening sites such as the orbit or spinal cord . The median time until chemotherapy is required is about 3 years 2-Symptomatic patients : Oral alkylating agents (chlorambucil ), given either alone or in combination, have been the mainstay of treatment for follicular lymphoma

A-Single agent therapy : Oral alkylating agents, chlorambucil, or cyclophosphamide, are the mainstay of treatment. These single agents are as effective as combination regimens and produce minimal toxicity, but secondary acute myelogenous leukemia (AML) is a concern. (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. i.e., a drop in red blood cells, platelets, and normal white blood cells Therefor Fludarabine and cladribine (It is a purine analog, which interferes with DNA synthesis) produce high response rates without secondary AML, but they are more myelosuppressive (i.e., bone marrow suppression, characterized by a decrease in blood cell production).  

B-Combination chemotherapy : Combination chemotherapy such as CVP (cyclophosphamide, vincristine , prednisone) or CHOP (cyclophosphamide, hydroxydaunomycin (Adriamycin , a new antitumor antibiotic ), Oncovin (vincristine ), prednisone) gives a higher response and longer time to first relapse than the use of single agent alkylators alone, but does not improve overall survival . Therefore patients in whom a more rapid response is desired, multiagent chemotherapy such as (CVP) or (CHOP) may be used .

C-Rituximab : Rituximab is a monoclonal antibody ( that binds specifically to the antigen CD20 expressed on B- lymphocytes, and it cause lysis of B lymphocytes . NHL of B-cell origin expresses CD20 in greater than 90% of cases . Rituximab has become one of the most widely used therapies for follicular lymphoma. Rituximab was initially used as salvage therapy and is also being used as first-line therapy, either alone or combined with CVP (R-CVP ) or CHOP (R-CHOP ) . Rituximab has the advantage of being suitable for retreatment therapy and, interestingly, produces a longer duration of remission after the second course than after the first course . Adverse effects are usually infusion related, especially after the first infusion of rituximab. Adverse effects include fever, chills, respiratory symptoms, fatigue, headache, pruritus, and angioedema. Patients should receive acetaminophen, 650 mg, and diphenhydramine, 50 mg, 30 minutes before the infusion

D-Radioimmunotherapy: Novel strategies for treatment of low-grade lymphomas include the combination of monoclonal antibodies directed against CD20 with a radioactive moiety attached. Two such entities are now approved by (FDA): ibritumomab-yttrium90 (Zevalin®) is a monoclonal antibody to which a radioactive isotope (either yttrium-90 or indium-111) is added. and tositumomab iodine131(Bexxar®) . They have the advantage of delivering radiation to tumor cells expressing the CD20 antigen and to adjacent tumor cells that do not express it. They have the disadvantage of damaging adjacent normal tissue (e.g., bone marrow) . They are licensed for the treatment of CD20-positive follicular B-cell non-Hodgkin's lymphoma, unresponsive to rituximab or which is relapsed and is being evaluated as first-line therapy in combination with CHOP .

B-High-grade (or aggressive) lymphoma treatment Diffuse Large B-Cell Lymphoma (DLBCL ) is the most common high-grade lymphoma . Treatment strategies are summarized for DLBCL as an example of how to treat High-grade lymphoma Intermediate/ high grade either: Stage I/II -----▻ Short course combined chemotherapy x 2 + involved field radiation ¦ Relapse / No response Salvage chemotherapy (Either) Good response -----▻ Consolidation high dose تقوية + Autologous ذاتي stem cell transplantation Or Relapse /No response -----▻ Palliative مسكن therapy Stage III/IV -----▻ combined chemotherapy x 6 Relapse /No response Good response -----▻ Consolidation high dose + Autologous stem cell transplantation Or Relapse /No response -----▻ Palliative therapy  

Salvage Therapy for Aggressive Lymphoma  Salvage therapy is more likely to induce response if the response to initial chemotherapy was complete (chemosensitivity) than if it was less than complete (chemoresistance) . High-dose chemotherapy with autologous HSCT is the therapy of choice for younger patients with chemosensitive relapse . Usually Salvage regimens incorporate drugs not used as initial therapy.

Commonly used regimens include DHAP (dexamethasone, high-dose cytarabine [Ara-C], and cisplatin [Platinol]), ESHAP (etoposide, methylprednisolone [Solumedrol], high-dose cytarabine [Ara-C], and cisplatin [Platinol]), and MINE (mesna (Mesna is used therapeutically to reduce the incidence of haemorrhagic cystitis and haematuria when a patient receives ifosfamide or cyclophosphamide for cancer chemotherapy., ifosfamide (is a nitrogen mustard alkylating agent, mitoxantrone [Novantrone, "antitumor antibiotic." ], and etoposide a DNA toxin). None is clearly superior to the others. ICE (ifosfamide, carboplatin (interact with DNA to interfere with DNA repair)., and etoposide) appears to be better tolerated than cisplatin-containing regimens, especially in elderly adults. Rituximab is being evaluated in combination with many salvage regimens.