UMF IASI 2015



LECTURE 3bNON-HODGKIN LYMPHOMAI. BackgroundThe term lymphoma describes a heterogeneous group of malignancies with different biology and prognosis. In general, lymphomas are divided into 2 large groups of neoplasms, namely non-Hodgkin lymphoma (NHL) and Hodgkin disease. About 85% of all malignant lymphomas are NHLs. The median age at diagnosis is the sixth decade of life, although Burkitt lymphoma and lymphoblastic lymphoma occur in younger patients. NHL includes many clinicopathologic subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy. Currently, several NHL classification schemas exist, reflecting the growing understanding of the complex diversity of the NHL subtypes. The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade). In the 1990s, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. The World Health Organization (WHO) classification further elaborates upon the REAL approach. This classification divides NHL into those of B-cell origin and those of T-cell and natural killer (NK)–cell origin.For clinical oncologists, the most practical way of sorting the currently recognized types of NHL is according to their predicted clinical behavior.The treatment of non-Hodgkin lymphoma (NHL) varies greatly, depending on tumor stage, grade, and type and various patient factors (eg, symptoms, age, performance status; see Treatment and Management). II. EpidemiologySince the early 1970s, the incidence rates of NHL have nearly doubled. Although some of this increase may be attributable to earlier detection (resulting from improved diagnostic techniques and access to medical care), or possibly to HIV-associated lymphomas, for the most part the rise is unexplained. NHL is the most prevalent hematopoietic neoplasm, representing approximately 4% of all cancer diagnoses and ranking seventh in frequency among all cancers. NHL is more than 5 times as common as Hodgkin disease. Incidence varies with race; white people have a higher risk than black and Asian American people. In general, the incidence of NHL is slightly higher in men than in women, with a male-to-female ratio of approximately 1.4:1.The median age at presentation for most subtypes of NHL is older than 50 years. The exceptions are high-grade lymphoblastic and small noncleaved lymphomas, which are the most common types of NHL observed in children and young adults. III. PreviousNext Section: Pathophysiology Etiology NHLs may result from chromosomal translocations, infections, environmental factors, immunodeficiency states, and chronic inflammation.Chromosomal translocations - chromosomal translocations and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype. t(14;18)(q32;q21) - occurs in 85% of follicular lymphomas and 28% of higher-grade NHLs. t(11;14)(q13;q32) - has a nonrandom association with mantle cell lymphoma.Infection - some viruses are implicated in the pathogenesis of NHL, probably because of their ability to induce chronic antigenic stimulation and cytokine dysregulation, which leads to uncontrolled B- or T-cell stimulation, proliferation, and lymphomagenesis. Epstein-Barr virus (EBV) is a DNA virus that is associated with Burkitt lymphoma (especially the endemic form in Africa), Hodgkin diseaseHIV infectionHuman T-cell leukemia virus type 1 (HTLV-1) causes a latent infection via reverse transcription in activated T-helper cells. Approximately 5% of carriers develop adult T-cell leukemia or lymphoma. Hepatitis C virus (HCV) is associated with the development of clonal B-cell expansions and certain subtypes of NHL. Kaposi sarcoma–associated herpesvirus (KSHV) is associated with body cavity–based lymphomas in patients with HIV infection and in patients with multicentric Castleman disease. Helicobacter pylori infection is associated with the development of primary gastrointestinal (GI) lymphomas, particularly gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Environmental factors - linked to the development of NHL include chemicals (eg, pesticides, herbicides, solvents, organic chemicals, wood preservatives, dusts, hair dye), chemotherapy, and radiation exposure. Immunodeficiency states - are associated with increased incidence of NHLCongenital immunodeficiency states (eg, severe combined immunodeficiency disease [SCID], Wiskott-Aldrich syndrome), acquired immunodeficiency