Christopher Fausel and Patrick J. Kiel
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Discuss the underlying pathophysiologic mechanisms of the lymphomas and how they relate to presenting symptoms of the disease.
2. Differentiate the pathologic findings of Hodgkin’s lymphoma (HL); follicular indolent non-Hodgkin’s lymphoma (NHL); and diffuse aggressive NHL and how this information yields a specific diagnosis.
3. Describe the general staging criteria for the lymphomas and how it relates to prognosis; evaluate the role of the International Prognostic Index (IPI) for providing prognostic information for NHL.
4. Contrast the treatment algorithms for early and advanced-stage disease for HL.
5. Delineate the clinical course of follicular indolent and diffuse aggressive NHL and the implications for disease classification schemes and treatment goals.
6. Outline the general treatment approach to follicular indolent and diffuse aggressive NHL for localized and advanced disease.
7. Interpret the current role for monoclonal antibody therapy in NHL.
8. Assess the role of autologous hematopoietic stem cell transplantation (SCT) for relapsed HL and NHL.
KEY CONCEPTS
B and T cells undergo neoplastic transformation that is governed by specific mutations in their chromosomes that result in populations of malignant lymphoma cells.
Specific pathologic characteristics distinguishing Hodgkin’s lymphoma (HL) from non-Hodgkin’s lymphoma (NHL) include morphology, cell surface antigens, and chromosomal mutations.
Classic signs and symptoms of the lymphomas include lymphadenopathy and B symptoms (i.e., fever, night sweats, and weight loss).
The diagnosis of malignant lymphomas is established by tumor biopsy sample, analysis of the biopsy tissue, and determination of the extent of the disease in the patient.
The goal of treatment of HL is cure for all stages of disease and first relapse.
Follicular indolent NHL is incurable, so therapy goals focus on inducing and maintaining remission duration while minimizing treatment-related toxicities.
Diffuse, aggressive NHL centers on curative-intent therapy using anthracyline-based combination chemotherapy for initial treatment and high-dose chemotherapy with autologous stem cell transplantation (SCT) for relapsed disease.
The recombinant monoclonal antibody rituximab is an effective treatment option for patients with B-cell origin CD20+ NHL as a single agent and enhances the efficacy of combination chemotherapy regimens.
INTRODUCTION
The malignant lymphomas are a clonal disorder of hematopoiesis with the primary malignant cells consisting of lymphocytes of either B-cell, T-cell, and NK-cell origin. These cells originate from a small population of lymphocytes that have undergone malignant transformation secondary to a series of genetic mutations. Lymphoma cells predominate in the lymph nodes; however, they can infiltrate other tissues, such as the bone marrow, CNS, GI tract, liver, mediastinum, skin, and spleen. A diagrammatic overview of the lymph node regions is depicted in Figure 93–1. Lymphoma is categorized into two general headings: Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL), both containing numerous histologic subtypes that are pathologically distinct disease entities. HL is distinguished from NHL by the presence of the pathognomonic Reed-Sternberg (RS) cell. Other lymphomatous disease entities are classified as types of NHL.
The clinical course varies widely among histologies of HL and NHL. More aggressive lymphoma subtypes are highly proliferating tumor cells that require aggressive therapeutic intervention with chemotherapy, radiation therapy, or both. By contrast, certain subtypes of NHL are characterized by a disease course that flares and remits intermittently over a period of several years either with or without treatment.
FIGURE 93–1. Representation of the anatomic regions used in the staging of Hodgkin’s disease. (From Rosenberg SA. Staging of Hodgkin disease. Radiology 1966;87:146.)
Patient Encounter 1, Part 1
A 33-year-old male professional with no remarkable medical history notes shortness of breath while exercising, which has progressively worsened over the past 3 weeks. Upon review of systems, it is discovered that he has experienced intermittent sensations of shortness of breath over the past 2 months. His only medication is PRN antihistamines and he reports no known drug allergies. A chest x-ray is remarkable for a 10 cm × 12 cm mediastinal mass.
Is this age group at risk for a particular malignant diagnosis that presents as a mediastinal mass?
What is necessary to establish a diagnosis for this patient?
EPIDEMIOLOGY AND ETIOLOGY
Hodgkin’s Lymphoma
Approximately 8,510 new cases of HL estimated to be diagnosed in the United States in 2009, with 1,290 deaths attributed to the disease. The age-specific incidence of HL is bimodal, with its greatest peak between ages 16 and 34 and a smaller peak in the fifth decade of life.1 The precise cause of HL is unknown, but certain associations have been noted to provide insight about possible etiologic factors. Viruses, such as the Epstein-Barr virus (EBV), have been implicated by epidemiologic, serologic, and molecular studies. The EBV genome has been detected in RS cells in up to 50% of cases in developed countries and more in developing nations. To date, no conclusive studies have correlated HL with HIV. Other possible risk factors identified include woodworking and familial factors such as same-sex siblings with HL.2
Non-Hodgkin’s Lymphoma
There are approximately 65,980 cases of NHL estimated to be diagnosed in the United States in 2009, with the number of deaths approaching 20,000. The incidence of the disease is increasing 4% per year, which has doubled the number of cases in the United States since 1950.3 This increase is related to the development of aggressive NHL in 20-to 40-year-old men with HIV, although the overall increase is independent of HIV disease, particularly for patients older than 65 years of age. The median age for diagnosis is 50 years, although children and young adults may be affected. The etiology of certain aggressive NHL subtypes is related to specific endemic geographic factors. Follicular or low-grade lymphoma is more common in the United States and Europe and is relatively uncommon in the Caribbean, Far East, Middle East, or Africa. The human T-cell leukemia virus I (HTLV-I) induces T-cell lymphoma/leukemia in both Japan and the Caribbean. Kaposi’s sarcoma-associated herpes virus, or human herpes virus 8 (HHV-8), and hepatitis C have been implicated in inducing NHL. Lymphomas of the GI tract are more prevalent in patients with celiac sprue, inflammatory bowel disease, or Helicobacter pyloriinfection. The incidence of Burkitt’s NHL is 7 cases per 100,000 population in Africa, compared with 0.1 per 100,000 in the United States. Malaria or EBV is thought to contribute to the chronic B-lymphocyte stimulation that leads to malignant transformation. EBV has been shown to transform lymphocytes in vitro to a monoclonal malignant population, which is believed to drive the development of disease in patients who have received a solid-organ transplant or bone marrow transplant or have other chronic immunosuppressed states. Patients with congenital diseases such as Wiskott-Aldrich syndrome, common-variable hypogammaglobinemia, X-linked lymphoproliferative syndrome, and severe combined immunodeficiency are also at risk.4 Environmental factors have been identified as contributing to the development of NHL. Certain occupations such as wood and forestry workers, butchers, exterminators, grain millers, machinists, mechanics, painters, printers, and industrial workers have a higher prevalence of disease. Industrial chemicals such as pesticides, herbicides, organic chemicals (e.g., benzene), solvents, and wood preservatives are also associated with NHL.
