You are in: eMedicine Specialties > Hematology > Stem Cells and Disorders Lymphoma, B-CellArticle Last Updated: Feb 9, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Ajeet Gajra, MD, Assistant Professor of Medicine, Director of Hematology/Oncology Fellowship Program, State University of New York Upstate Medical University; Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Veterans Affairs Medical Center Ajeet Gajra is a member of the following medical societies: American Association for Cancer Research, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology Coauthor(s): Neerja Vajpayee, MD, Clinical Assistant Professor, Clinical Assistant Professor, Hematopathology Division, Department of Pathology, State University of New York, Upstate Medical University, Syracuse; Sara Grethlein, MD, Associate Dean for Graduate Medical Education, Associate Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York at Upstate Editors: Michael Paul Kosty, MD, Associate Director, Associate Professor, Department of Internal Medicine, Divisions of Supportive Care Services and Hematology and Oncology, Ida M and Cecil H Green Cancer Center, Scripps Clinic; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Wendy Hu, MD, Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University Author and Editor Disclosure Synonyms and related keywords: non-Hodgkin lymphoma, NHL, lymph node, lymphoid tissue, indolent lymphomas, aggressive lymphomas, Burkitt lymphoma, B-cell neoplasms, T/NK-cell neoplasms, Hodgkin lymphoma, Hodgkin's lymphoma, B-cell chronic lymphocytic leukemia, CLL, B-cell CLL, B-cell small lymphocytic lymphoma, lymphoblastic lymphomas, T-cell acute lymphocytic leukemias, diffuse large B-cell lymphoma, follicular lymphoma, follicular large cell lymphoma, mantle cell NHL, small lymphocytic lymphoma, splenic marginal zone lymphoma, extranodal B-cell lymphoma of mucosa-associated lymphoid tissue, MALT, mediastinal diffuselarge B-cell lymphoma, indolent NHL, lymphoproliferative malignancy, lymphoproliferative disease, Revised European-American LymphomaClassification, REAL Classification, immunocytoma, mycosis fungoides, Sézary syndrome, lymphadenopathy, Waldeyer ring, INTRODUCTIONSection 2 of 11
  BackgroundNon-Hodgkin lymphoma (NHL) is a heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment (Armitage, 1993). NHL usually originates in the lymphoid tissues and can spread to other organs. However, unlike Hodgkin disease, NHL is much less predictable and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment. Most (ie, 80-90%) NHLs are of B-cell origin. The following discussion pertains to B-cell NHL, although the classification as outlined below includes all lymphoproliferative diseases. Furthermore, management discussed in this article refers only to B-cell NHL in previously healthy individuals and is not applicable to patients with HIV or other immunocompromised conditions. NHL can be divided into 2 general prognostic groups: the indolent lymphomas and the aggressive lymphomas. Indolent lymphomas have a relatively good prognosis, with median survival time as long as 10 years, but they are not usually curable in advanced stages. Early-stage (I and II) indolent NHL can be treated effectively with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with combination chemotherapy regimens. In general, with modern treatment of patients with NHL, the overall survival rate at 5 years is approximately 50-60%. Thirty percent of patients with aggressive NHL can be cured. Most relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients with a divergent histology of both indolent and aggressive disease (Cabanillas, 1992). A subset of aggressive lymphomas, Burkitt lymphoma and lymphoblastic lymphoma, are designated as high grade by the International Working Formulation (IWF) to reflect the rapidly progressive behavior of these subtypes. While indolent NHL is responsive to radiation therapy and chemotherapy, a continuous rate of relapse is usually observed in advanced stages. However, patients can often be re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may achieve complete remission (CR) with combination chemotherapy regimens with or without aggressive high-dose consolidation therapy with marrow or stem cell support. Aggressive lymphomas are increasingly observed in patients who are HIV positive, and treatment of these patients requires special consideration. PathophysiologyThe World Health Organization (WHO) modification of the Revised European-American Lymphoma (REAL) Classification recognizes 3 major categories of lymphoid malignancies based on morphology and cell lineage. The categories include B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma. Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For instance, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma are different manifestations of the same neoplasm, as are lymphoblastic lymphomas and T-cell acute lymphocytic leukemias. Within B- and T-cell categories, 2 subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms. WHO classification of lymphomas
The more than 20 clinicopathologic entities described here can be divided into more clinically useful indolent or aggressive lymphomas as follows: Clinical classification of lymphoproliferative disorders (prescreening development questionnaire [PDQ] modification of REAL classification of lymphoproliferative diseases)
FrequencyUnited StatesIn 2001, an estimated 56,200 new cases of NHL were diagnosed, with 26,300 deaths. NHL accounts for 5% of new cancers in men and 4% of new cancers in women. A striking increase in NHL incidence rates has occurred over the last 4 decades, referred to as an epidemic of NHL. The lifetime risk of being diagnosed with NHL is 2.08%. The incidence rate is increasing approximately 3% per year and has increased more than 80% since 1973. Several hypotheses address the increasing incidence of NHL. New classification systems and techniques, such as gene rearrangement studies establishing clonality, have led to diagnoses of NHL in patients who would have previously been diagnosed with benign disorders such as pseudolymphoma or atypical lymphoid hyperplasia. Better imaging techniques and improved biopsy techniques are likely to have contributed to the apparent increase in incidence. The aging population, the increasing number of immunosuppressive drugs, transplantation medicine, and the AIDS epidemic have contributed to the increased incidence of NHL. InternationalCertain endemic geographical factors appear to influence the development of NHL in specific areas. In Africa, the incidence of Burkitt lymphoma is 5.7-7.6 per 100,000 population as compared to 0.1 per 100,000 population in the United States (see Burkitt Lymphoma). In the Middle East, heavy chain disease (alpha) is a disorder of B-lymphoid cells that is characterized by diffuse thickening of the small intestine caused by a lymphoplasmacytic infiltrate with secretion of incomplete immunoglobulin A (IgA) heavy chains. This clinicopathologic entity is rarely encountered in individuals other than those of Mediterranean ethnicity. Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean, Africa, China, Japan, and the Middle East (see Lymphoma, Follicular). HTLV-1–associated adult T-cell lymphoma/leukemia occurs commonly in Japan and in the Caribbean (see Human T-Cell Lymphotrophic Viruses). Mortality/MorbidityNHL was responsible for 5% of cancer deaths in the United States. In 1997, NHL was the leading cause of death from cancer in men aged 20-39 years. RaceIncidence is the highest in white people. It is reported at 15.9 per cases 100,000 population for white males, compared to 12.0 cases per 100,000 population for African American people. The incidence rates are 54% higher among white males than Japanese American people and 27% higher among white males than among Chinese American people. Incidence rates are also lower among Native American people and Hispanic people. SexNHL is more common in male subjects, with a reported incidence of 19.2 cases per 100,000 population as compared with 12.2 cases per 100,000 population in women. However, in some sites, such as the thyroid, the incidence may be higher in women. AgeThe median age at presentation for all subtypes of NHL is older than 50 years. High-grade lymphoblastic and small noncleaved cell lymphomas are the only subtypes of B-cell NHL that are observed more commonly in children and young adults. CLINICALSection 3 of 11
History
PhysicalThe physical examination of a patient with an advanced high-grade lymphoma may reveal high fever, tachycardia, and respiratory distress. However, the physical examination more typically reveals pallor (suggesting anemia) or purpura, petechiae, or ecchymoses (suggesting thrombocytopenia). Examination should include palpation of all lymph node–bearing areas as well as assessment of hepatomegaly and splenomegaly. Pharyngeal involvement, a thyroid mass, evidence of pleural effusion, abdominal mass, testicular mass, or cutaneous lesions are examples of findings that might direct further investigations and subsequent therapy. A neurologic examination is appropriate at diagnosis. Certain associations of involvement between various organ sites are noteworthy. Approximately 25% of patients with involvement of Waldeyer ring have involvement of the gastrointestinal tract, and the converse is also true. This finding occurs most commonly in mantle cell lymphoma. Patients with paranasal sinus involvement, testicular involvement, and epidural lymphoma are particularly prone to have meningeal involvement and thus require a diagnostic lumbar puncture. One quarter of patients with bone marrow involvement by large cell lymphoma also have CNS disease. Patients with one testicle involved are likely to relapse in the contralateral testis. CausesSeveral known associations and genetic abnormalities that may play a role in the etiology of NHL in a particular patient exist.
DIFFERENTIALSSection 4 of 11
Hodgkin Disease Infectious Mononucleosis Metastatic Cancer, Unknown Primary Site Sarcoidosis
|
| Lymphoma | Immunophenotype |
|---|---|
| Follicular | CD20+, CD3-, CD10+, CD5- |
| Small lymphocytic | CD 20+, CD3-, CD10-, CD5+, CD23+ |
| MALT | CD20+, CD3-, CD 10-, CD5-, CD23- |
| Marginal zone | CD20+, CD3-, CD 10-, CD5-, CD23- |
| Mantle cell | CD20+, CD3-, CD10-, CD5+, CD23-, CD 43+, PRAD1+ |
| Diffuse large B-cell | CD20+, CD3-, CD5-, CD45+ |
| Mediastinal large B-cell | CD20+, CD3-, CD45+ |
| Burkitt | CD20+, CD3-, CD10+, CD5-, Tdt- |
| Lymphoblastic | CD20-, CD3+, Tdt+ |
| Peripheral T-cell | CD20-, CD3+ |
| Anaplastic large cell | CD20-, CD3+, CD30+, CD15-, EMA+, ALK+ |
| Hodgkin | CD30+, CD15+ |
The histologic findings in B-cell NHL are varied. The salient features of the most common subtypes are described below.
Follicular lymphoma
At low magnification, a predominantly nodular growth pattern is observed in lymph nodes. Two principal cell types are observed in varying proportions: small cells with irregular or cleaved nuclear contours and scant cytoplasm that are referred to as centrocytes (small cleaved cells) and larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm that are referred to as centroblasts. In most follicular lymphomas, small cleaved cells comprise the majority of the cellularity. Peripheral blood involvement sufficient to produce lymphocytosis (usually <20,000/µL) is observed in about 10% of patients. Bone marrow involvement occurs in 65% of patients and characteristically takes the form of para-trabecular lymphoid aggregates. Splenic white pulp and hepatic portal triads are also frequently involved.
Diffuse large B-cell lymphoma
The common morphologic features that unite this group are the relatively large cell size (usually 4-5 times that of a small lymphocyte) and a diffuse pattern of growth. In other respects, a fair degree of morphologic variation exists. In most cases, the tumor cells have a round or oval nucleus that appears vesicular because of margination of chromatin at the nuclear membrane, but large multilobated or cleaved nuclei predominate in some cases. Nucleoli may be 2-3 in number and located adjacent to the nuclear membrane, or they may be single and centrally placed. Cytoplasm is usually present in moderate abundance and may be pale or basophilic. Other more anaplastic tumors may contain multinucleated cells with large inclusionlike nucleoli that closely resemble Reed-Sternberg cells, and phenotyping is often necessary to distinguish these 2 entities.
Burkitt lymphoma
Involved tissues are effaced by a diffuse infiltrate of intermediate-sized lymphoid cells, 10-25 µm in diameter, containing round or oval nuclei with coarse chromatin, several nucleoli, and a moderate amount of faintly basophilic or amphophilic cytoplasm. The nuclear size approximates that of benign macrophages within the tumor. A high mitotic index is typical, as is apoptotic tumor cell death, accounting for the presence of numerous tissue macrophages with their ingested tissue debris. These macrophages are often surrounded by a clear space, creating the characteristic starry sky pattern.
Radiation therapy
Because patients with B-cell lymphoma often have disseminated disease, radiation therapy plays a limited role. It is used in early-stage limited disease as outlined below; it also has a role as consolidative therapy in aggressive lymphomas that respond to chemotherapy. With most histologic types of follicular lymphoma, doses of 44 cGy can achieve local control of disease. In large cell lymphoma, the dose-response curve of radiation therapy is less well established. In addition, radiation has a role in managing some of the complications (eg, superior vena cava syndrome, bone involvement with lymphoma with impending pathological fracture).
Chemotherapy
Chemotherapy forms the cornerstone of therapy in lymphoma and has a curative, as well as a palliative, role in this disease. The details of chemotherapeutic agents are outlined below.
Biologic therapy
Biologic therapy is comprised of interferon therapy and monoclonal antibodies. While the status of interferon therapy is discussed in this section, the role of monoclonal antibodies is discussed with the specific subtypes of B-cell lymphoma (see Treatment of specific lymphoma subtypes, below).