states (eg, AIDS), and induced immunodeficiency states (eg, immunosuppression in transplanted patients). Chronic inflammation - observed in patients with autoimmune disorders, such as Sj?gren syndrome and Hashimoto thyroiditis, promotes the development of MALT and predisposes patients to subsequent lymphoid malignancies. IV. Next Section: Pathophysiology PathophysiologyNHLs are tumors originating from lymphoid tissues, mainly of lymph nodes. Various neoplastic tumor cell lines correspond to each of the cellular components of antigen-stimulated lymphoid follicles. NHL represents a progressive clonal expansion of B cells or T cells and/or NK cells arising from an accumulation of lesions affecting proto-oncogenes or tumor suppressor genes, resulting in cell immortalization. These oncogenes can be activated by chromosomal translocations (ie, the genetic hallmark of lymphoid malignancies), or tumor suppressor loci can be inactivated by chromosomal deletion or mutation. In addition, the genome of certain lymphoma subtypes can be altered with the introduction of exogenous genes by various oncogenic viruses. Several cytogenetic lesions are associated with specific NHLs, reflecting the presence of specific markers of diagnostic significance in subclassifying various NHL subtypes. Almost 85% of NHLs are of B-cell origin; only 15% are derived from T/NK cells, and the small remainder stem from macrophages. These tumors are characterized by the level of differentiation, the size of the cell of origin, the origin cell's rate of proliferation, and the histologic pattern of growth. PreviousNext Section: Pathophysiology V. ClinicalV.1. PreviousNext Section: Pathophysiology HistoryThe clinical manifestations of non-Hodgkin lymphoma (NHL) vary with such factors as the location of the lymphomatous process, the rate of tumor growth, and the function of the organ being compromised or displaced by the malignant process. The Working Formulation classification groups the subtypes of NHL by clinical behavior—that is,low-grade, intermediate-grade, and high-grade.V.1.a. Low-grade lymphomasPeripheral adenopathy that is painless and slowly progressive is the most common clinical presentation in these patients. Spontaneous regression of enlarged lymph nodes can occur in low-grade lymphoma, potentially causing confusion with an infectious condition. Primary extranodal involvement and B symptoms (ie, temperature >38°C, night sweats, weight loss >10% from baseline within 6 mo) are not common at presentation, but they are common in patients with advanced, malignant transformation (ie, evolution from a low-grade to an intermediate- or high-grade lymphoma) or end-stage disease. Bone marrow is frequently involved and may be associated with cytopenia or cytopenias Fatigue and weakness are more common in patients with advanced-stage disease. V.1.b. Intermediate- and high-grade lymphomasThese types of lymphomas cause a more varied clinical presentation. Most patients present with adenopathy. More than one third of patients present with extranodal involvement; the most common sites are the gastrointestinal (GI) tract ORL - including the Waldeyer ring, skin, bone marrow, sinuses, genitourinary (GU) tract, thyroid, and central nervous system (CNS). B-symptoms are more common, occurring in approximately 30-40% of patients. V.1.c. Particularities :Lymphoblastic lymphoma, a high-grade lymphoma, often manifests with an anterior superior mediastinal mass, superior vena cava (SVC) syndrome, and leptomeningeal disease with cranial nerve palsies. Patients with Burkitt lymphoma (occurring in western cauntries) often present with a large abdominal mass and symptoms of bowel obstruction. Obstructive hydronephrosis secondary to bulky retroperitoneal lymphadenopathy obstructing the ureters can also be observed in these patients. Primary CNS lymphomas are high-grade neoplasms of B-cell origin. Most lymphomas originating in the CNS are large cell lymphomas or immunoblastomas, and they account for 1% of all intracranial neoplasms. These lymphomas are more commonly observed in patients who are immunodeficient because of conditions such as Wiskott-Aldrich syndrome, transplantation, or AIDS.V.2. Next Section: Physical Examination Physical ExaminationLow-grade lymphomasPeripheral adenopathySplenomegaly: Splenomegaly is