60 Lymphomas and multiple myeloma 12/23/2018 1
Lymphomas Lymphoma is cancer of the lymphatic system. Lymphomas are subdivided into two main categories: Hodgkin's lymphoma (HL) and non- Hodgkin's lymphoma (NHL). The site of malignancy is usually a lymph node. Extranodal disease, most frequently of the stomach, skin, oral cavity and pharynx, small intestine and CNS, can occur and is more common in NHL than HL. 12/23/2018 2
Hodgkin's lymphoma Hodgkin s lymphoma (HL) account for about 30% of lymphomas. It is predominantly a disease of young adults, having a peak incidence between the ages of 15 and 35 years. HL is distinguished from NHL by the presence of the pathognomonic Reed-Sternberg (RS) cell which is a ( large abnormal binucleate lymphocyte ). 12/23/2018 3
Etiology The cause of Hodgkin's lymphoma is unknown, but a number of risk factors has been identified. The Epstein-Barr virus which can cause glandular fever, has been shown to play an important role in Hodgkin's lymphoma, accounting for about 50 % of all cases. A Patients who have reduced immunity, for example, AIDS or those taking immunosuppressants, may have an increased risk of developing HL. 12/23/2018 4
Pathology The characteristic pathological finding in HL is the identification of a large, abnormal binucleate lymphocyte called a Reed- Sternberg cell. Hodgkin's lymphoma is divided into two distinct categories: 1- Classical Hodgkin's lymphoma. 2- Nodular lymphocyte-predominant Hodgkin's lymphoma ( NLPHL). 12/23/2018 5
Classical Hodgkin's lymphoma is divided into four histological sub classifications 1- Nodular sclerosis: is the most common form of HL. It is predominated in young adults and females, and has an excellent prognosis. 2- Mixed cellularity: is the second most common type of classic HL and more common in males. 3- Lymphocyte depleted: this carries a poor prognosis and is more common in HIV-positive individuals. 4- Lymphocyte rich: this is a rare type of classic HL. NLPHL accounts for 5% of HL cases and is more common in men. 12/23/2018 6
Clinical Presentation of HL HL usually presents with painless enlargement of lymph nodes, often in the neck. Patients will present with B symptoms which are fever, night sweats and/or weight loss. Others include malaise, itching (25%) or pain at the site of enlarged nodes after drinking alcohol. Bone pain may result from skeletal involvement. 12/23/2018 7
Primary involvement of the gut, central nervous system or bone marrow is rare. If lymph nodes in the chest are involved, patients may present with breathlessness. 12/23/2018 8
Laboratory findings Laboratory findings include normochromic, normocytic anaemia. A raised erythrocyte sedimentation rate and eosinophilia. One-third of patients have a leucocytosis due to an increase in neutrophils. Advanced disease is associated with lymphopenia (lymphocytes <0.6 109 L 1). Plasma lactate dehydrogenase (LDH) is raised in 30 40% of patients at diagnosis and has been associated with a poor prognosis. 12/23/2018 9
Investigations and staging Once the diagnosis has been made on biopsy, further investigations are needed to assess disease activity and the extent of its spread through the lymphoid system or other body sites. The staging of HL is assessed by the Cotswolds modification of the Ann Arbor classification system: 12/23/2018 10
Cotswald Staging Classification for Hodgkin s Disease: 1- Stage I Involvement of a single lymph node region or lymphoid structure. 2- Stage II Involvement of two or more lymph node regions on the same side of the diaphragm. 3- Stage III Involvement of lymph node regions or structures on both sides of the diaphragm. III1 with or without involvement of splenic, hilar, coeliac or portal nodes. III2 with involvement of para-aortic, iliac or mesenteric nodes. 4- Stage IV Involvement of extranodal site. 12/23/2018 11
The tests required to establish the stage includes: A complete history, physical examination, FBC, urea and electrolytes (U and Es), chest X-ray and computed tomography (CT). Other useful tests include erythrocyte sedimentation rate (ESR), serum LDH and liver function tests (LFTs). Positron emission tomography (PET) can be used to detect active residual disease. 12/23/2018 12
Treatment HL is potentially curable and, in general, sensitive to both chemotherapy and radiotherapy. Stage of disease is the biggest factor in treatment choice and outcome. 12/23/2018 13
Early-stage (favourable) disease The cure rate for patients with stages I and IIA disease is greater than 90%. Patients with stages I and IIA disease may be cured with radiotherapy alone (wide or extended field irradiation). However, due to radiation-related late effects and secondary malignancy and the incidence of relapse (25 30%), most receive combined modality treatment (chemotherapy and radiotherapy). This usually consists of two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by involved field radiation therapy (IFRT) The aim of chemotherapy is to destroy subclinical disease outside the field of radiotherapy. 12/23/2018 14
Early-stage (unfavourable) disease Patients with stage I or II presenting with bulky disease, B symptoms or with more than two sites of disease are treated with four to six cycles of combination chemotherapy, for example, ABVD, and radiotherapy to sites of bulky disease. 12/23/2018 15
Advanced disease Patients with advanced disease (stages III and IV) are treated with combination chemotherapy. The first widely used combination chemotherapy regimen was MOPP (mechlorethamine, vincristine (Oncovin), procarbazine and prednisolone). ABVD has replaced MOPP chemotherapy as the regimen of choice as it is as effective but less toxic in terms of fertility, haematological toxicity, and the development of acute leukaemia and myelodysplasia. 12/23/2018 16