PATHOPHYSIOLOGY
Pluripotent stem cells in the bone marrow are able to differentiate to both lymphoid and myeloid progenitor cells. Lymphoid progenitor cells undergo gene rearrangement to yield either B-cell or T-cell lineage precursor cells. Normal maturation for naive B cells includes expression of cell surface antibody or the cells typically undergo apoptosis (programmed cell death). These cells are differentiated from other B cells, such as memory cells, by virtue of cell surface antigen (CD5+ or CD5−and CD27−) and bound antibody (IgM+ and IgD+). Once naive B cells recognize antigen with their cell surface antibody, they accumulate in the lymph nodes, spleen, or other lymphoid tissue. The DNA of these B cells is susceptible to three different types of genetic modification: receptor editing, somatic hypermutation, and class switching within the germinal center of the lymph node. Germinal centers are microanatomic structures located within lymph nodes that develop with clonal B-cell expansion secondary to antigen stimulation. Under normal circumstances, these genetic changes allow for adaptation of the immune system to the repeated exposure to environmental antigens.
Hodgkin’s Lymphoma
The pathophysiology of HL is defined by the presence of the RS cell in a grouping of lymph nodes. The RS cell is a large cell morphologically with a multinucleated structure with pronounced eosinophilic nucleoli.5 In the affected lymph nodes, the RS cells are contained in a reactive milieu of T lymphocytes, eosinophils, histiocytes, and plasma cells, which makes them difficult to distinguish from these background cells. The natural course of the disease, if left untreated, is less than a 5% probability of surviving 5 years.
RS cells are genetically derived preapoptotic germinal center B cells. There is evidence to suggest that a protein called c-FLIP that inhibits apoptosis garners protection for RS cells. RS cells express cell-surface antigens CD30 and CD15 while lacking other common B-cell antigens such as CD20. RS cells lack the expression of surface immunoglobulin likely owing to the lack of immunoglobulin transcription factors in normal B cells. The overexpression of a proproliferative and antiapoptotic transcription factor NF-κB is believed to contribute to the expansion and survival of RS cells.6
Table 93–1 WHO Classification of Lymphoid Neoplasms
B-Cell Neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
Mature (peripheral) B-cell 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
Burkitt’s lymphoma/Burkitt’s cell leukemia
T-Cell and NK-Cell Neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic lymphoma/ALL
Mature (peripheral) T-cell neoplasms
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell lymphoma/leukemia (HTLV1+)
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic gamma-delta T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides/Sezary 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
HL
Nodular lymphocyte-predominant HL
Classical HL
Nodular sclerosis HL (grades 1 and 2)
Lymphocyte-rich classical HL
Mixed cellularity HL
Lymphocyte depletion HL
HL is classified into disease subtypes based on the number and morphologic appearance of RS cells and the background cellular milieu. These are listed in the WHO classification of lymphoid neoplastic diseases in Table 93–1.7Nodular sclerosing HL is the most common form of HL, representing 70% of cases. It is more common in young adults and is marked by the presence of the RS variant cell, the lacunar cell. The second most common form of HL, accounting for approximately 25% of cases, is the mixed-cellularity variant, with others accounting for less than 5% of cases. Factors identified as negative disease prognostic indicators are listed in Table 93–2. 8
Non-Hodgkin’s Lymphoma
The pathophysiology of NHL is governed by numerous environmental and genetic events culminating with a monoclonal population of malignant lymphocytes. B cells represent the cells of origin in excess of 90% of cases of NHL. Figure 93–2 outlines normal B-cell maturation with accompanying cell-surface antigens.
Table 93–2 Negative Prognostic Factors for HL and NHL
International Prognostic Score—Advanced HL
Albumin less than 4 g/dL (40 g/L)
Hemoglobin less than 10.5 g/dL (7.3 µmol/L)
Male sex
Age greater than 45 years
Stage IV disease
WBC greater than or equal to 15,000/mm3 (15 × 10 9/L)
Lymphocytopenia (count less than 600/mm3 (0.6 × 10 9/L), or less than 8% (0.08) of white blood cell count or both)
International Prognostic Index—Diffuse, Aggressive NHL
Age greater than 60 years
Stage III/IV disease
Extranodal disease greater than 1 site
ECOG performance status 2 or greater
Serum LDH greater than 1 × normal limit
FIGURE 93–2. Pathway of normal B-cell differentiation and relationship to B-cell lymphocytes. (From Armitage JO, Longo DL. Malignancies in lymphoid cells. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:544.)
Evolving data are correlating chromosomal mutations with specific disease subtypes. Cytogenetic abnormalities involving translocations of antigen receptor genes are prevalent in NHL. These include T-cell receptor genes in T-cell lymphomas and immunoglobulin genes in B-cell lymphomas. The principal defect appears to be an error in the assembly of the regulatory gene segment of an antigen receptor gene, resulting in inappropriate binding to an oncogene. This results in dysregulaton of cell growth and proliferation, giving rise to the malignant clone of lymphocytes. Oncogenes that have been identified in different lymphomatous diseases include c-myc, a regulator of gene transcription; bcl-1, important in the regulation of mitosis; bcl-2, a regulator of apoptosis; and bcl-3, NF-κB, and bcl-6, which regulate cell differentiation.9 Classic translocations for NHL include t(8;14) in Burkitt’s lymphoma, t(14;18) in follicular lymphomas, t(11;14) mantle cell lymphoma, and t(11;18)/t(1;14) in mucosa-associated lymphoid tissue (MALT).