observed in approximately 40% of patients; the spleen rarely is the only involved site at presentation.HepatomegalyIntermediate- and high-grade lymphomasRapidly growing and bulky lymphadenopathySplenomegalyHepatomegalyLarge abdominal mass: This usually occurs in Burkitt lymphoma.Testicular massSkin lesions: Lesions are associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic large cell lymphoma, and angioimmunoblastic lymphoma.Chest radiograph: The chest radiograph may demonstrate a bulky mediastinal mass, which is associated with primary mediastinal large B-cell lymphoma or lymphoblastic lymphoma.V.2. PreviousNext Section: Physical Examination Complications Potential disease-related complications include the following:Cytopenias (ie, neutropenia, anemia, thrombocytopenia) secondary to bone marrow infiltration; alternatively, autoimmune hemolytic anemia is observed in some types of NHL (eg, small lymphocytic lymphoma /chronic lymphocytic leukemia [SLL/CLL]) Bleeding secondary to thrombocytopenia, disseminated intravascular coagulation (DIC), or vascular invasion by the tumorInfection secondary to leukopenia, especially neutropeniaCardiac problems secondary to large pericardial effusion or arrhythmias secondary to cardiac metastasesRespiratory problems secondary to pleural effusion and/or parenchymal lesionsSuperior vena cava (SVC) syndrome secondary to a large mediastinal tumorSpinal cord compression secondary to vertebral metastasesNeurologic problems secondary to primary CNS lymphoma or lymphomatous meningitisGI obstruction, perforation, and bleeding in a patient with GI lymphoma (may also be caused by chemotherapy)Pain secondary to tumor invasionLeukocytosis (lymphocytosis) in leukemic phase of diseaseVI. Differential Diagnoses A significant number of medical disorders can produce local or generalized lymph node enlargement. Thus, the diagnosis of NHL relies on pathological confirmation following appropriate tissue biopsy. The following are some of the conditions that can result in clinical manifestations similar to those observed in lymphoma patients: metastatic disease to lymph nodes secondary to carcinoma, melanoma, or sarcomaother hematologic malignancies or lymphoproliferative disorders: granulocytic sarcoma, multicentric Castleman diseasebenign lymph node infiltration or reactive follicular hyperplasia secondary to infection (eg, tuberculosis; other bacterial, fungal, and, rarely, viral infections), and collagen-vascular diseases Hodgkin lymphoma, which requires a different treatment strategy than NHLIf the diagnosis of NHL is doubtful, acquire a second or third opinion from an expert hematopathologist before instituting therapy. Flow cytometry and cytogenetics should also be performed and can be especially helpful in difficult situations. VII. WorkupVII.1. Positive diagnosesThe diagnoses of NHL is made only on a histopathologic exam combined wit immunophenotypic and cytogenetic analysis of a biopsy sample taken of an lymphadenopathy or other specific tumor.Biopsy - a well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph node is the mainstay of pathologic diagnosis. Excisional lymph node biopsy is required because lymphoma diagnosis relies heavily on careful assessment of altered nodal architecture accompanying lymphomatous infiltrates. Fine-needle aspiration (FNA) is insufficient for establishing a diagnosis; needle-core biopsies have a limited role in establishing a diagnosis of NHL. Biopsy of extranodal sites - in approximately 30-35% of adult patients with NHL, the extranodal sites are the primary presenting sites. The most common site is the GI tract. Processing extranodal biopsy material for lymphoma protocol studies is important whenever suspicion of a hematolymphoid neoplasm exists.Histologic Findings - NHLs are a heterogeneous group of lymphoproliferative malignancies, with varying morphologic features depending on the specific subtype. The abnormal lymphocytes in the lymph node, bone marrow, or extranodal sites can be small cleaved or noncleaved, intermediate, or large cell and can have a follicular or diffuse pattern. In contrast with reactive follicular hyperplasia, lymphomas usually alter the lymph node architecture, and the capsule is usually involved. PreviousNext Section: CBC Count Immunophenotypic Analysismay be useful in resolving