Interferon therapy was the first biologic treatment studied in NHL. It is widely used in Europe for the treatment of indolent lymphomas, but it is seldom used in the United States. This difference is based on 2 studies. A French trial demonstrated benefits in overall and progression-free survival when interferon followed a doxorubicin-containing chemotherapy regimen to treat patients with poor prognosis (Solal-Celigny, 1998). However, a US-based trial demonstrated no advantage to interferon therapy for treatment of patients with indolent lymphomas (Fisher, 2000).
Initial studies reported an increase in disease-free and overall survival rates compared with those observed for combination chemotherapy alone (Smalley, 1992; Solal-Celigny, 1998). With more mature data of one of these studies, no overall significant difference in overall survival occurred (Andersen, 1993). Data for the use of interferon maintenance therapy suggest prolonged disease-free survival but no consistent overall survival benefit (Hagenbeek, 1998). The role for interferon therapy in patients with indolent lymphomas, therefore, remains under clinical evaluation.
Monoclonal antibodies are the latest addition to the armamentarium against B-cell lymphoma. Table 3 lists the various monoclonal antibodies currently in use or under investigation in treatment of B-cell lymphoma.
Table 3. Monoclonal Antibodies for Treatment of NHL
| Antibody | Antigen | Conjugate |
|---|---|---|
| Rituximab (Rituxan)* (IDEC Pharmaceuticals/Genentech) | CD20 | None |
| CAMPATH-1H* (Humanized IgG1† ; Millennium Pharmaceuticals, Inc) | CD52 | None |
| Tositumomab (Bexxarr)* (GlaxoSmithKline/Corixa Corporation) | CD20 | 131I‡ |
| Ibritumomab tiuxetan (Zevalin) (IDEC Pharmaceuticals) | CD20 | CD20, 90Y§ |
| Epratuzumab (Immunomedics, Inc) | CD22 | 131I, 90Y |
| Hu1D10 | HLA-DRII | None |
| Bevacizumab (IDEC Pharmaceuticals) | VEGF¶ | None |
| Lym-1 (Oncolym) (Berlex Laboratories, Inc/Peregrine Pharmaceuticals, Inc) | HLA-DR | 131I |
*Food and Drug Administration (FDA) approved
† Immunoglobulin G
‡ Iodine I 131
§ Yttrium Y 90
IIHuman leukocyte antigen
¶ Vascular endothelial cell growth factor
This section first discusses the broad treatment outline for different stages of indolent and aggressive B-cell lymphoma followed by some details regarding therapy of the more common subtypes (ie, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma).
Indolent stage I and contiguous stage II adult NHL
Encountering localized presentations is unusual in most indolent subtypes of B-cell NHL. However, the goal of treatment should be cure in patients who are shown to have truly localized disease after undergoing appropriate staging procedures.
Long-term disease control within radiation fields can be achieved in a significant number of patients with indolent stage I or stage II NHL by using doses of radiation that usually range from 2500-4000 cGy to involved sites or to extended fields that cover the adjacent nodal sites (Lawrence, 1988; Denham, 1996).
The value of adjuvant chemotherapy (ie, single-agent chlorambucil, doxorubicin-based combination chemotherapy) has not been proven conclusively (Kelsey, 1994; Seymour, 1996).
In the rare circumstance when radiation therapy is contraindicated in a patient who is asymptomatic, chemotherapy, as used for patients with advanced disease, can be employed or watchful waiting can be considered. Patients with involvement that cannot be encompassed by radiation therapy are treated as patients with stage III or IV indolent lymphoma. Follicular large cell and mantle cell NHLs are often treated as aggressive lymphomas.
Aggressive stage I and contiguous stage II adult NHL
Radiation therapy alone can achieve long-term disease control in 90% of treated patients when a dose of 3500-5000 cGy is used. However, the disease-free survival rate using radiation alone varies from 60-70% at 5 years (Kaminski, 1986). The success of combination chemotherapy in early-stage disease has led to combinations of chemotherapy and radiation therapy or chemotherapy alone. In 2 large randomized prospective trials, a combination of chemotherapy (ie, cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone, and bleomycin [CHOP]) and radiation therapy resulted in a better outcome than CHOP alone (Miller, 1998; Glick, 1995). Further details of adjuvant radiation therapy are outlined in Diffuse large B-cell lymphoma, below.
Extranodal sites, including the gastrointestinal tract, thyroid, and bone, may be involved with aggressive NHL. Because extranodal site presentations frequently have an unpredictable pattern of relapse, chemotherapy is often used as the primary treatment modality. However, adjuvant radiation to the regions of disease involvement following chemotherapy appears to have the same improvement in disease-free and overall survival rates as for nodal disease (Glick, 1995).
Indolent, noncontiguous stage II/III/IV adult NHL
Optimal treatment of advanced stages of indolent B-cell NHL remains controversial. The reasons for controversy include the fact that the vast majority of patients with advanced stages of indolent NHL are not cured with the current therapeutic options. The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. Hence, deferred treatment must be considered.
The role of interferon alfa in this patient population remains unclear. Standard therapy includes alkylating agents as single agents or as components of combination chemotherapy or purine nucleosides (eg, fludarabine and 2-chlorodeoxyadenosine [cladribine], abbreviated 2-CDA). The purine analogues have excellent activity in the small lymphocytic subtype and now constitute the standard treatment for that variant. Because none of these therapies is curative for advanced-stage disease, innovative approaches are under clinical evaluation. These include intensive therapy with chemotherapy and total-body irradiation followed by autologous or allogeneic bone marrow or peripheral stem cell transplantation and the use of monoclonal antibodies, including rituximab and other radiolabeled monoclonal antibodies.
Recent data support the use of maintenance therapy with rituximab in patients with indolent lymphoma (Hainsworth, 2005). In this trial, patients with indolent lymphoma who were treated with chemotherapy in the past were treated with rituximab and randomized to receive maintenance rituximab at 6-month intervals for 2 years or to retreatment with rituximab at progression. Progression-free survival was prolonged in the maintenance group (31.3 vs 7.4 mo, P=.007).
Thus, treatment options include an entire spectrum from watchful waiting to aggressive myeloablative therapy with hematopoietic precursor cell rescue. Any specific option should be chosen only after a detailed and open discussion with the patient, and the treatment selected should be based on patient factors, including age, life expectancy, comorbidities, patient preferences, and goals of therapy. Considerations for treatment include the following:
Aggressive noncontiguous stage II/III/IV adult B-cell lymphoma
The treatment of choice for patients with advanced stages of aggressive B-cell lymphoma is combination chemotherapy, either alone or supplanted by local field radiation.
