23 - Non-Hodgkin s Lymphoma
Editors: Skeel, Roland T.
Title: Handbook of Cancer Chemotherapy, 7th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 23 - Non Hodgkin's Lymphoma
Chapter 23
Non Hodgkin's Lymphoma
Richard S. Stein
John P. Greer
I. Epidemiology
There is a worldwide epidemic of non Hodgkin's lymphoma (NHL) with more than 60,000 cases diagnosed in the United States each year. Part of the increase is related to the development of NHL in patients with the human immunodeficiency virus (HIV). However, additional factors contributing to the NHL epidemic are listed in Table 23.1. The incidence of lymphomas is age related, with a steady increase in incidence from childhood through age 80; the median age of patients at the time of diagnosis of NHL is between 60 and 65 years. Lymphomas are the fifth most common cancer in the United States and they represent 4% of all cancers.
Extranodal presentations occur in 15% to 25% of adult cases in the United States with higher figures observed in Europe and the Far East. As the incidence of NHL has increased, there has been a disproportionate increase in cases with disease arising at extranodal sites as compared to that in nodal sites, in cases with a diffuse histologic pattern as compared to a follicular pattern, and in cases with an intermediate- to high-grade pattern as compared to low-grade disease. NHL of the brain has risen four times as rapidly as that in other extranodal sites, partly due to the association with HIV. However, the rise in central nervous system (CNS) lymphoma has also occurred in immunocompetent hosts as well. Familial aggregation of NHL plays a small role in the epidemic even though there is a twofold to fourfold increased risk for NHL in close relatives of patients with lymphoma or other hematopoietic neoplasms.
In addition to the association with HIV, other viruses have specific clinical associations with NHL. Chronic hepatitis C infection is often present in patients with type II cryoglobulin and many of these patients have an underlying indolent B-cell lymphoma. Helicobacter pylori infection in the stomach has been associated with gastric and duodenal ulcers, and it has been associated with gastric lymphoma, specifically, a low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALToma).
The mechanism of developing lymphoma has best been studied in the lymphomas occurring in immunodeficiency states. These disorders can be divided into congenital (or primary) immunodeficiencies and acquired (or secondary) immunodeficiencies (Table 23.2). Common components to all these disorders are defects in immunoregulation, particularly in T-cell immunity, resulting in decreased cytokines and uncontrolled B-cell growth in lymphoid tissue, often in association with the Epstein-Barr virus (EBV) genome. Additionally, chronic inflammation, immune hyperactivity, and immunosuppression are elements of autoimmune disorders that predispose patients to lymphoma. With two exceptions, nearly all lymphomas that occur in association with immune suppression are B-cell lymphomas; ataxia
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telangiectasia is associated with T-cell lymphoma and as many as one tenth of the lymphomas that occur in organ transplant patients are of T-cell origin. Additionally, T-cell lymphomas have an increased incidence in patients with nontropical sprue, angioimmunoblastic lymphadenopathy, and lymphomatoid papulosis.
Table 23.1. Epidemiologic factors associated with an increased risk of non Hodgkin's lymphoma | |
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II. Pathologic classification of lymphoma
NHL is composed of a diverse group of malignancies in which the cell of origin is a lymphocyte. If the site of origin is the bone marrow, the disorder may be classified as a form of lymphocytic leukemia, but when disease is present in both nodes and marrow, the distinction between leukemia and lymphoma is somewhat arbitrary. The disorders included in NHL differ in many basic characteristics. At the time of presentation, some types of lymphoma such as small cleaved cell lymphoma (alternatively regarded as grade I follicular lymphoma) are almost always disseminated and the bone marrow is usually involved by lymphoma. By contrast, patients with large B-cell lymphoma present with disease limited to one or two lymph node areas in approximately one third of cases; in this histologic type of lymphoma, bone marrow involvement is seen at presentation less than 20% of the time.
Some types of lymphoma, primarily those lymphomas with a follicular pattern under the microscope, have a slow indolent course. Patients with small cleaved cell lymphoma, the most common follicular lymphoma, may initially do well with no treatment or with minimal therapy. Median survival for these patients is
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between 8 and 12 years, with patients experiencing a series of responses and relapses before the disease becomes refractory to further therapy and terminates fatally. In contrast, other types of lymphoma such as diffuse large B-cell lymphomas are fatal in 4 to 12 months in the absence of therapy but may be cured by combination chemotherapy in 40% to 50% of cases. For over 80% of patients with NHL, including the types previously discussed, the cell of origin is a B lymphocyte; for less than 15% of cases, the cell of origin is a T lymphocyte.