Characterization of the morphology of the lymphocytes, the reactivity of the other cells in the lymph node, and the lymph node architecture is essential in obtaining a diagnosis and predicting disease course. The nodal presentation of NHL is divided into two main categories: follicular, corresponding with low-grade disease, and diffuse, corresponding with aggressive disease. A follicular disease pattern in the inspected lymph node is indicative of a more indolent or low-grade disease progression that has survival measured in years if left untreated. In contrast, a diffuse pattern of lymph node infiltration is a marker of highly aggressive disease, resulting in death within weeks to months if left untreated. Follicular NHL is the most common indolent subtype, comprising 22% of NHL cases, where diffuse, large B-cell lymphoma is the most common aggressive histology in 31% of cases. The cells of origin for follicular NHL tend to be more mature, nondividing lymphocytes, whereas aggressive NHL is derived from rapidly dividing lymphoid precursors, such as immunoblasts, lymphoblasts, and centroblasts. A unique feature of the biology of NHL is that follicular low-grade histologies can undergo further malignant transformation, and a segment of malignant lymphocytes transforms further into a diffuse, large B-cell lymphoma population. This syndrome, called Richter’s transformation, may occur in up to 20% of follicular low-grade lymphoma patients and involves multiple genetic events, including abnormalities of chromosomes 11 and 12 and tumor-suppressor genes.10
The classification of NHL has undergone several revisions as the histology, molecular biology, and clinical course of the disease have been more precisely defined. Classification schemes such as the Working Formulationcategorize disease on aggressiveness into three general categories: Low grade—survival estimated in years without treatment; intermediate grade—survival estimated in months without treatment; and high grade—survival measured in days to weeks for untreated disease. This scheme is limited in its clinical applicability because the large number of distinct clinical disease entities is not categorized by this classification. The Working Formulation classification of NHL and diseases unclassifiable by that system are presented in Table 93–3. The WHO has updated a classification scheme published in 1994 by the International Lymphoma Study Group called the Revised European American Classification of Lymphoid Neoplasms (REAL) that broadly categorizes histologic subtypes into B-and T-cell subtypes. This newer classification incorporates immunologic, morphologic, genetic, and clinical attributes of various NHL histologies.
Table 93–3 Working Formulation for NHL
Patient Encounter 1, Part 2
PMH: Allergies as a child
FH: Remarkable for colon cancer with maternal grandmother and lung cancer paternal grandfather
SH: Nonsmoker; social drinker
Meds: Loratidine 10 mg orally daily as needed
ROS: As mentioned previously
PE: T 38.0°C (100.4°F)
Labs: WNL, except LDH—2302
CXR: Patient is seen by a hematologist who recommends an open-lung biopsy by a cardiothoracic surgeon. The biopsy is conducted and pathology assessment shows nodular sclerosing Hodgkin’s disease. The hematologist then conducts a staging workup with CT scans of the chest, abdomen/pelvis and performs a bone marrow biopsy.
What therapy is appropriate for this patient?
Prognostic factors present at diagnosis have been identified for NHL. Age, presence of B symptoms, performance status, number of nodal and extranodal sites, lactate dehydrogenase (LDH) concentration, bulky disease (greater than 10 cm), advanced stage, and β2-microglobulin concentration have been correlated with survival. The International Prognostic Index (IPI) is a predictive model for aggressive NHL to be treated with doxorubicin-containing chemotherapy regimens.11 This index is used as a tool for selecting therapy for patients who may warrant a more intense treatment regimen based on known poor prognostic factors.
Clinical Presentation and Diagnosis of Malignant Lymphomas
General
Nonspecific; can range from an asymptomatic patient with a less aggressive lymphoma to a patient that is gravely ill with advanced disease
Symptoms
• Lymphadenopathy, generally in the cervical, axillary, supraclavicular or inguinal lymph nodes
• Splenomegaly
• Shortness of breath, dry cough, chest pressure (patients with mediastinal mass)
• GI complications (nausea, vomiting, early satiety, constipation, and diarrhea)
• Back, chest or abdominal pain
Signs
• Fever*
• Night sweats*
• Weight loss greater than 10% within last 6 months*
• Pruritis Laboratory Tests
• LDH
• Erythroid sedimentation rate (ESR)
• Serum chemistries
• CBC with differential
Other Diagnostic Tests
• Physical exam with careful attention to lymph node inspection
• Imaging—chest x-ray, chest CT, abdominal/pelvic CT; PET scan or gallium scan may be used to confirm presence of active disease after treatment
• Bone marrow biopsy
• Biopsy of suspected lymph node(s)—either open lymph node biopsy or core biopsy preferred over fine needle aspirate
• Hematopathology evaluation of biopsy specimen—morphologic inspection, immunohistochemistry for cell surface antigens to characterize lymphoma cells, cytogenetic analysis.
*Known collectively as B symptoms.
TREATMENT OF HL
Desired Outcome
Staging of HL with a standard staging classification is necessary to guide appropriate treatment with chemotherapy, radiotherapy, or both. The number of involved sites, disease involvement on one or both sides of the diaphragm, localized or disseminated extranodal disease, and B-symptoms are factors in assignment of stage. The Cotswald staging system, a revision of the original Ann Arbor classification, is outlined in Table 93–4.12
The principal goal in treating HL is to cure the patient of the primary malignancy. HL is a disease sensitive to both radiation and chemotherapy, resulting in an 80% rate of cure with modern therapy. Treatment strategy generally is divided into approaches for early-stage I/II localized disease and stage III/IV advanced disease. Regardless of the stage of the disease, all patients are treated with curative intent. Other goals during treatment include:
Table 93–4 Cotswald Staging Classification for Hodgkin’s Disease (1989 Revision of Ann Arbor Staging)
• Complete resolution of symptoms of disease
• Minimization of acute treatment-related toxicity
• Minimization of long-term treatment-related toxicity
• Provision of high-level supportive care to ameliorate the toxicities of chemotherapy and/or radiation therapy to optimize quality of life during treatment
• Selection of palliative therapy for refractory disease.
Nonpharmacologic Therapy
Patients presenting with stage I/II disease generally are curable with subtotal lymphoid irradiation, which involves treatment of the mantle and paraaortic fields. Radiation alone has overall 90% cure rate, with greater than a decade of follow-up. However, up to one-third of patients will relapse at the site of original disease presentation. If a patient relapses, then it likely will occur in the first 3 years after therapy has been completed. Fortunately, most of these patients are still curable with salvage chemotherapy.
Standard doses of radiotherapy for HL generally total 3,600 cGy to each field in daily fractions of 180 cGy over 4 weeks. Clinically involved areas are given boost doses of 550 to 900 cGy in three to five fractions, resulting in a total dose to the involved area of upwards of 4,500 cGy. Radiation may be given as consolidation following completion of a complete course of chemotherapy in patients with advanced HL.13,14 This treatment typically is reserved for patients who have an unconfirmed response to chemotherapy or who have bulky disease on presentation.
Treatment with these doses of radiotherapy produces significant toxicity. Both acute and late effects of radiotherapy occur. Acute effects of mantle-field irradiation include nausea, vomiting, anorexia, xerostomia, dysguesia, pharyngitis, dry cough, fatigue, diarrhea, and rash. Prophylaxis with antiemetics such as dexamethasone or prochlorperazine helps to prevent or treat nausea. These effects generally are transient and resolve shortly following completion of treatment. Delayed effects from radiotherapy are more concerning in that they may be permanent and present months to years after therapy is complete. Pneumonitis, pericarditis, hypothyroidism, infertility (with pelvic field irradiation), coronary artery disease, deformities in bone and muscle growth in adolescents and children, herpes-zoster reactivation, Lhermitte’s sign, and secondary malignancies are not uncommon. Patients cured with radiotherapy are at increased risk for breast cancer, lung cancer (particularly in smokers), stomach cancer, melanoma, and NHL depending on the involved radiation field.