Chemotherapy is doxorubicin-based and can provide long-term disease-free survival rates in 35-45% of patients (Longo, 1991; Shipp, 1990; Fisher, 1993). A prospective trial of 4 regimens (ie, [1] CHOP; [2] prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin [ProMACE-CytaBOM]; [3] moderate-dose methotrexate, bleomycin, Adriamycin, cyclophosphamide, Oncovin, and dexamethasone [m-BACOD]; and [4] methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin [MACOP-B]) for patients with diffuse large cell lymphoma showed no difference in overall survival rates or time to treatment failure at 3 years (Fisher, 1993). Other randomized trials have confirmed no advantage among standard doxorubicin-based combinations versus CHOP. In B-cell lymphomas, the addition of rituximab to CHOP chemotherapy increases both remission rates and overall survival. CHOP-R is the current standard of care.
No benefit of adjuvant radiation therapy was observed in advanced-stage aggressive NHL. In patients aged 60 years and older, several randomized trials have confirmed the superiority of CHOP over other less toxic regimens in progression-free and overall survival rates. Thus, unless obvious contraindications to the use of one or more of these agents exist, age itself is not considered a reason to preclude CHOP chemotherapy in elderly patients.
Based on current evidence, patients with aggressive NHL with high IPI scores seem likely to benefit from high-dose chemotherapy with autologous hematopoietic precursor cell rescue. Results from ongoing trials will ascertain the subsets of patients who consistently benefit from this approach.
Follicular lymphoma
Follicular lymphoma is by far the most common of the indolent NHLs and represents almost 25% of all new cases of NHL; therefore, the treatment of follicular lymphoma serves as a paradigm for this group of diseases. Follicular lymphoma can be graded according to the percentage of blasts (grade I-III); follicular lymphoma grade III has a more aggressive course and is often treated similarly to diffuse large B-cell lymphoma. The median survival of patients with follicular lymphoma exceeds 9 years (Gallagher, 1986).
A watch and wait strategy in follicular lymphoma is appropriate (standard treatment) for patients who are asymptomatic and have blood cell counts within the reference range and no critical visceral involvement, although most patients ultimately develop progressive disease and require therapy, commonly within 12-18 months. Alkylating agents, such as chlorambucil or cyclophosphamide, remain the cornerstone of treatment for follicular lymphoma. Most patients (ie, approximately 75%) respond to such treatment; however, only a minority (ie, 25-35%) achieves a CR, and relapse is inevitable. The median duration of first response is 2.5 years (Johnson, 1995). Treatment with more intensive therapy (eg, CHOP) can induce a higher rate of complete response (ie, approximately 65%), but it has not been demonstrated to alter the natural history of disease (Dana, 1993).
Following relapse, significant palliation can be achieved with repeated therapy with alkylating agents, although response rates are somewhat lower and remissions are generally shorter (Johnson, 1995). Therefore, patients die from the effects of progressive lymphoma or its treatment. Histologic transformation to aggressive histology (eg, diffuse large B-cell lymphoma) also remains a significant problem. Transformation is often heralded by the onset of rapid progression at one site in association with B symptoms, and transformation can occur in as many as 40% of patients (Bastion, 1997). Transformation portends poor short-term prognosis in most series, with median survival less than 1 year, although the aggressive lymphoma may be curable with intensive chemotherapy, especially in those patients who present with limited disease.
Molecular remission in follicular lymphoma refers to the conversion to negativity by PCR assay for the t(14;18) in peripheral blood or bone marrow following therapy, and molecular remission implies a lower disease burden in those patients in clinical remission. Molecular remission following chemotherapy or autologous bone marrow transplantation following in vitro B-cell purging has been associated with improved disease-free survival in some reports (Apostolidis, 2000).
As a single agent, the purine analog antimetabolite fludarabine phosphate can induce remission in 40-50% of patients with relapsed or refractory indolent B-cell NHL, although CR is uncommon (approximately 10%). Fludarabine appears to be particularly active in the subset of small B-lymphocytic lymphoma. Superiority of this agent in CLL over chlorambucil has been demonstrated convincingly in a recently reported randomized trial (Rai, 2000). In newly diagnosed follicular lymphoma, the overall response rate is 65% (37% CR), with a median duration of response of 16 months (Solal-Celigny, 1996).
In a randomized study of 309 patients with newly diagnosed B-cell NHL, the overall response rate (69%) and the CR rate (39%) were significantly higher with fludarabine than standard CVP chemotherapy, which produced a response rate of 53% and a CR of 17% (Hagenbeek, 1998). Myelosuppression was more common following fludarabine, but no difference in the frequency of serious infections occurred between the 2 groups.
Although the increased remission rate in the fludarabine arm is encouraging, in the short-term follow-up, no significant difference in survival existed. Furthermore, in another randomized study of previously treated patients, fludarabine achieved response rates and survival similar to CVP. Therefore, fludarabine does not clearly alter the natural history of relapsed disease (Klasa, 1999). A new oral formulation of fludarabine has been developed recently and seems to have adequate plasma concentrations with predictable bioavailability. Once established, this would further simplify the use and administration of this agent for indolent B-cell lymphomas.
The concept of monoclonal antibody therapy is not new. More than 20 years ago, murine antibodies against B1 (CD20) were demonstrated to induce remission in patients with relapsed B-cell NHL. However, the development of humanized monoclonal antibodies has significantly increased their clinical activity. In addition to direct cytotoxic effects, humanized monoclonal antibodies can induce both complement-dependent cytotoxicity and cellular immune response.
Rituximab is a chimeric (mouse/human) monoclonal anti-CD20 and the first monoclonal antibody approved in the treatment of cancer. It induces remission in approximately 50% of patients with relapsed and refractory follicular lymphoma, although most responses are not complete (McLaughlin, 1998; Foran, 2000). The response rate is significantly lower in patients with nonfollicular indolent B-cell NHL, such as lymphoplasmacytic or small B-cell lymphocytic lymphoma. However, the median duration of remission in patients with follicular lymphoma is in the range of 1 year, with no evidence of plateau in progression-free survival (McLaughlin, 1998; Foran, 2000). Rituximab also seems active in the treatment of bulky disease (Davis, 1999). Re-treatment of those who had a prior response induces another response in 40% of patients, with a projected median duration of 16 months or longer. Whether a longer course of therapy (ie, 8 wk) improves the response rate is not yet known.