Six to eight cycles of ABVD is considered the current standard treatment for advanced disease. A number of regimens have been investigated for example, BEACOPP (bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide,vincristine, procarbazine, prednisolone)). 12/23/2018 17
Other options for patients unlikely to tolerate ABVD include ChlVPP (chlorambucil, vinblastine, procarbazine,prednisolone) and CHOP (cyclophosphamide, doxorubicin (hydroxydaonorubicin), vincristine (Oncovin), prednisolone, rituximab. 12/23/2018 18
Salvage therapy for relapsed disease : Response to salvage therapy depends on previous therapy, and length of remission. Choice of salvage therapy should be guided by response to initial therapy and patient's ability to tolerate therapy. Since the success of salvage treatment has been shown to be influenced by the length of remission after initial chemotherapy." Therefore the disease can be classified as : 1- Primary refractory disease (patients who never achieved a complete remission). 2- Early relapse (within 12 months of complete remission). 3- Late relapse (after more than 12 months of complete remission) 12/23/2018 19
Patients with primary refractory disease or with early relapse are candidates for high-dose chemotherapy with autologus stem cell transplantation. Patients with late relapse can be treated with their initial chemotherapy, radiation therapy, salvage regimen or considered for high-dose chemotherapy with autologus stem cell transplantation. 12/23/2018 20
Salvage regimens: In an effort to avoid cross-resistance, most salvage regimens incorporate drugs not used in the initial therapy. Commonly used salvage regimens include. 1- DHAP (dexamethasone, cytarabine, and cisplatin). 2- ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin). 3- ICE (etoposide, ifosfamide and carboplatin,) 4- IVA ( Epirubicin, Etoposide and Ifosfamide) 12/23/2018 21
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. NHL is slightly more common in men than in women 12/23/2018 22
Aetiology 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. Exposure to certain chemicals such as pesticides and solvents can increase the risk of developing NHL. There is an increased incidence of gastro-intestinal lymphomas in patients with Crohn s disease. 12/23/2018 23
Clinical Presentation of NHL The most common presentation of NHL is painless lymphadenopathy, frequently in the neck area in the supraclavicular and cervical regions. Spread of disease is haematogenously (via the blood), and so extranodal sites may be involved. Signs and symptoms of infection, anaemia or thrombocytopenia may be present in patients with bone marrow involvement. Hepatosplenomegaly may also be present. 12/23/2018 24
Patients may also present with any of the following symptoms: unexplained loss of weight, unexplained fever, drenching night sweats. These symptoms are described as B symptoms and patients without these symptoms are classified as category A. B symptoms are more commonly seen in advanced or aggressive NHL but may be present in all stages and histological subtypes. 12/23/2018 25
Laboratory findings Laboratory examinations may reveal anaemia, a raised erythrocyte sedimentation rate and a raised serum LDH level. There may be a reduction in circulating immunoglobulins, and a monoclonal paraprotein may be seen in a small number of cases. 12/23/2018 26
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. 12/23/2018 27
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 12/23/2018 28
Treatment When designing a treatment plan for an individual patient, various factors must be taken into account, these include the: patient's age general health The extent or stage of the lymphoma The particular histological subtype. 12/23/2018 29
Indolent (low-grade) lymphoma tends to run a slow course and although it is not curable, patients survive for prolonged periods with minimal symptoms. Aggressive (high-grade) lymphomas result in death within weeks or months if untreated. These lymphomas are very responsive to chemotherapy and up to 50 60% may be cured with combination chemotherapy. 12/23/2018 30
Indolent non-hodgkin's lymphoma Follicular lymphoma is the most common of the indolent lymphomas. For the minority of patients presenting with limited stage disease (stage I), radiotherapy to the involved field is generally used. the majority (80%) of patients present with advanced disease (stages II IV) where the aim of treatment is to reduce disease bulk and offer symptom relief. Rituximab, cyclophosphamide, vincristine, prednisolone (R-CVP) is used as the first-line treatment for advanced (stage III or IV) follicular lymphoma. 12/23/2018 31
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) can also be used as first-line treatment for young patients with aggressive disease and is an option in relapsed disease. Other effective chemotherapy regimens in the treatment non- Hodgkin s lymphoma includes FC (Fludarabine and Cyclophosphamide) and CHOP ( Cyclophosphamide, Doxorubicin (hydroxydaunorubicin),vincristine (Oncovin) and Prednisolone). 12/23/2018 32
If patients fail to tolerate the standard treatment options, an oral alkylating agent, for example, chlorambucil, with or without a steroid can be used. 12/23/2018 33