Pharmacologic Therapy
Chemotherapy compared with radiotherapy for Stage I or II nonbulky HL has produced equivocal results in major clinical trials.15 A National Cancer Institute (NCI) trial comparing MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and radiotherapy showed no overall difference in survival. However, an Italian randomized trial comparing radiotherapy and chemotherapy in early-stage HL showed a significant survival advantage for the radiotherapy arm. This difference has been attributed to the higher salvage rate for patients who relapsed in the radiotherapy arm and received subsequent treatment with salvage chemotherapy. A complete listing of chemotherapy regimens used in HL with drugs, dosing, administration, and treatment interval is presented in Table 93–5.
In an attempt to reduce relapse rate and late toxicity, combined-modality therapy using lower doses of radiation and an abbreviated course of chemotherapy has been evaluated.16 The goal of decreased relapse rate has been achieved, but no overall survival benefit has been documented. A limitation of this approach is exposing patients to the additive toxicities of chemotherapy. Trials that have investigated this approach typically have incorporated between two and four cycles of a standard regimen for HL, such as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with involved-field radiation. At present, combined-modality therapy is considered to be a standard of care for stage I/II HL.
Table 93–5 Common Treatment Regimens in HL
MOPP—every 28 days
Mechlorethamine 6 m/m2 IV × 1, days 1,8
Vincristine 1.4 mg/m2 IV × 1, days 1,8
Procarbazine 100 mg orally daily, days 1–14
Prednisone 40 mg orally daily, days 1–14
ABVD—every 28 days
Doxorubicin 25 mg/m2 IV × 1, days 1, 15
Bleomycin 10 units IV × 1, days 1, 15
Vinblastine 6 mg/m2 × 1, days 1, 15
Dacarbazine 375 mg/m2 IV, days 1,15
MOPP/AVD hybrid—every 28 days
Mechlorethamine 6 mg/m2 IV × 1 day 1
Vincristine 1.4 mg/m2 IV × 1; day 1
Procarbazine 100 mg orally daily, days 1–7
Prednisone 40 mg orally daily, days 1–14
Doxorubicin 35 mg/m2 IV × 1 day 8
Bleomycin 10 units IV × 1 day 8
Vinblastine 6 mg IV × 1 day 8
ChlVPP—every 28 days
Chlorambucil 6 mg orally daily, days 1–14
Vinblastine 6 mg/m2 IV × 1, days 1–8
Procarbazine 100 mg orally daily, days 1–14
Prednisone 40 mg orally daily, days 1–14
BEACOPP (escalated)—every 21 days
Bleomycin 10 mg/m2 IV, day 8
Etoposide 200 mg/m2 IV daily × days 1–3
Doxorubicin 35 mg/m2, day 1
Cyclophosphamide 1,200 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 8
Procarbazine 100 mg/m2 orally daily, days 1–14
Prednisone 40 mg orally daily, days 1–5
Gemcitabine 1,250 mg/m2 IV × 1 days 1, 8 every 21 days
BCV (high-dose with autologous SCT)a
Carmustine 400 mg/m2 IV × 1 day
Etoposide 800 mg/m2 IV daily × 3 days
Cyclophosphamide 1,800 mg/m2 IV daily × 4 days
BEAM (high-dose with autologous SCT)a
Carmustine 300 mg/m2 IV × 1day
Etoposide 800 mg/m2 IV × 1 day
Cytarabine 1,600 mg/m2 IV × 1 day
Melphalan 140 mg/m2 IV × 1 day
a Used for both HL and NHL.
Advanced Disease
Treatment of advanced-stage (stage III–IV) HL is focused on the use of multiagent chemotherapy for six to eight total cycles. MOPP is of historical significance because it was the first chemotherapy regimen to cure HL when it was introduced in the 1960s. However, the significant toxicity, including sterility and secondary leukemia, prompted investigators to evaluate other regimens. ABVD was compared with MOPP or ABVD alternating with MOPP.17 This pivotal phase III Cancer and Leukemia Group B (CALGB, an alliance of cancer centers under the supervision of the National Cancer Institute that conducts national clinical trials in cancer) trial comparing these regimens in 361 patients with stage III or IV HL documented a higher complete response (CR) in the ABVD containing arms (82% and 83%) versus MOPP (65%). There was increased hematologic toxicity in the MOPP arm. A recent update of the data show the 8-year freedom from progression of 37% in the MOPP arm and about 50% in the ABVD containing arms. A survival advantage has yet to be demonstrated. ABVD is now considered standard therapy for initial treatment of stage III or IV HL. Further information on ABVD may be found in Table 93–6.
More recently, a German study compared a dose-escalated regimen of BEACOPP (with white blood cell colony stimulating factor support) with standard-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, gemcitabine (BEACOPP) and COPP alternating with ABVD (C—cyclophosphamide instead of mechlorethamine for MOPP).18 The escalated BEACOPP was superior to the other arms in freedom from treatment failure at 5 years and was superior to COPP alternating with ABVD in overall survival at 5 years. The escalated BEACOPP regimen had a higher number of cases of secondary leukemia, and the procarbazine increases the risk of infertility. Currently, this regimen has not been adopted widely in the United States, but considerable interest has been generated in evaluating it in patients with advanced-stage HL with a high number of poor prognostic factors.
Relapse in HL has the potential for cure with chemo-therapy for both localized and advanced HL. For patients with early-stage HL, the chance of relapse is about 10% to 30%. Advanced-stage HL patients, who have approximately a one-third chance of relapse within the first 3 years of therapy, still retain a chance for cure. Management of relapsed HL can be broadly subcategorized into three different categories: relapse after treatment for early-stage disease, relapse after treatment with chemotherapy for advanced disease, and relapse in patients with advanced disease who do not achieve a remission. For these patients, the definitive therapy is high-dose chemotherapy with autologous stem cell transplantation (SCT).19 This treatment offers a cure rate of approximately 40%.
Patient Encounter 1, Plan 3: Creating a Care Plan
Based on the information presented, create a care plan for this patient including goals of therapy, antineoplastic therapy plan, and necessary supportive care.
The role of SCT in HL has evolved from data with conventional four-drug regimens demonstrating that patients with lower dose intensity had a higher rate of relapse. Data comparing high-dose chemotherapy with lower doses of the same regimen yielded a significant benefit in the high-dose arm, leading to early closure of the study. High-dose chemotherapy is given to patients who are in first relapse with encouraging results. A series of 58 patients had a progression-free survival of over 60% with a median follow-up of 2.3 years. The safety profile of autologous SCT continues to improve as improvements in supportive care are realized, and current estimates of mortality from autologous SCT for HL approximate 5%. Morbidity commonly associated with the preparative regimens in HL, aside from infectious and bleeding complications, includes the additive pulmonary toxicity of bleomycin coupled with carmustine in inducing potentially fatal pulmonary pneumonitis.