a diagnostic dilemma in patients with an atypical morphology. provides information about lineage and clonality, which are complementary to the histology of a given case. is also useful for subclassifying certain lymphoma subtypes, which has therapeutic and prognostic importance. helps to distinguish reactive from neoplastic lymphoid infiltrates, lymphoid from nonlymphoid malignancies, and specific lymphoid neoplasms.PreviousNext Section: CBC Count Cytogenetic Studies - have contributed to the understanding of the biology and prognosis of lymphoma. Cytogenetic studies are critical to the discovery of oncogene abnormalities that now are known to be intimately involved in the pathogenesis of NHL. VII.2. Approach Considerations for stagingThe workup in a patient with suspected non-Hodgkin lymphoma (NHL) should include the following:Complete blood cell (CBC) countSerum chemistry studies, including lactate dehydrogenase (LDH)Serum beta2-microglobulin levelHIV serologyChest radiographyComputed tomography (CT) scan of the neck, chest, abdomen, and pelvisPositron emission tomography (PET) scanExcisional lymph node biopsyBone marrow aspirate and biopsyHepatitis B testing in patients in whom rituximab therapy is planned because reactivation has been reportedOther studies may be indicated, depending on the clinical presentation.VII.2.a. Next Section: CBC Count CBC CountIn the early stage of disease, patients with NHL may have blood counts within the reference range. As the disease progresses, a CBC count with differential and platelet count in patients with NHL may show the following: Anemia secondary to bone marrow infiltration, autoimmune hemolysis (particularly associated with small lymphocytic lymphoma [SLL]/chronic lymphocytic leukemia [CLL]), bleeding, anemia of chronic disease Thrombocytopenia, leukopenia, or pancytopenia secondary to bone marrow infiltration or autoimmune cytopeniasLymphocytosis with circulating malignant cells (common in patients with low-grade lymphomas)Thrombocytosis (paraneoplastic syndrome associated with lymphomas or reactive secondary to blood loss)VII.2.b. PreviousNext Section: CBC Count Serum Chemistry StudiesSerum chemistry studies may show the following:Elevated lactate dehydrogenase (LDH): indicates poor prognosis; correlates with increased tumor burdenAbnormal liver function test (LFT) results: secondary to hepatic involvement, hypermetabolic tumor growth, chronic inflammationHypercalcemia: in patients with acute form of adult T-cell lymphoma-leukemia (ATLL)Elevated beta2-microglobulin level may be seen (prognostic value). Occasionally, NHL is associated with monoclonal gammopathy. A Coombs test may be positive result (especially in SLL/CLL). Hypogammaglobulinemia may be present HIV serology should be obtained, especially in patients with diffuse large cell immunoblastic or small noncleaved histologies. HTLV-1 serology should be obtained in patients with ATLL. VII.2.c. Bone marrow aspirate and biopsyPerform this procedure for staging rather than diagnostic purposes. In bone marrow sections, the neoplastic cells may infiltrate in a focal (ie, paratrabecular or nonparatrabecular, depending on the type of lymphoma), interstitial, or diffuse pattern. VII.2.d. PreviousNext Section: CBC Count RadiographyA chest radiograph yields positive information in approximately one fourth of patients with NHLs. It may identify hilar or mediastinal adenopathy, pleural or pericardial effusions, and parenchymal involvement. The chest radiograph may demonstrate a bulky mediastinal mass, which is associated with primary mediastinal large B-cell lymphoma or lymphoblastic lymphoma. Obtain an upper GI series with small bowel follow-through in patients with head and neck involvement (eg, tonsil, base of tongue, nasopharynx, Waldeyer ring) and those with a GI primary lesion. VII.2.e. PreviousNext Section: CBC Count CT, Bone Scan, and Gallium ScanA CT scan of the neck, chest, abdomen, and pelvis is used to detect enlarged lymph nodes, hepatosplenomegaly, or filling defects in the liver and spleen. Currently, it is the most widely used test for initial staging, assessing treatment response, and conducting follow-up care.VII.2.f. PreviousNext Section: CBC Count Positron Emission Tomography and UltrasonographyWhole body F-18 2-deoxyglucose (FDG) positron emission