With the exception of some infusion-related toxicity, rituximab is well tolerated. Infusion-related toxicity, including tumor lysis syndrome and cytokine release syndrome, can occur in patients with circulating tumor cells or an elevated WBC count, particularly with the initial administration of rituximab. Consider other modes of cytoreduction in patients with circulating disease and administer rituximab cautiously.
When administered to patients newly diagnosed with follicular lymphoma with low tumor burden, rituximab induced a remission in 73% of patients, including a CR in 26%. Relapses were noted, with a median duration of response of 12 months or longer (Colombat, 2001). In another report (patients not selected for low tumor burden), 54% of patients administered rituximab as an initial therapy achieved a response, although CR was rare, at only 5% (Hainsworth, 2000). In the latter study, maintenance rituximab was administered, and, therefore, ascertaining its impact on relapse is difficult. Single-agent rituximab evidently is not curative, although it is an important palliative treatment with relatively low short-term toxicity.
Rituximab has also been administered in combination with cytotoxic chemotherapy and other biologic agents. It appears to be fairly well tolerated, although significant hematologic toxicity was noted in combination with fludarabine, requiring a dose reduction in some cases. In a phase II study, the combination of CHOP and rituximab achieved a 100% response rate, including CR in 22 of 38 patients (58%). Seventy-four percent of the patients remained in remission at a median of 2.5 years of follow-up (Czuczman, 1999). However, no randomized data are currently available in indolent B-cell NHL, and careful study is required to determine if these combinations result in improved survival.
Radioimmunotherapy is a novel therapeutic approach to combating follicular B-cell NHL that is currently awaiting FDA approval. It exploits the sensitivity of lymphoma cells to radiation and the natural properties of monoclonal antibodies. The monoclonal antibody is labeled with gamma- and beta-emitting radioactive isotope (eg, 131I) in order to enhance the antibody's capacity to kill tumor cells. The radiolabeled antibody binds to the CD20 antigen while emitting cytotoxic beta particles; the gamma emissions are used to scan the patient and to adjust the radiation dose. This process produces a crossfire effect, where the destruction of tumor cells is enhanced by radiation emissions from different directions.
One radiolabeled anti-CD20 monoclonal antibody radiolabeled with 131I is tositumomab, and it has been studied extensively using the dosimetric approach. In the original schedule, a total whole-body radiation dose of 75 cGy is delivered (Kaminski, 1996). Early results have been encouraging, with objective response rates of 65% (17% CR) in the heavily pretreated regimen versus 28% (3% CR) for the prior chemotherapy regimen (Kaminski, 1998). 131I tositumomab is associated with the development of human anti-mouse antibodies (HAMA) in about two thirds of the patients. However, the development of HAMA with 131I tositumomab does not seem to preclude later treatment with chimeric monoclonal antibodies such as rituximab (Kaminski, 2000).
90Y ibritumomab (Zevalin) is another radiolabeled monoclonal antibody that has demonstrated high response rates (82% with CR 26%) in follicular lymphoma (Witzig, 1999). At interim analysis in a randomized study including 143 patients, the response rate was higher with 90Y ibritumomab (80%) than with rituximab, which produced a 44% response rate (Witzig, 1999). Note that these radiolabeled antibodies are capable of inducing profound myelosuppression, particularly in patients with significant preexisting bone marrow infiltration by lymphoma. Furthermore, they are expensive, and whether they result in superior survival is not yet known.
High-dose therapy with autologous bone marrow transplantation is feasible and has been evaluated as consolidation in patients with follicular lymphoma (Apostolidis, 2000; Bierman, 1997). Approximately 30-40% of those treated following relapse achieved long-term disease-free survival, although late relapses can occur. In one cohort of patients treated in first remission, the projected risk of relapse rate at 10 years was only 30%, although in another study the median duration of remission was shorter, at approximately 4 years (Freedman, 1999). High-dose therapy may improve the remission duration when compared with historical controls but has not yet been demonstrated to improve survival, possibly on the basis of early treatment-related toxicity and the development of secondary myelodysplasia. Patients with histologic transformation, a group with historically poor prognosis, may have an improved outcome following high-dose consolidation (particularly those patients with chemosensitive disease).
Allogeneic stem cell transplantation is associated with a relatively high mortality rate due predominantly to the complications of graft versus host disease. However, it appears to have a low risk of subsequent relapse, possibly because of graft versus lymphoma effect. An apparent plateau in failure-free survival rates suggests that allogeneic stem cell transplantation may offer cure to some patients with follicular lymphoma and may be appropriate for selected younger patients (van Besien, 1998). With the advent of nonmyeloablative allogeneic stem cell transplants, this modality may be available to a larger group of patients because it does not carry the risks of acute early toxicity and mortality, unlike the myeloablative stem cell transplant.
A patient-specific vaccine engineered from lymphoma-associated idiotype coupled with an immune-stimulating keyhole limpet hemocyanin adjuvant may lower the risk of subsequent relapse in those patients who generate a response (Hsu, 1997). While constructing these patient-specific vaccines using the original hybridoma rescue technique is laborious and time consuming, it can now be accomplished much more quickly using a recombinant/PCR-based technology, making this a feasible strategy. Therefore, recombinant idiotype vaccination is now being tested in a randomized trial including patients in first remission of follicular lymphoma to determine if an anti-idiotype response can indeed decrease the risk of relapse.
Small lymphocytic lymphoma, B-cell CLL
See Chronic Lymphocytic Leukemia.
Splenic marginal zone lymphoma
Typically, patients present with splenomegaly without lymphadenopathy, although bone marrow involvement is common. A splenectomy is often required to establish the diagnosis, and remission afterwards may be prolonged. Following splenectomy, symptoms or signs of progressive disease may occur; however, the progression-free interval may be substantial. Systemic therapy at this point is similar to that used for CLL.
Extranodal B-cell lymphoma of MALT
MALT lymphomas are usually localized and are most frequently observed in the stomach, lung, salivary gland, thyroid, and lacrimal gland. An association of MALT lymphomas with autoimmune disease is well known. The development of gastric MALT lymphomas has been attributed to antigenic stimulation associated with chronic H pylori gastritis. Indeed, the standard initial treatment for early-stage disease now is antibiotic therapy to eradicate the infection; regression of lymphoma occurs in some patients.
Surgical excision is the primary treatment (and in most cases is required to make the diagnosis). Further treatment may not be needed. When the tumor is incompletely excised, radiotherapy may be appropriate. In the minority of patients presenting with a more widespread disease, systemic chemotherapy is effective. The majority of MALT lymphomas respond to treatment similar to that for follicular lymphoma. However, evolution to diffuse large B-cell lymphoma requires an anthracycline-containing regimen.