Table 93–6 Practical Information for ABVD and CHOP
Patients who are not deemed candidates for high dose chemotherapy with autologous SCT may receive multiagent salvage chemotherapy, such as etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) or dexamethasine, cytarabine, and cisplatin (DHAP). If less aggressive therapy is desired, patients can be offered palliation with single-agent gemcitabine or vinblastine.20
TREATMENT OF NHL
Desired Outcome
Treatment of NHL depends primarily on histologic subtype (follicular low grade versus diffuse aggressive) and staging (local stage I/II versus advanced stage III/IV) to guide appropriate treatment strategy with observation, chemotherapy, radiotherapy, or chemotherapy and radiation. As with HL, the number of involved sites, disease involvement on one or both sides of the diaphragm, localized or disseminated extranodal disease, and B-symptoms are factors in staging assignment. The Ann Arbor staging system is outlined in Table 93–7.21
Treatment goals for NHL depend on the presence of follicular low-grade versus diffuse aggressive disease. For follicular low-grade NHL, the disease is considered to be incurable with standard therapies There is a small prospect for cure using allogeneic SCT owing to the graft-versus-lymphoma effect of donor T cells. Many patients with follicular low-grade NHL are older than 60 years of age, making allogeneic SCT impractical owing to the high treatment-related mortality for older patients.
The treatment goals for low-grade NHL include:
• Observation of the disease until the patient exhibits Observation of the disease until the patient exhibits obvious progression that limits functional capacity or is life-threatening for low-grade NHL
• Treatment that induces the disease into remission with resolution of disease symptoms and manageable toxicity
• Judicious selection of treatment options to avoid long-term toxicity because patients may require several different chemotherapy treatment regimens over a period of years for low-grade NHL
• Prevention of infectious complications of treatment
Table 93–7 Ann Arbor Staging of NHL
The treatment aim for patients with aggressive histologies is cure of the malignancy. There are some histologic subtypes that exhibit an aggressive clinical course that are not considered to be curable. These patients are still treated with curative-intent chemotherapy or may be considered for a clinical trial.
Nonpharmacologic Therapy
For patients with low-grade follicular NHL, deferring initiation of therapy until progression of disease is standard. The median survival is 6 to 10 years, with some patients waiting several years before the disease becomes symptomatic, making observation a reasonable front-line therapy for most of these patients. Radiation therapy has a limited role in NHL relative to HL. NHL is a systemic disease, and radiation typically has been reserved for consolidation therapy following chemotherapy in patients presenting with a large extranodal mass.
For early-stage diffuse, aggressive NHL, combined-modality therapy was tested versus a longer course of chemotherapy.22 Overall survival favored the cyclophosphamide doxorubicin vincristine prednisone (CHOP)/radiation arm for 5 years (82% versus 72%). There was a trend toward increased toxicity, particularly hematologic and cardiac toxicity, in the CHOP alone arm. The results of this trial have established combined-modality therapy as first-line treatment for early-stage NHL. Unique presentations of NHL, such as CNS primary disease, may incorporate radiation into treatment algorithms.23
Pharmacologic Therapy
Follicular Low-Grade NHL
The management of low-grade lymphomas is an area of controversy. Chemotherapy such as single-agent oral cyclophosphamide or fludarabine is often offered initially. In patients in whom a more rapid response is desired, multiagent chemotherapy such as cyclophosphamide vincristine prednisone (CVP) or cyclophosphamide doxorubicin vincristine prednisone (CHOP) may be used. None of these therapies is associated with an improvement in overall survival, making it impossible to select an unequivocal first-line regimen.24–26 These regimens are detailed in Table 93–8.
Introduction of the monoclonal antibody rituximab has prompted interest in a novel modality of therapy for this disease. Rituximab is a chimeric murine/human monoclonal antibody that binds specifically to the antigen CD20 expressed on pre-B and mature B lymphocytes.27 NHL of B-cell origin expresses CD20 in greater than 90% of cases. CD20 is believed to play a role in early differentiation and activation of the cell cycle. After the Fab domain of rituximab binds to CD20, the Fc domain acts to recruit complement and other components of the immune system to induce cell-mediated cytotoxicity with subsequent lysis of the bound lymphocytes. Rituximab also may produce apoptosis of the bound lymphocyte with the act of binding to the CD20 receptor. Rituximab has specific affinity for binding to lymphocytes and lymphoid tissue, begins depleting B lymphocytes with the first dose, and results in sustained suppression for 6 to 9 months with as few as three doses. B-cell recovery begins 6 months following administration of the drug. The drug has a half-life of 60 hours with the first dose that increases with subsequent dosing to approximately 150 hours, allowing for weekly dosing. The initial clinical experience with rituximab involved 166 patients with CD20+ low-grade lymphoma treated with four doses of 375 mg/m2 of rituximab weekly.28 The overall response rate was 48%, with 6% representing complete responses and the remainder representing partial responses. The median follow-up of 12 months demonstrated a median time to progression of 13 months by intention-to-treat analysis. Most adverse events were related to intolerance of the first infusion with hypotension, fever, chills, nausea, and bronchospasm. These data established the role of rituximab as a viable treatment option in patients with indolent follicular NHL. Further research has examined rituximab as maintenance therapy administered once every 3 months for up to 2 years following CHOP+/-R in patients with relapsed or resistant disease. Compared to an observational group, rituximab resulted in increased progression-free survival (51 versus 14 months) and 3-year overall survival rates (85% versus 77%).29
Table 93–8 Treatment Regimens for Low-Grade, Follicular NHL
Cyclophosphamide (100 mg/m2) orally daily
Fludarabine 25 mg/m2 IV daily, days 1–5
Rituximab 375 mg/m2 IV day 1 given weekly for 4 or 8 weeks
CVP every 21 days
Cyclophosphamide 800 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 1
Prednisone 100 mg orally daily, days 1–5
rCVP every 21 days
Rituximab 375 mg/m2 IV day 1
Cyclophosphamide 800 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 1
Prednisone 100 mg orally daily, day 1–5
CHOP every 21 days
Cyclophosphamide 750 mg/m2 IV, day 1
Doxorubicin 50 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 1
Prednisone 100 mg orally daily, day 1–5
rCHOP every 21 days
Rituximab 375 mg/m2 IV, day 1
Cyclophosphamide 750 mg/m2 IV, day 1
Doxorubicin 50 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 1
Prednisone 100 mg orally daily, day 1–5
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 the FDA: ibritumomab-yttrium 90 (Zevalin) and tositumomab-iodine131 (Bexxar). Both agents are active in disease that has become refractory to rituximab. The radiation component necessitates compounding both medications in a nuclear medicine pharmacy. High-dose chemotherapy is being evaluated for low-grade follicular NHL, but its role is currently limited to clinical trials. Bendamustine, a unique alkalyting agent with a novel chemical structure, has been studied in a phase II trial of rituximab-refractory and transformed NHL. Among 74 assessable patients, an overall response rate of 77% was noted with a progression free survival of 7.1 months.30
Diffuse, Aggressive NHL
The mainstay of therapy for diffuse, aggressive NHL has been the administration of anthracycline-based combination chemotherapy, which generally consists of programs of four or more drugs. Therapy options for intermediate- and high-grade NHL generally are segregated between localized (stage I/II) and disseminated (stage III/IV) disease. Combined-modality therapy with an abbreviated course of CHOP and local radiation is considered a standard of care for stage I/II disease.