tomography (PET) scan can be used for the initial evaluation of patients with NHL; however, this scan is more useful for posttreatment evaluation to differentiate early recurrences or residual disease from fibrosis or necrosis. This PET scan has a higher predictive value for relapse than classic CT scan imaging. PreviousNext Section: CBC Count VII.2.g. ECHO cardigraphy - should be performed to measure the left ventricular ejection fraction (LVEF) of patients who are being considered for treatment with anthracyclines. In general, anthracyclines should not be administered to those patients with LVEF of less than 50%.VII.2.h. PreviousNext Section: CBC Count Magnetic Resonance ImagingObtain an MRI of the brain and spinal cord of patients who are suspected of having primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma. An MRI scan can also be performed to identify focal areas of marrow involvement in those patients suspected to have bone marrow involvement but in whom random bone marrow biopsy findings have been negative. VII.2.i. PreviousNext Section: CBC Count PreviousNext Section: CBC Count Lumbar PunctureLumbar puncture for cerebrospinal fluid (CSF) examination should be performed in patients with the following conditions:Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, or nasopharyngeal involvement, or two or more extranodal sites of disease High-grade lymphoblastic lymphomaHigh-grade small noncleaved cell lymphomas (eg, Burkitt and non-Burkitt types)HIV-related lymphomaPrimary CNS lymphomaNeurologic signs and symptomsPreviousNext Section: CBC Count VII.3. PreviousNext Section: CBC Count Staging Staging is important in selecting a treatment and determining prognosis. CT scans of the neck, chest, abdomen, and pelvis, as well as bilateral bone marrow aspirate and biopsy, are necessary to stage the lymphoma. Noncontiguous lymph node involvement, uncommon in Hodgkin disease, is more common among patients with NHL. The Ann Arbor staging system is the most commonly used staging system for patients with NHL. This system divides NHL into 4 stages, as follows:Stage I NHL involves a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)Stage II NHL involves 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ in addition to criteria for stage II (IIE) Stage III involves lymph node regions on both sides of the diaphragm (III) that also may be accompanied by localized involvement of an extralymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE) Stage IV represents disseminated or multifocal involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement The stages can also be appended by A or B designations. Patients with A disease do not have systemic symptoms. The B designation is applied in patients with any of the following symptoms: Unexplained loss of more than 10% of body weight in the 6 months before diagnosisUnexplained fever with temperature above 38°CDrenching night sweatsVIII. Prognosis The 5-year relative survival rate of patients with NHL is approximately 63%. The survival rate has steadily improved over the last 2 decades, thanks to improvements in medical and nursing care, the advent of novel therapeutic strategies (ie, monoclonal antibodies), validation of biomarkers of response, and the implementation of tailored treatment. The prognosis for patients with NHL depends on the following factors:Tumor histology (based on Working Formulation classification)Tumor stagePatient ageTumor bulkPerformance statusSerum lactate dehydrogenase (LDH) levelBeta2-microglobulin levelPresence or absence of extranodal diseaseIn general, these clinical characteristics are thought to reflect the following host or tumor characteristics:Tumor growth and invasive potential (eg, LDH, stage, tumor size, beta2-microglobulin level, number of nodal and extranodal sites, bone marrow involvement) Patient's response to tumor (eg, performance status, B symptoms)Patient's tolerance of intensive therapy (eg, performance status, patient age, bone marrow involvement)The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive NHL, also appears to be useful for predicting the outcome of patients with low-grade lymphoma and mantle cell lymphoma. This index is also used to identify patients at high risk of relapse, based on specific sites of involvement, including bone