Mantle cell lymphoma
Mantle cell lymphoma comprises about 5% of adult NHLs in the United States and Europe. In the past, these lymphoid neoplasms were frequently included in the IWF category E (diffuse small cleaved cell lymphomas). Mantle cell lymphoma is a tumor of older adults, with a male predominance. Patients usually have widespread disease at diagnosis; involved sites include lymph nodes, spleen, Waldeyer ring, and, often, bone marrow and extranodal sites such as the gastrointestinal tract (lymphomatous polyposis). The course is moderately aggressive, with a median survival of 3-5 years. A more aggressive blastoid variant is described with a median survival of 3 years (Fisher, 1995).
In early retrospective analyses, Southwest Oncology Group (SWOG) investigators found that patients with advanced-stage mantle cell lymphoma who were treated with CHOP chemotherapy had lower failure-free survival rates and overall survival times than patients with other lymphoma subtypes (Fisher, 1995).
The European Organization for Research and Treatment of Cancer (EORTC) also recently reported that patients with mantle cell lymphoma who were treated with aggressive doxorubicin-containing combination therapy had response rates similar to those of IWF intermediate-grade disease, but no evidence of a curable mantle cell lymphoma subset was present (Teodorovic, 1995). Patients with mantle cell lymphoma treated with CVP with or without interferon had rates of relapse similar to those of IWF low-grade disease; however, patients with mantle cell lymphoma had a significantly shorter overall survival time than patients with IWF low-grade disease. Considered together, these data confirm the uniquely unfavorable natural history of mantle cell lymphoma and suggest the need for innovative approaches in its management. High-dose therapy with autologous stem cell rescue alone does not seem to significantly impact the disease based on results from early clinical
trials.
Bortezomib (Velcade) was recently approved in December 2006 by the US Food and Drug Administration (FDA) for mantle cell lymphoma.
Historically, patients with early-stage (localized disease [stage I and II disease]) aggressive lymphomas were treated with radiation therapy alone. However, more recently, patients with localized disease have been treated with combination chemotherapy alone or in combination with localized radiation therapy.
A 1995 Eastern Cooperative Oncology Group (ECOG) randomized phase III trial of 8 cycles of CHOP with or without radiation therapy for early-stage intermediate-grade NHL found the use of low-dose radiation (3000 cGy) as consolidation for patients achieving CR after CHOP was significantly better than CHOP alone in terms of disease-free survival. This study excluded stage I patients with favorable features and did not address the issue of how much chemotherapy is necessary when used as a component of combined modality therapy (Glick, 1995).
A recent SWOG study further supports the use of radiation therapy with abbreviated chemotherapy in this setting (Miller, 1998). In this study, 401 patients with localized intermediate- or high-grade NHL were randomized to receive 3 cycles of CHOP followed by involved field radiation therapy or to receive 8 cycles of CHOP alone. A minimum of 4000 cGy was administered to all sites of initial disease, with an addition boost to 5500 cGy for residual overt disease.
Patients treated with abbreviated CHOP and radiation had significantly better progression-free survival rate (77% versus 64%, P = 0.03) and overall survival rate (82% versus 72%, P = 0.02) than patients treated with CHOP alone. A subset analysis of 127 patients younger than 60 years with stage I disease and normal Karnofsky performance score indicated a 97% 4-year survival rate (4 deaths). This study concluded that CHOP (3 cycles) plus radiation is more effective and less toxic than CHOP (8 cycles) alone for early-stage diffuse large B-cell lymphoma. Future studies should focus on patients who are symptomatic, patients older than 60 years, or those with bulky stage II disease.
From 1986-1991, 1138 previously untreated patients with stage II (bulky), III, or IV intermediate-grade or high-grade NHL were randomized to receive either standard chemotherapy (ie, CHOP) or 1 of the third-generation regimens (ie, m-BACOD, ProMACE-CytaBOM, MACOP-B). No difference in response rate, time to treatment failure, or overall survival rate occurred between CHOP and newer regimens. Moreover, the newer regimens were more toxic and expensive. Other randomized comparisons have failed to show an advantage of the third-generation regimens over CHOP. A list of commonly used chemotherapy regimens is outlined in Table 4.
Table 4. Combination Chemotherapy Regimens Useful as Primary Treatment of Aggressive Lymphoma
| Regimen | Drugs and Dosages |
|---|---|
| CHOP | Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 IV on day 1 Vincristine 1.4 mg IV on day 1; not to exceed 2 mg Prednisone 100 mg PO on days 1-5 Repeat q21d |
| BACOP | Bleomycin 5 U/m2 IV on days 15, 22 Doxorubicin 25 mg/m2 IV on days 1, 8 Cyclophosphamide 650 mg/m2 IV on days 1, 8 Vincristine 1.4 mg/m2 IV on days 1, 8; not to exceed 2 mg Prednisone 60 mg/m2 PO on days 15-28 Repeat q28d |
| m-BACOD | Methotrexate 200 mg/m2 IV on days 1, 8 Leucovorin 10 mg/m2 PO q6h for 8 doses starting 24 h after methotrexate Bleomycin 4 U/m2 IV on day 1 Cyclophosphamide 600 mg/m2 IV on day 1 Vincristine 1 mg/m2 IV on day 1 Dexamethasone 6 mg/m2 PO on days 1-5 Repeat q21d |
| ProMACE/MOPP | Prednisone 60 mg/m2 PO on days 1-14 Methotrexate 1500 mg/m2 IV on day 14 Leucovorin 50 mg/m2 IV q6h for 5 doses starting 24 h after methotrexate Doxorubicin 25 mg/m2 IV on days 1, 8 Cyclophosphamide 650 mg/m2 IV on days 1, 8 Etoposide 120 mg/m2 IV on days 1, 8 Repeat q28d ProMACE is administered for a variable number of cycles, based on tumor response, then MOPP therapy is administered for the same number of cycles. |
| MACOP-B | Methotrexate 400 mg/m2 IV on weeks 2, 6, 10; one-fourth dose is administered as IV bolus, the remaining is administered over 4 h Leucovorin 15 mg PO q6h for 6 doses starting 24 h after methotrexate Doxorubicin 50 mg/m2 IV on weeks 1, 3, 5, 7, 9, 11 Cyclophosphamide 350 mg/m2 IV on weeks 1, 3, 5 , 7, 9, 11 Vincristine 1.4 mg/m2 IV on weeks 2, 4, 6, 8, 10, 12 Bleomycin 10 U/m2 IV on weeks 2, 4, 6, 8, 10, 12 Prednisone 75 mg/d PO for 12 wk, taper to 0 during weeks 10-12 Trimethoprim-sulfamethoxazole 1 double-strength tablet bid daily for 12 wk |
Although CHOP (in combination with rituximab) remains the best available standard therapy, it is curative in less than 50% of patients, indicating the need for new treatment approaches. The following recommended treatment strategies should be adjusted according to the level of risk, as defined by the prognostic factors validated by the IPI.