The standard therapy for disseminated disease since the 1970s has been CHOP. This regimen conferred a response of 50% to 60%, with a long-term survival of approximately 30%. However, the 1980s were notable for the development of newer combination chemotherapy regimens that incorporated increasing numbers of agents with varying schedules. More complex chemotherapy regimens were shown in phase II trials to have higher response rates than CHOP. The CALGB designed a phase III randomized four-arm trial to assess the impact on survival of three more intensive regimens compared with CHOP.31 This phase III cooperative group trial randomized 899 patients with intermediate- or high-grade (Working Formulation classification) NHL to CHOP or one of the three more intensive advanced-generation regimens. There were no significant differences in response rate or overall survival, which was consistent among all subgroups. Severe toxicity and death were higher in the advanced-generation treatment programs relative to CHOP. This pivotal trial has cemented CHOP’s position as front-line therapy in diffuse NHL.
The next hypothesis tested was whether combining monoclonal antibody therapy with chemotherapy could increase activity against diffuse, aggressive NHL. A French study randomized patients 60 to 80 years of age with newly diagnosed diffuse, large B-cell NHL to either CHOP for eight cycles or CHOP plus rituximab for eight cycles.32 At relatively early follow-up of 2 years, the combination arm had a superior complete response rate (76% versus 63%) and event-free survival (57% versus 38%), with comparable toxicity in each arm. Similar findings in younger patients have been reported recently, making CHOP plus rituximab first-line therapy for advanced-stage diffuse, aggressive NHL (Table 93–9).
Table 93–9 Treatment Regimens for Diffuse, Aggressive NHL
CHOP every 21 days
Cyclophosphamide 750 mg/m2 IV, day 1
Doxorubicin 50 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 1
Prednisone 100 mg orally daily, days 1–5
rCHOP every 21 days
Rituximab 375 mg/m2 IV day 1
Cyclophosphamide 750 mg/m2 IV, day 1
Doxorubicin 50 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 1
Prednisone 100 mg orally daily, days 1–5
m-BACOD every 21 days
Methotrexate 200 mg/m2 IV, days 8, 15
Bleomycin 4 mg/m2 IV, day 1
Doxorubicin 45 mg/m2, day 1
Cyclophosphamide 600 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, day 1
Dexamethasone 6 mg orally daily, days 1–5
Leucovorin 10 mg orally q 6 hours, 24 hours following methotrexate × 8 doses
ProMACE-CytaBOM every 28 days
Prednisone 60 mg orally daily, days 1–14
Doxorubicin 25 mg/m2 IV, day 1
Cyclophosphamide 650 mg/m2 IV, day 1
Etoposide 120 mg/m2 IV, day 1
Cytarabine 300 mg/m2 IV, day 8
Bleomycin 5 units IV, day 8
Vincristine1.4 mg/m2 IV, day 8
Methotrexate120 mg/m2, day 8
Leucovorin 25 mg/m2 IV q 6 hours, 24 hours following methotrexate × 5 doses
MACOP-B
Methotrexate 400 mg/m2 IV, day 8
Doxorubicin 50 mg/m2 IV, days 1, 15
Cyclophosphamide 350 mg/m2 IV, days 1,15
Vincristine 1.4 mg/m2 IV, days 8,15
Prednisone 75 mg orally daily, × 12 weeks
Bleomycin 10 units IV, day 28
Leucovorin 15 mg orally q 6 hours, 24 hours following methotrexate × 6 doses
Hyper-CVAD
Cyclophosphamide 300 mg/m2 IV q 12 hours, days 1–3 (with mesna)
Doxorubicin 50 mg/m2 IV, day 1
Vincristine 1.4 mg/m2 IV, days 1,11
Dexamethasone 40 mg orally daily, days 1–4 and 11–14
Methotrexate 15 mg intrathecal, day 2
Cytarabine 30 mg intrathecal, day 2
Hydrocortisone 15 mg intrathecal, day 2
Above drugs given on courses 1,3,5,7
Methotrexate 1,000 mg/m2 IV over 24 hours, day 1
Cytarabine 3,000 mg/m2 IV q 12 h, days 2,3
Leucovorin 25 mg IV × 1 then 25 mg orally q 6 hours for 7 doses
Methotrexate 15 mg intrathecal, day 2
Above drugs given on courses 2, 4, 6, 8
Relapsed Disease
ESHAP
Etoposide 40 mg/m2 IV per day continous infusion, days 1–4
Cisplatin 25 mg/m2 IV per day continuous infusion, days 1–4
Cytarabine 2,000 mg/m2 IV × 1, day 5
Methylprednisone 250 mg IV q 12 hours, days 1–4
DHAP
Dexamethasone 40 mg orally or IV daily, days 1–4
Cisplatin 100 mg/m2 IV continuous infusion, day 1
Cytarabine 2,000 mg/m2 IV q 12 hours for 2 doses on day 2
ICE
Etoposide 100 mg/m2 IV daily, days 1–3
Carboplatin AUC 5 (max dose 800 mg) IV, day 2
Ifosfamide 5,000 mg/m2 IV continuous infusion × 1 on day 2 (with 100% replacement with mesna)
Special Populations
There are certain histologic subtypes of diffuse, aggressive NHL that respond less well to treatment with conventional regimens such as CHOP. Burkitt’s lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, and primary CNS lymphoma are examples of disease that benefit from more intensive therapy. Regimens such as hyper-CVAD, which alternate cycles of hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone with high-dose cytarabine and methotrexate, may be substituted for CHOP.