Table 23.2. Pre-lymphomatous conditions | ||||||||||||||||||||||||
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In view of this clinical diversity, accurate classification of NHL is essential for scientific and clinical purposes. Ideally, a classification system should identify types of NHL that are scientifically and clinically meaningful. A classification system should define entities that are relatively homogeneous from a clinical, morphologic, immunologic, and genetic point of view. One would also want a classification system that was associated with concordance among pathologists regarding the classification of individual cases. Unfortunately, such an ideal classification system does not exist. Nevertheless, a clinical consideration of NHL must start with a discussion of the classification of lymphoma.
Problems related to the pathologic classification of NHL can best be appreciated from a historical perspective. In the 1960s, Rappaport proposed a classification of NHL that divided the disorders on the basis of whether the predominant cell was small, large, or a mixture of small and large cells. Lymphomas were also categorized as nodular or diffuse. Studies conducted using this system demonstrated that nodular lymphomas composed of small lymphocytes were generally indolent disorders,
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whereas the so-called histiocytic lymphoma was curable with combination chemotherapy. However, the Rappaport system predated the understanding that lymphocytes were B cells or T cells and that the nodules of nodular lymphoma are composed of the same cells found in germinal follicles. Additionally, studies eventually established that the so-called histiocytic lymphoma was actually composed of many disorders, most of which were B-cell disorders and a minority of which were T-cell disorders. These findings established the need for better terminology and for a more scientific classification system.
In the 1970s, the Lukes-Collins classification in the United States and the Kiel classification developed by Lennert in Europe, subdivided lymphoma into B-cell and T-cell disorders. As flow cytometry and studies of surface markers were in their infancy, such systems were difficult to use and it was not clear that the entities being discussed were meaningful entities that could be identified reliably. In this setting, the National Cancer Institute assembled a working panel of hematopathologists who created the New Working Formulation. This classification considered many of the concepts of immunologically oriented systems. However, instead of defining entities on the basis of their immunologic cell of origin, the New Working Formulation defined broad categories of lymphoma on the basis of general clinical prognosis. Specifically, the NewWorking Formulation defined low-grade lymphoma, intermediate-grade lymphoma, and high-grade lymphoma. The idea of this classification was to use the pathologic appearance of the lymphoma to tell the clinician how the lymphoma needed to be treated.
In the New Working Formulation, low-grade lymphomas are indolent lymphomas such as chronic lymphocytic leukemia (also known as small B-cell lymphoma) and follicular (nodular) small cleaved cell lymphoma. In asymptomatic patients, even in patients with widespread disease, watchful waiting (i.e., no initial treatment) may be appropriate management. These disorders are associated with a high response rate to single-agent or combination chemotherapy, but after a prolonged clinical course (8 to 12+ years), these diseases are usually fatal.
Intermediate-grade lymphomas were defined by the New Working Formulation as more aggressive lymphomas, associated with a fatal course within months to less than 2 years in the age of single-agent chemotherapy but curable 40% to 50% of the time in the era of combination chemotherapy. This category includes diffuse large cell lymphoma as well as diffuse forms of small cleaved cell lymphoma. Although most intermediate-grade lymphomas are B-cell lymphomas, this category also includes some T-cell lymphomas such as anaplastic large cell lymphoma (ALCL).
High-grade lymphomas as defined by the New Working Formulation are those lymphomas associated with a very high growth fraction and a rapidly lethal clinical course in the absence of effective therapy. This category includes Burkitt's and Burkitt's-like NHL. At the time the New Working Formulation was designed, the complete remission rate in patients with high-grade lymphoma was only 20%. However, in the intervening years, as cure rates in intermediate-grade NHL maintained a plateau of 40% to 50%, complete response rates in high-grade lymphoma rose from the 20% range to the 40% to 50% range with
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the use of more aggressive chemotherapy. Nevertheless, while response rates for intermediate- and high-grade lymphoma have come together, this distinction is still relevant as high-grade lymphomas will not show such response if treated with standard CHOP therapy, a regimen that is acceptable for intermediate grade NHL.