Younger patients (ie, £60 y) at low or intermediate risk have 5-year survival rates greater than 50%. They should be treated with 6-8 cycles of a standard doxorubicin-containing regimen such as CHOP.
The 5-year survival rate in younger patients (ie, £60 y) deemed at high-intermediate or high risk is less than 50%. Because the clinical features that correlate with relapse are also associated with a decreased likelihood of achieving an initial remission, these patients should be offered participation in clinical trials of dose-intensive treatment strategies aimed at improving the rates and durability of complete responses. Efforts to augment dose intensity of induction and consolidation therapy include the use of colony-stimulating factors and infusion administration of chemotherapy, as well as conventional and repetitive high-dose therapy with hematopoietic stem cell support. The current status of such an approach is addressed in a section below.
All patients older than 60 years should undergo evaluation of cardiac, pulmonary, and renal function and coexistent illness, which may complicate therapy. Most older patients with advanced-stage aggressive NHL have 5-year survival rates of less than 50% as a result of decreased initial response, poor tolerance to therapy, and the need for dose reduction because of age. Approaches to elderly patients should include interventions aimed at preserving or increasing dose intensity and improving tolerance to chemotherapy with the use of cytokines and infusion chemotherapy. Selected physiologically younger patients may be eligible for consolidation with high-dose therapy and hematopoietic stem cell support.
The French Group (Groupe d'Etude des Lymphomes de l'Adulte) was the first to demonstrate that the addition of monoclonal antibody rituximab to the CHOP regimen improved disease-free survival in elderly patients (Coiffier, 2002). A subsequent trial demonstrated an advantage to CHOP and rituximab over CHOP alone in good-risk patients younger than 60 years (Pfreundschuh, 2004). The French Group also demonstrated the merits of the ACVBP regimen (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), the CNS prophylaxis, and intensive consolidation phase is more active than CHOP in patients with advanced disease (Tilly, 2000). The merits of the addition of rituximab to this regimen need to be compared with the CHOP-rituximab combination.
Patients with compromised cardiac function require individualized approaches, such as the use of a regimen that does not contain an anthracycline (eg, CVP; cyclophosphamide, vincristine, procarbazine, and prednisone [C-MOPP]; cyclophosphamide, etoposide, and prednisone [CEPP]). Alternatively, a reduction in the total anthracycline dose may be attempted (eg, by alternating CHOP with C-MOPP or CEPP), or doxorubicin, such as dexrazoxane (Zinecard), may be administered by a continuous infusion along with the anthracycline because the former is shown to exert cardioprotective effect when used with an anthracycline.
Patients who are not cured with initial chemotherapy represent a relatively unfavorable group. Using salvage chemotherapy regimens, such as those shown in Table 5, response rates near 50% have been reported. However, complete response rates are generally in the 20-30% range, and long-term relapse-free survival has been observed in fewer than 5% of patients treated with salvage chemotherapy.
Table 5. Salvage Chemotherapy Regimens Used Commonly in Recurrent Aggressive NHL
| Regimen | Drugs and Dosages |
|---|---|
| DHAP | Dexamethasone 40 mg PO/IV on days 1-4 Cytarabine 2 g/m2 over 3 h q12h for 2 doses on day 2, start after completing cisplatin infusion, reduce to 1 g/m2 for age >70 y Cisplatin 100 mg/m2 continuous IV infusion over 24 h on day 1 Repeat q3-4wk |
| ESHAP | Etoposide 60 mg/m2 IV on days 1-4 Methylprednisolone 500 mg IV on days 1-4 Cytarabine 2 g/m2 over 2 h on day 5 after completing cisplatin Cisplatin 25 mg/m2/d continuous IV infusion on days 1-4 Repeat q3-4wk |
| EPOCH | Etoposide 50 mg/m2/24h continuous IV infusion on days 1-4 Vincristine 0.4 mg/m2/24h continuous IV infusion on days 1-4 Doxorubicin 10 mg/m2/24h continuous IV infusion on days 1-4 Cyclophosphamide 750 mg/m2 IV on day 6 Prednisone 60 mg/m2 PO on days 1-6 Repeat q21d |
| MINE | Mesna 1.33 g/m2 mixed with ifosfamide over 1 h on days 1-3, followed by 500 mg IV 4 h after the ifosfamide Ifosfamide 1.33 g/m2 IV over 1 h on days 1-3 Mitoxantrone 8 mg/m2 IV over 15 min on day 1 Etoposide 65 mg/m2 IV over 1 h on days 1-3 Repeat q21d |
Because of the limited long-term disease-free survival achieved with salvage combination chemotherapy, the major approach to salvage therapy has become high-dose chemotherapy with or without total-body irradiation in conjunction with autologous peripheral blood stem cell transplantation. Among patients younger than 60 years, advances in supportive care, such as the use of colony-stimulating factor, have decreased the mortality rate associated with this therapy to 5%. Preparative regimens commonly used in the treatment of NHL are shown in Table 6.
Table 6. Preparative Regimens Commonly Used Prior to High-Dose Chemotherapy in NHL
| Regimen | Drugs and Dosages |
|---|---|
| Cy-TBI | Cyclophosphamide 60 mg/kg/d on days 6, 5 Total-body irradiation 12 Gy administered in 6 fractions of 2 Gy each, 2 fractions daily on days 4, 3, 2 |
| Cy-VP-TBI | Etoposide 1800 mg/m2 on day 7 Cyclophosphamide 50 mg/kg/d on days 6, 5, 4 Total-body irradiation 10 Gy administered in 5 fractions of 2 Gy each, 2 fractions daily on days 3, 2, 1 fraction on day 1 |
| CBV | Cyclophosphamide 1800 mg/m2 on days 6, 5, 4, 3 Carmustine (BCNU) 400 mg/m2 on day 2 Etoposide 2400 mg/m2 on day 7 |
| BEAM | Carmustine (BCNU) 300 mg/m2 on day 6 Etoposide 200 mg/m2 on days 5, 4, 3, 2 Ara-C 200 mg/m2 on days 5, 4, 3, 2 Melphalan 140 mg/m2 on day 1 |
Mediastinal diffuse large B-cell lymphoma
Primary mediastinal B-cell lymphoma is a distinct clinicopathologic entity, requiring knowledge of both morphology, immunophenotype, and presenting site for diagnosis. It accounts for approximately 7% of diffuse large B-cell lymphomas. These patients are treated with 4-6 cycles of CHOP chemotherapy followed by involved field radiation therapy. The presence of bulky disease, pleural effusion at presentation, and a positive gallium scan after CHOP chemotherapy are poor prognostic factors.