Patients with CNS NHL have disease that is poorly responsive to therapy because of inadequate penetration of standard doses of chemotherapy across the blood–brain barrier. High-dose methotrexate, ranging from 2,500 to 8,000 mg/m2 is a mainstay of therapy. Treatment may be augmented by direct instillation of intrathecal chemotherapy into the cerebrospinal fluid. Drugs that are commonly instilled intrathecally include methotrexate, cytarabine (conventional formulation and liposomal products) and corticosteroids. Medication errors causing death or permanent disability caused by inadvertent administration of intrathecal vincristine has been extensively reported in the medical literature. The WHO has published specific recommendations aiming to prevent further administration errors associated with vinca alkaloids.33
The recent appreciation of the etiology of H. pylori in the etiology of peptic ulcer disease and the association between colonization and MALT has spurred the more aggressive treatment of this organism with antibiotics. Generally, 7 to 14 days of combination therapy including; omeprazole, clarithromycin, and amoxicillin or tetracycline, metronidazole, and bismuth subsalicylate have been shown to provide rates of H. pylori clearance near 90%.
Mantle cell lymphoma, which comprises 6% of NHL cases, is defined by a chromosomal translocation of t(11;14) (q13;32). This translocation results in the overexpression of cyclin D1 coupled with NF-κB which plays a critical role in intracellular protein regulation and protranscription factors leading to increased cell survival. Bortezomib, a novel proteosome inhibitor disrupts the regulation and degradation of proteins required for cell cycle regulation. Bortezomib was approved by the FDA in 2006 for the treatment of patients with mantle cell lymphoma who have failed initial treatment. A study conducted in 155 patients demonstrated that bortezomib resulted in a overall response rate of 31% with a median duration of survival of 9.3 months.34
With over half of patients expected to relapse with disease, salvage therapy plays a major role in the attempt to cure patients with recurrence. Multiple drug programs such as ESHAP and DHAP can induce a complete response, but the long-term cure rates with these regimens are less than 10%. Salvage therapy can induce remissions with subsequent relapses; however, the chance for a CR and the duration of remission is further diminished.
Now high-dose chemotherapy with autologous SCT has been studied as an alternative to standard dose regimens in the setting of first relapse.35 The best-studied indication for SCT is for patients with intermediate- or high-grade disease that fails to respond to first-line therapy. A 3- to 5-year survival of upwards of 40% is achieved in patients who have good performance and disease that demonstrates a significant response to one or two cycles of salvage chemotherapy. The procedure-related mortality has ranged from 5% to 10% in published reports. However, as with HL, with more broad application of peripheral blood stem cells and improved supportive care, this figure continues to decline. The role of allogeneic bone marrow transplantation (BMT) in this setting is limited due to donor availability, older age of patients and the high treatment-related morbidity and mortality.
Patients with HIV-related lymphoma represent a therapeutic dilemma in that many have high-grade disease of B-cell origin. A common presentation is that of extranodal disease, frequently in the GI tract, CNS, and bone marrow. Therapy for this population thus far has fared poorly, with a median survival of 6 to 12 months, which decreases to 3 months with CNS involvement.36 It remains to be seen if improved antiretroviral therapy will have an impact on the incidence and treatment options for these patients. The addition of rituximab to chemotherapy has failed to improve overall survival in this patient population and is associated with increased infectious complications relative to chemotherapy alone.37
OUTCOME EVALUATION
Treatment success in lymphoma is measured in successive stages, the first being inducing tumor regression and the degree of that regression: complete response (CR) versus partial response (PR) versus stable disease (SD) versus progressive disease (PD). The RECIST criteria, a uniform criteria assessing tumor response, developed by the National Cancer Institute are the standard methodology that physicians utilize to gauge treatment efficacy. Both HL and NHL may have residual masses following completion of treatment, adding to the difficulty in establishing a definitive remission from treatment. Clinical trials with limited numbers of patients have been published suggesting value of PET scans and/or gallium scans to rule out whether residual tumor masses following treatment contain viable tumor.38 PET scans hold the promise of a future role because the 2-fluoro-2deoxyglucose contrast material is taken up more avidly by metabolically active tumor cells relative to necrotic tumor cells.
Long-term follow-up monitors patients for continued disease remission or relapse with careful physical examination of the lymph nodes and sites of prior disease involvement and imaging studies. Patients will have routine chest x-rays and CT scans to screen for disease recurrence. Patients require long-term monitoring for toxicities of their primary treatment, either chemotherapy or radiation therapy.
Most patients treated for lymphoma with chemotherapy or radiation notice a regression of palpable lymphadenopathy within days. This is due to the high sensitivity of the rapidly proliferating malignant lymphocytes to chemotherapy and radiotherapy. This necessitates implementation of tumor lysis syndrome precautions with aggressive sodium bicarbonate–containing IV fluid resuscitation and allopurinol for patients with moderate to high tumor burdens. Most chemotherapy treatments for lymphoma have a significant risk of infectious complications. Combination chemotherapy for both HL and NHL is associated with rates of severe leukopenia and/or neutropenia ranging from 20% to 100% of patients. Consideration must be given to supportive care with prophylactic antibiotics and myeloid colony-stimulating factors (CSFs). The American Society of Clinical Oncology has published guidelines stating that CSFs may be used as primary prevention when the incidence of febrile neutropenia with the chemotherapy is approximately 20% and no other equally effective and less myelosuppresive regimen is available or for secondary prevention where the patient already has experienced febrile neutropenia with the previous cycle of chemotherapy.39 Effective antiemetic support is currently available that can control chemotherapy-induced nausea and vomiting reasonably well for most standard-dose regimens.40
For female survivors of HL who are treated with radiation to the thoracic cavity, there is an increase in the incidence of breast cancer, and baseline mammograms are recommended at the conclusion of treatment.41 For HL patients, exposure to bleomycin can induce pulmonary fibrosis, which often is subclinical. Patients who relapse and require high-dose chemotherapy and are treated with the drug carmustine in the conditioning regimen are at a higher risk of morbidity and mortality from idiopathic pulmonary syndrome/diffuse alveolar hemorrhage during SCT treatment. These patients are also at risk for exacerbation of underlying bleomycin-induced pulmonary damage if they ever require mechanical ventilation with high oxygen requirements. Combination chemotherapy that contains alkylating agents or etoposide carries the risk of a secondary acute myeloid leukemia or myelodysplastic syndrome. The cumulative dose of doxorubicin used for most lymphoma regimens is unlikely to cause cardiac toxicity with the standard six cycles. Neuropathy with vincristine or vinblastine may necessitate its removal from subsequent cycles if severe. Historically, it is more severe with vincristine. Treatment with fludarabine can harbor the risk of opportunistic infections such as Pneumocystis carinii pneumonia (PCP) for months following completion of therapy.
Patient Care and Monitoring
1. Verify chemotherapy regimen dosages with a standardized reference and assess for dose adjustment for renal or hepatic dysfunction.
2. Assess appropriateness of supportive care for each chemotherapy regimens such as antiemetics or CSFs.
3. Prior to initiation of treatment with chemotherapy determine if tumor lysis syndrome precautions need to be implemented.