marrow, CNS, liver, testis, lung, and spleen. These patients may be considered for clinical trials that aim at improving the current treatment standard. Clinical features included in the IPI that are independently predictive of survival include the following:Age - Younger than 60 years versus older than 60 yearsLDH level - Within the reference range versus elevatedPerformance status -Eastern Cooperative Oncology Group (ECOG) grade 0-1 versus 2-4Ann Arbor stage - Stage I-II versus III-IVNumber of extranodal sites - Zero to 1 versus more than 1With this model, relapse-free and overall survival rates at 5 years are as follows:Low risk = 0-1 risk factors - 75%Intermediary risk = 2-3 risk factors - 50%High risk = 4-5 risk factors - 25%For patients with follicular lymphoma—the second most common subtype of NHL—the Follicular Lymphoma International Prognostic Index (FLIPI) score appears to be more discriminating than the IPI. Age (>60 y)Ann Arbor stage (III-IV)Hemoglobin level (< 12 g/dL)Number of nodal areas (>4)Serum LDH level (above normal)Three risk groups are defined: low risk (0-1 adverse factor), intermediate risk (2 factors), and poor risk (3 or more adverse factors).Other prognostic factorsTime to achieve CR and response duration: Patients who do not achieve complete remission by the third cycle of CHOP chemotherapy have worse prognosis than those who achieve rapid CR.Immunophenotype: Patients with aggressive T- or NK-cell lymphomas generally have worse prognoses than those with B-cell lymphomas, except the Ki-1 anaplastic large T- or null cell lymphomas.Cytogenetic abnormalities and oncogene expression: Patients with lymphomas with 1, 7, and 17 chromosomal abnormalities have worse prognoses than those with lymphomas without these changes.PreviousNext Section: Pathophysiology IX. TreatmentThe treatment of non-Hodgkin lymphoma (NHL) varies greatly, depending on the following factors:Tumor stagePhenotype (B-cell, T-cell or natural killer (NK) cell/null-cell)Histology (ie, low-, intermediate-, or high-grade)SymptomsPerformance statusPatient ageComorbiditiesIX.a. General approachesMost of the chemotherapy for NHL, whether combination or single-drug, can be administered in an outpatient setting, at an infusion clinic. In the infusion clinic, specially trained oncology nurses, who are supervised by oncologists, administer the chemotherapy. Growth factor support (eg, GCSF, GM-CSF, erythropoietin) is also administered in an outpatient treatment setting. Infusional chemotherapy (eg, infusional cyclophosphamide, doxorubicin, and etoposide [CDE], which should be administered continuously for 4 days) should be administered as inpatient treatment.High-dose chemotherapy and bone marrow and/or stem cell transplantation are administered in an inpatient setting of a tertiary hospital with an approved transplant center. For the initial treatment of patients with intermediate- or high-grade lymphoma and patients with bulky disease, an inpatient setting is recommended in order to monitor for tumor lysis syndrome and to manage appropriately. Admit patients with NHL for complications of disease progression (eg, pain control for intractable pain) or adverse effects from chemotherapy (eg, dehydration secondary to diarrhea, vomiting requiring IV hydration, severe mucositis). Patients with fever during neutropenia should be admitted for broad-spectrum antibiotic therapy. IX. b. Next Section: Management of Indolent NHL Management of Indolent NHLFollicular lymphoma (grade I-IIIa) comprises 70% of this group. Other entities in this group include small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, and marginal zone lymphomas (MZL, nodal or extranodal). Indolent stage I and contiguous stage II NHLStandard management consists of radiotherapy alone.Offering adjuvant chemotherapy to selected patients with stage I-II NHL who have unfavorable prognostic factors (eg, B symptoms, >2 nodal sites), and to those with follicular mixed histology is not unreasonable. Early treatment in asymptomatic patients has not been shown to improve survival. Indolent noncontiguous stage II, III, and IV NHLAdvanced indolent lymphomas have been accepted to be not curable with currently available therapies. However, sustained complete remissions can be achieved with various treatment modalities. The use of rituximab, a