Relapsed indolent non-hodgkin's lymphoma Relapsed patients may be re-treated with rituximab if the time to relapse post-rituximab is greater than 6 months. If the time to relapse is less than 6 months, Yttrium-90 labelled ibritumomab tiuxetan (Zevalin ) with a radioactive moiety attached may be considered. 12/23/2018 34
Aggressive non-hodgkin's lymphoma The most common presentation is diffuse large B-cell lymphoma (DLBCL). The treatment for advanced-stage aggressive NHL is six cycles of the combination of R-CHOP chemotherapy. 12/23/2018 35
Relapsed aggressive non-hodgkin's lymphoma over the half of all patients have refractory disease or relapse after first treatment. In younger patients with aggressive NHL, the aim will be to introduce remission with further chemotherapy, using an alternative, salvage regimen, and then to consolidate remission with high-dose therapy (HDT). HDT is usually supported by mobilised peripheral blood stem cells (PBSCs) and an autologous PBSC transplantation (auto-pbsct). 12/23/2018 36
Commonly used salvage regimens include ICE (ifosfamide, carboplatin, etoposide), ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) DHAP (cisplatin, cytarabine, dexamethasone) 12/23/2018 37
Gemcitabine may be of benefit for patients with relapsed or refractory disease after two lines of treatment. Gemcitabine is used in combination with other agents, such as cisplatin and methylprednisolone. Rituximab can also be added to these salvage regimens. 12/23/2018 38
Multiple myeloma Myeloma is a malignant disease of the plasma cells of bone marrow, accounting for 1% of all malignant disease. There is a clonal expansion of abnormal, proliferating plasma cells producing a monoclonal paraprotein, mainly IgG or IgA and rarely IgM and IgD. The paraproteinaemia may be associated with excretion of light chains in the urine (Bence Jones protein), which are either kappa or lambda. 12/23/2018 39
Epidemiology and Etiology: The median age of diagnosis is over 60 years and the disease occurs more Frequently in men than in women. The etiology of multiple myeloma is unknown. Pathology Although a small number of malignant plasma cells are present in the circulation, the majority are present in the bone marrow. The malignant plasma cells produce cytokines, which stimulate osteoclasts and result in net bone absorption. The resulting lytic lesions cause bone pain, fractures and hypercalcaemia. Marrow involvement can result in anaemia or pancytopenia. 12/23/2018 40
Symptoms Bone pain Symptom of anemia Symptoms of Renal failure Symptoms of hypercalcemia Recurrent infections Rarely, symptoms of hyperviscosity and bleeding due to thrombocytopenia. Amyloidosis (develops in 10% ) (Amyloidosis is an extracellular deposition of an insolouble protein called amyloid in various tissues which affect the normal function and structure of the affected tissue). 12/23/2018 41
Investigations The diagnosis of myeloma requires two of the following criteria: An increase in bone marrow plasma cells Radiological evidence of lytic bone lesions Paraproteinaemia or Bence Jones protein Bone marrow aspiration, plasma and urinary electrophoresis, and a skeletal survey are thus required. 12/23/2018 42
Treatment Multiple myeloma is an incurable disease; however, advancements in the treatment of myeloma have extended survival significantly. Almost all patients will become refractory to initial treatment. Non-pharmacologic Therapy Autologous stem cell transplantation results in higher response rates and extends overall survival. 12/23/2018 43
Pharmacologic Therapy Immediate support : High fluid intake to treat renal impairment and hypercalcaemia. Analgesia for bone pain. Bisphosphonates, Pamidronate and zolendronic acid for hypercalcaemia and to delay other skeletal related events. Allopurinol to prevent urate nephropathy. Plasmapheresis, as necessary, for hyperviscosity. Plasmapheresis is an operation to take blood from someone, then to separate the red blood cells from the plasma, and to return the red blood cells suspended in a saline solution to the patient. 12/23/2018 44
1-Conventional-Dose Chemotherapy Patients who present with symptomatic disease will be started on therapy. Two regimens used are : (VAD )vincristine, doxorubicin & dexamethasone (MP) melphalan and prednisone. VAD like chemotherapy regimens are used most often in transplant candidates because it avoids the alkylating agent melphalan, thus minimizing damage to the stem cell compartment 2-Corticosteroids High-dose dexamethasone (40 mg/day) is an option for patients who cannot tolerate chemotherapy or have few highrisk features. Advantages of this regimen include ease of administration 12/23/2018 45 and lack of hematologic adverse effect.
3-Thalidomide (Thalomid ) Thalidomide as monotherapy or combination therapy is beneficial in the treatment of multiple myeloma.. Thalidomide may be given in combination with dexamethasone, resulting in greater response rates than when given alone. Common side effects of thalidomide therapy include somnolence, constipation, peripheral neuropathy, deep vein thrombosis. Prophylactic anticoagulation should be considered to prevent deep vein thrombosis associated with thalidomide therapy. There are substantial teratogenic effects of thalidomide if used during pregnancy. 4-Bortezomib It induce myeloma cell death. It Approved for the treatment of relapsed disease. 12/23/2018 46
5-Lenalidomide: Lenalidomide is an immunomodulating agent related to thalidomide that was recently approved for the treatment of patients with multiple myeloma. Lenalidomide lacks the common side effects of thalidomide, such as constipation and peripheral neuropathy. 12/23/2018 47