Burkitt lymphoma
Although Burkitt and Burkitt-like lymphomas comprise fewer than 10% of adult diffuse lymphomas, these diseases account for the majority of childhood B-cell lymphomas. Histologic criteria have been used to differentiate Burkitt and Burkitt-like lymphomas. Whereas Burkitt lymphomas are notable for remarkable uniformity of nuclear size and contour, Burkitt-like variants have greater variability in nuclear size and shape. Differences also appear to exist in the molecular genetics of Burkitt and Burkitt-like lymphomas. For example, c-myc rearrangements were detectable in 94% of the former but not in the latter (Yano, 1992). Clinical features also tend to vary because patients with Burkitt lymphoma are younger (median age 31 y) than patients with Burkitt variants (median age 56 y), and the former group more commonly presents with extranodal (primarily gastrointestinal) disease.
Despite these differences, significant differences in the response to therapy or previously identified prognostic factors do not seem to exist. In both subtypes, localized disease, serum LDH levels within the reference range, and normal performance status are favorable prognostic features. Many of the treatment regimens for adult Burkitt lymphoma are based on pediatric protocols. An intensive clinical trial using aggressive combination chemotherapy patterned after that used in childhood Burkitt lymphoma has been described and has been very successful for adult patients (Soussain, 1995; Magrath, 1996; Adde, 1998).
Most adult treatment regimens include brief high-dose combination chemotherapy with CNS prophylaxis with and without cranial irradiation. For example, a high-dose brief-duration combination chemotherapy program including cyclophosphamide, doxorubicin, etoposide, vincristine, bleomycin, methotrexate, and prednisone was associated with a response rate of 85% and a disease-free survival rate of 65% (median follow-up of 29 mo) in patients with advanced-stage disease (McMaster, 1991).
Patients with diffuse small noncleaved cell/Burkitt lymphoma have a 20-30% lifetime risk of CNS involvement. CNS prophylaxis (usually 4-6 injections of methotrexate intrathecally) is recommended for all patients. In a series of 41 patients treated with systemic and intrathecal therapy, 44% of those who presented with CNS disease and 13% of those who relapsed with CNS involvement became long-term disease-free survivors (Magrath, 1996). CNS relapse patterns were similar regardless of irradiation, but increased neurologic deficits were noted among those irradiated. The utility of high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell rescue remains a topic of active investigation in Burkitt lymphoma. In some institutions, treatment includes the use of consolidative bone marrow transplantation (Sweetenham, 1996). The early encouraging results obtained with more intensive approaches underscore the need to enroll these patients in clinical trials.
Surgical interventions rarely are required in this disease and are usually limited to diagnostic procedures, such as excisional biopsy. In the unusual event of a pathologic fracture of a bone secondary to involvement by lymphoma, orthopedic surgery may be necessary to stabilize the bone. Central venous access devices, especially when stem cell or bone marrow transplantation is considered, require a surgical consultation.
Radiation oncologists are often consulted because radiation plays a role in management of B-cell lymphoma; it is considered the treatment of choice in early-stage indolent lymphoma and has a role in consolidation of treatment in localized aggressive lymphoma.
Typically, no dietary restrictions exist for patients with NHL. Patients with prolonged neutropenia following chemotherapy, especially if undergoing high-dose chemotherapy with hematopoietic precursor cell rescue, are provided with a reduced-bacteria diet. Patients with high tumor burden undergoing chemotherapy may be at risk for tumor lysis syndrome and sometimes require a diet low in uric acid and potassium.
No restrictions on the activity of patients with NHL exist.
See Tables 3-6 in Medical care summaries of medications discussed.
Inhibit cell growth and proliferation.
| Drug Name | Doxorubicin (Adriamycin, Rubex) |
|---|---|
| Description | Inhibits topoisomerase II and produces free radicals, which may cause DNA destruction. Combination of these events can inhibit growth of neoplastic cells. |
| Adult Dose | CHOP: 50 mg/m2 IV on day 1 q3wk; dose varies from 60-75 mg/m2 as a single dose when administered as a single agent or in the absence of other significant myelosuppressive agents Alternatively, 20-30 mg/m2/d for 2-3 d, repeat in 4 wk |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; preexisting myelosuppression |
| Interactions | May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels of doxorubicin; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity |
| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus |
| Precautions | Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in impaired hepatic function |
| Drug Name | Vincristine (Oncovin) |
|---|---|
| Description | Vinca alkaloid. Mechanism of action is uncertain. May involve a decrease in reticuloendothelial cell function or an increase in platelet production. |
| Adult Dose | CHOP: 1.4 mg/m2, as high as 2 mg, IV push on day 1 q3wk; more frequent dosing is possible in the absence of other neurotoxic chemotherapy or depending on specific regimen |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; IT administration (may be fatal) |
| Interactions | Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; asparaginase, CYP450 3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim, filgrastim), or nifedipine increases toxicity; CYP450 3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects |
| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus |
| Precautions | Caution in severe cardiopulmonary disease, hepatic impairment (adjust dose), or preexisting neuromuscular dysfunction |
| Drug Name | Cyclophosphamide (Neosar, Cytoxan) |
|---|---|
| Description | Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Adult dose and schedule varies with indication in management of lymphoma. |
| Adult Dose | CHOP: 750 mg/m2 IV on day 1, repeat q3wk Follicular lymphoma: 50-100 mg/m2/d PO or 400-1000 mg/m2 PO in divided doses for 4-5 d 400-1800 mg/m2 (30-40 mg/kg) IV in divided doses over 2-5 d; may repeat at 2- to 4-wk intervals; alternatively, administer 10-15 mg/kg IV q7-10d or 3-5 mg/kg bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; severely depressed bone marrow function |
| Interactions | Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may red |