Malignant Lymphomas

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 con trast, 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.

Mesenteric

Para-aortic

Mediastinal

Para-aortic

Popí teal

Waldeyer's ring

Cervical, supraclavicular, occipital, and preauricular

Mediastinal

Infraclavicular

Axillary and pectoral

Hilar-

Epitrochlear and brachial

Mesenteric

Inoumal and 'emoral

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 x 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. 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.

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. 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 pylori infection. 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 hypogamma-globinemia, 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 apop-tosis (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 lymph-oid 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-kB 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. Nodular 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 ^mol/L) Male sex

Age greater than 45 years Stage IV disease

WBC greater than or equal to 15,000/mm3 (15 x 10 9/L)

Lymphocytopenia (count less than 600/mm (0.6 x 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 x 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.)

O 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-kB, 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, lymph-oblasts, 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 Formulation categorize 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 clin ical 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

Classification

Immunophenotype

Low Grade

Small lymphocytic Follicular, smal I cleaved cell Follicular mixed small cleaved cell and large tell

Intermediate Grade

Follicular, large cell Diffuse, small cleaved ceil

Diffuse, mixed small and large cell

Diffuse, targe cell

Diffuse, large cell

High Grade

Immunoblastic lymphoblastic Diffuse, small none leaved cell

100% B-cell

10% nuEI-ceEl 70% B-cellr 20% T-cell, 10% null-cell

50% B-cell, 50% T-celE 5% R- tell. <55% T-cell 100% B-ceEl

Lymphomas not included in Working Formulation' Mycosis fungoides, mantle-eel I lymphoma, monocytoid B-cell lymphoma, mucosa-associated lymphoid tissue (M.ALT), anaplasTit large cell lymphoma,-angiocentrls lymphoma, angioiminunoblastlc lymphadenopathy (AILD), Castle man's disease, adult T-cell I eu'kem i a/ly m phoma.

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

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 P2-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

• Weight loss greater than 10% within last 6 months*

• Pruritis Laboratory Tests

• 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, immun-ohistochemistry 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.

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)

Stage Description

I I nvol veme nt of a sing le I ym ph rtode reg ion of lymphoid structure r spleen, thymus, Waideyer's ring)

II In vo Ivem ent of t wo o r mo re lym ph node regions on the same side of the diaphragm, The number of anatomic sites is indicated by a subscript

III l n volve merit of ly m ph nod e reg ion s o r st r u c tu re on both Sides of the diaphragm III,: With or without involvement of splenic, hilar..

celiac, or portal nodes III; Involvement of para-aortic, iliac, or mesenteric.

IV I nvol vem en t of ext r a nod a I srte(s) bey on cf that designated E

Designations Applicable to All Stages

A No symptoms

R Feveir night sweats, and weight loss

X Bulky disea se g reater than 1 /3 t he width of the mediastinum or greater nhari 10 cm maximal dimension of nodal mass h In vol vement of a sing le ext ranoda I site, contiguous or proximal to a known nodal site CS Clinical stage

PS Pathologic stage

• 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/m IV x 1, days 1,8 2

Vincristine 1.4 mg/m IV x 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/m IV x 1, days 1, 15

Bleomycin 10 units IV x 1, days 1, 15 2

Dacarbazine 375 mg/m IV, days 1,15

MOPP/AVD hybrid—every 28 days 2

Mechlorethamine 6 mg/m IV x 1 day 1 2

Vincristine 1.4 mg/m IV x 1; day 1 Procarbazine 100 mg orally daily, days 1-7 Prednisone 40 mg orally daily, days 1-14 Doxorubicin 35 mg/m IV x 1 day 8 Bleomycin 10 units IV x 1 day 8 Vinblastine 6 mg IV x 1 day 8 ChlVPP—every 28 days Chlorambucil 6 mg orally daily, days 1-14 Vinblastine 6 mg/m IV x 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 2

Bleomycin 10 mg/m IV, day 8 2

Etoposide 200 mg/m IV daily x days 1-3 2

Doxorubicin 35 mg/m , day 1

Cyclophosphamide 1,200 mg/m IV, day 1 2

Vincristine 1.4 mg/m IV, day 8 2

Procarbazine 100 mg/m orally daily, days 1-14

Prednisone 40 mg orally daily, days 1-5

Gemcitabine 1,250 mg/m IV x 1 days 1, 8 every 21 days

BCV (high-dose with autologous SCT)a 2

Carmustine 400 mg/m IV x 1 day 2

Etoposide 800 mg/m IV daily x 3 days Cyclophosphamide 1,800 mg/m IV daily x 4 days

BEAM (high-dose with autologous SCT)a 2

Carmustine 300 mg/m IV x 1day 2

Etoposide 800 mg/m IV

x 1 day

Cytarabine 1,600 mg/m IV

x 1 day

Melphalan 140 mg/m2 IV x 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 car-mustine in inducing potentially fatal pulmonary pneumonitis.

Table 93-6 Practical Information for ABVD and CHOP

Regimen

Drug Class

Phamacokinedcs

Unique Toxicities

ABVD

Doxorubicin Bleomycin Vinblastine Dacarbazlne chop

Cyclophosphamide Doxorubicin Vincristine Prednisone

Anthracydine Antitumor antibiotic Vlnca alkaloid Alkylating agent

Alkylating agent Anthracycline Vinca alkaloid Corticosteroid

Hepalic metabolism Renal clearance CYP 3A4/5 metabolism Hepalic metabolism

Prodrug; CYP'}A4/S,2D6 Hepalic metabolism CYP3A4/5

100% oral bioavailability

Cardiomyopathy Pulmonary fibrosis Neuropathy, constipation Myelosuppfession

Hemorrhagic cystitis Cardiomyopathy Neuropathy, constipation Hypergfycemia, osteopenia

Patients who are not deemed candidates for high dose chemotherapy with autolog-ous SCT may receive multiagent salvage chemotherapy, such as etoposide, methyl-prednisolone, 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 extranod-al 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 allogen-eic 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

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Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

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