4. Take a thorough medication history with particular attention to nonprescription or herbal medications.
5. Provide patient education regarding common toxicities associated with chemotherapy such as nausea/vomiting, mucositis, myelosuppression, and alopecia.
6. For doxorubicin-containing regimens, total the cumulative dosage received by the patient to monitor for cardiac toxicity.
7. For bleomycin-containing regimens total the cumulative dosage received by the patient to monitor for pulmonary fibrosis.
8. Educate patients regarding short and long term complications associated with radiation therapy.
9. Monitor patient for signs of response of tumor to chemotherapy.
10. Provide contact numbers for patient in the event of a fever and a response plan if the patient is considered to be at risk for neutropenic fever.
A limitation of rituximab treatment is the severe and potentially fatal infusion-related reactions. Deaths have been reported resulting from the profound hypotension and circulatory collapse seen with the drug, particularly on the first dose. The package labeling recommends premedication with acetaminophen and diphenhydramine before each infusion. For the first infusion, the drug should be administered at 50 mg/h. The infusion rate may be increased by 50 mg/h every 30 minutes to a maximum of 400 mg/h if no infusion-related reactions occur. If infusion-related reactions do occur, the manufacturer recommends stopping the infusion or temporarily slowing it until symptoms resolve. The infusion should be reinstituted at a rate that is one-half the previous rate. For subsequent rituxamab infusions, the rate may commence at 100 mg/h and be increased at 100 mg/h increments every 30 minutes for a maximum of 400 mg/h as tolerated. Other associated toxicities of rituxamab include fever, chills, headache, asthenia, nausea, vomiting, angioedema, bronchospasm, and skin reactions. Despite these toxicities, rituximab is an effective treatment option for patients with indolent low-grade NHL as a single agent or in combination with standard chemotherapy regimens for more aggressive NHL histologies. Radiolabeled rituximab causes more myelosuppression than rituximab alone and, similar to combination cytotoxic chemotherapy regimens, has a long-term risk of inducing secondary leukemias.42
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. Cartwright RA, Watkins G. Epidemiology of Hodgkin’s disease: A review. Hematol Oncol 2004;22:11–26
2. Yung L, Linch D. Hodgkin’s lymphoma. Lancet 2003;361:943–951
3. Fisher SG, Fisher RI. The epidemiology of non-Hodgkin’s lymphoma. Oncogene 2004;23:6524–6534
4. Evans LS, Hancock BW. Non-Hodgkin lymphoma. Lancet 2003;362:139–146
5. Kuppers R, Hansmann ML. The Hodgkin and Reed/Sternberg cell. Int J Biochem Cell Biol 2005;37:511–517
6. Re D, Thomas RK, Behringer K, Diehl V. From Hodgkin’s disease to Hodgkin lymphoma: Biologic insights and therapeutic potential. Blood 2005;105:4553–4560
7. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissue: Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–3849
8. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. N Engl J Med 1998;339:1506–1514
9. Kuppers R, Klein U, Hansmann ML, Rajewsky K. Cellular origin of human B-cell lymphomas. N Engl J Med 1999;341:1520–1529
10. Tsimberidou AM, Keating MJ. Richter syndrome: Biology, incidence and therapeutic strategies. Cancer 2005;103:216–228.
11. The International non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993;329:987–994
12. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswold meeting. J Clin Oncol 1989;7: 1630–1636.
13. Alerman BMP, Raemaekers JMM, Tirelli U, et al. Involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med 2003;348:2396–2406
14. Horning SJ, Williams J, Bartlett NL, et al. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin’s disease: Eastern Cooperative Oncology Group pilot study 1402. J Clin Oncol 2000;18:972–980
15. Aisenberg AC. Problems in Hodgkin’s disease management. Blood 1999; 93:761–779
16. Specht L, Gray RG, Clarke MG, Peto R. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin’s disease: A meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin’s Disease Collaborative Group. J Clin Oncol 1998;16:830–843.
17. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484
18. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 2003;348:2386–2395
19. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: Results of a BLNI randomised trial. Lancet 1993; 341:1051–1054
20. Santoro A, Bredenfeld, Devizzi L, et al. Gemcitabine in the treatment of refractory Hodgkin’s disease: Results of a multicenter phase II trial. J Clin Oncol 2000;18:2615–2619
21. Lu P. Staging and classification of lymphoma. Semin Nucl Med 2005;35:160–164
22. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate-and high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998;339:21–26
23. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10. J Clin Oncol 2002;20:4643–4648
24. Hagenbeek A, Eghbali H, Monfardini S, et al. Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin’s lymphoma. J Clin Oncol 2006;24:1590–1596
25. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417–1423
26. Peterson BA, Petroni GR, Frizzera G, et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: A study of the cancer and leukemia group B. J Clin Oncol 2003;21:5–15
27. McCune SL, Gockerman JP, Rizzieri DA. Monoclonal antibody therapy in the treatment of non-Hodgkin’s lymphoma. JAMA 2001;286:1149–1152
28. McLaughlin P et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four dose treatment program. J Clin Oncol 1998;16:2825–2833
29. Van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcomes of relapsed/resistant follicular nonhodgkins lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295–3301.
30. Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: Results from a phase II multicenter, single agent study. J Clin Orthod 2008;26:201–210
31. Fisher RI, et al. Comparison of standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993;328:1002–1006
32. Coiffer B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 2002;346: 235–242.
33. http://www.who.int/patientsafety/highlights/PS_alert_115_vincristine.pdf
34. Kane RC, Dagher R, Farrell A, et al. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 2007;13:5291–5294
35. Stebbing J, Marvin V, Bower M. The evidence-based treatment of AIDS-related non-Hodgkin’s lymphoma. Cancer Treat Rev 2004;30:249–253
36. Thierry P, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplant as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995;333:1540–1545
37. Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase III trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin’s lymphoma: AIDS-Malignancies Consortium Trial 010. Blood 2005;106:1538–1543
38. Juweid ME, Wiseman GA, Vose JA, et al. Response assessment of aggressive non-Hodgkin’s lymphoma by Integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography. J Clin Oncol 2005;21:4652–4661
39. Smith TJ, et al. Update of Recommendations for the Use of White Blood Cell. Growth Factors: An Evidence-Based Clinical Practice Guideline 2006. www.asco.org.
40. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: Update 2006. J Clin Oncol 2006;17:2971–2994
41. Deniz K, O’Mahony S, Ross G, Purushotham A. Breast cancer in women after treatment for Hodgkin’s disease. Lancet Oncol 2003;4: 207–214
42. Armitage JO, Carbone PP, Connors JM, Levine A, Bennett JM, Kroll S. Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. J Clin Oncol 2003;21:897–906.