monoclonal antibody targeting CD20 antigen present in benign and malignant B-cells, in combination with systemic chemotherapy, has resulted in an improved duration of remission and survival for patients with indolent B-cell lymphomas when compared to chemotherapy. Asymptomatic patients, especially older patients and patients with concomitant medical problems, deferred therapy with careful observation is an option. The treatment of symptomatic patients with indolent lymphomas should be focused on achieving the best possible quality of response without producing excessive toxicity.Single-agent treatment with chlorambucil or cyclophosphamide (with or without prednisone) is useful in elderly patients with significant comorbidities. Combination chemotherapies are used in younger patients with the goal of achieving a complete remission Rituximab plus chemotherapy gives the best results : R-CHOP (cyclophosphamide, hydroxydaunomycin [Adriamycin], vincristine [Oncovin], and prednisone), R-CVP (cyclophosphamide, vincristine, and prednisone), and R-FC (fludarabine plus cyclophosphamide). IX.c. PreviousNext Section: Management of Indolent NHL Management of Aggressive NHLDiffuse large B-cell lymphoma is the most common type of NHL. Other distinct entities in this group include immunoblastic, anaplastic, lymphoblastic, large-cell, Burkitt, and Burkitt-like lymphomas (high-grade lymphomas). Mantle cell lymphomas also behave aggressively. a. Aggressive stage I and contiguous stage II (nonbulky or < 10 cm) NHLThe preferred treatment option for patients with intermediate-grade NHL is combination chemotherapy (3 cycles of CHOP) plus involved-field radiation therapy. Patients with high-grade disease should be strongly considered for treatment with more aggressive regimens beyond CHOP. b. Aggressive noncontiguous stage II, III, and IV NHLApproximately 40-50% of these patients are cured with standard chemotherapy, approximately 35-40% will respond but ultimately progress or relapse, and the remainder will be have disease that is refractory to primary treatment. The following regimens may be used with similar results: R-CHOPPrednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM) Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD)Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B)R-Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine) plus rituximab has been shown to achieve a high rate of durable remission in patients with mantle cell lymphoma. It is a toxic regimen and is typically used in patients with good performance status, who can tolerate it; otherwise, R-CHOP is used.[29] Bendamustine and rituximab combination has been successfully used in patients with mantle cell lymphoma in the first and second-line setting. Currently, 6-8 cycles of CHOP chemotherapy in combination with rituximab is the standard of care in patients with advanced disease. CNS prophylaxis, usually with 4-6 injections of methotrexate intrathecally, is recommended for patients with paranasal sinus or testicular involvement, diffuse small noncleaved cell or Burkitt lymphoma, or lymphoblastic lymphoma. CNS prophylaxis for bone marrow involvement is controversial. IX.d. PreviousNext Section: Management of Indolent NHL Complications of TherapyPotential chemotherapy and other treatment-related complications include the following:Cytopenias (ie, neutropenia, anemia, thrombocytopenia)Nausea or vomitingInfectionFatigueNeuropathyDehydration after diarrhea or vomitingCardiac toxicity from doxorubicinCatheter-related sepsisCatheter-related thrombosisSecondary malignanciesTumor lysis syndromeAtherosclerosis* Tumor lysis syndromeThis syndrome commonly occurs after treatment of high-grade bulky NHLs because of their exquisite sensitivity to therapy, which is caused by their high proliferative capacity. Tumor lysis syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and renal failure. Death from cardiac asystole can occur from hyperkalemia. Measures to prevent this complication include aggressive hydration, allopurinol administration, and urine alkalinization. Frequent monitoring of input and output, electrolytes, uric acid, and creatinine is necessary. Dialysis is sometimes required. HYPERLINK "" \l "2" Next Section: Cytotoxic agents ................
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