On the basis of the assumption that the scientific study of lymphomas requires the delineation of scientifically meaningful entities, the REAL (Revised European American Classification of Lymphoid Neoplasms) classification system was developed to delineate the entities that hematopathologists, immunologists, and molecular biologists had defined in the last 15 years. It has since been adopted and modified by the World Health Organization (WHO) as the REAL/WHO classification system.
The REAL/WHO classification system (Table 23.3) has the advantage of recognizing lymphomas that can be defined at the pathologic and molecular level but that are obscured by the use of the New Working Formulation. Entities such as mantle cell lymphoma, with its specific t(11;14) translocation, and ALCL are recognized as distinct entities in this system. However, in the REAL classification system (see Table 23.3), the largest entity, diffuse large B-cell disease (31% of cases), is likely a heterogeneous disease, and the division of follicular lymphoma (22% of cases) into three grades does not clarify the classification of those entities. Thus, the REAL/WHO classification may have the advantage of delineating uncommon lymphomas, while neglecting the lymphomas most commonly encountered in clinical practice. Only time will tell if this approach leads to a more scientific clinical analysis of lymphoma.
III. Staging of lymphoma
The Cotswold modification of the Ann Arbor classification is generally used for patients with NHL as well as for patients with Hodgkin's lymphoma (HL). Despite the widespread use of this model, the clinical applicability of the four-stage model to NHL is uncertain. For practical purposes, many clinicians believe that there may be only two stages of NHL: limited disease (stage I) and advanced disease (stages II, III, and IV). In contrast to HL, it has been established that radiation therapy has no role in the curative treatment of stage II NHL. In fact, in the case of intermediate-grade lymphoma, for stage I disease, radiation therapy alone has been supplanted by chemotherapy plus radiation therapy as the treatment of choice. Additionally, in contrast to HL, which arises at an extranodal site in less than 1% of cases, approximately 10% to 20% of NHLs have an extranodal presentation.
Perhaps as important as the staging of lymphoma in general is the International Prognostic Index (IPI) for use in patients with intermediate-grade lymphoma. This prognostic index (Table 23.4) predicts the probability of cure in intermediate-grade NHL on the basis of the age, stage, performance status, number of extranodal sites of disease, and lactate dehydrogenase (LDH) level. For patients of all ages, 5-year survival was 73%for low-risk patients, 51%for low intermediate-risk patients, 43% for high-/intermediate-risk patients, and 26% for high-risk patients. For patients under the age of 60, an age adjusted prognostic system was developed (see Table 23.4). For
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patients younger than 60, 5-year survival was 83% for low-risk patients, 69% for low-/intermediate-risk patients, 46% for high-/intermediate-risk patients, but only 32% for high-risk patients.
Table 23.3. Revised European American Classification of Lymphoid Neoplasms/World Health Organization classification of lymphoid neoplasms | ||
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Table 23.4. International Prognostic Index for non Hodgkin's lymphoma | ||||||||||||||||||||||||||||||||||||
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The evaluation of the patient with NHL begins with history and physical examination. When performing the physical examination, special care must be given to examining the Waldeyer's ring, epitrochlear nodes, femoral nodes, and popliteal nodes sites that are almost never involved in HL but that may be involved in a small percentage of cases of NHL. The bone marrow biopsy is generally regarded as a key diagnostic procedure in the staging of NHL, owing to the high incidence of involvement, especially in small cleaved cell lymphoma (follicular lymphoma grade I). However, in follicular lymphoma grade I, the presence or absence of marrow involvement generally does not affect therapy as asymptomatic patients are treated with watchful waiting or single-agent chemotherapy regardless of marrow involvement. Thus, the clinical necessity of marrow biopsy is uncertain. In other histologic types of NHL, the test is important as a baseline test because of prognosis and the possible use of autologous bone marrow or stem cell transplantation at the time of relapse. Nevertheless, if a patient with NHL is going to be treated with chemotherapy, omitting the baseline bone marrow evaluation clearly does not compromise care.
Baseline computed tomography (CT) scans are an essential part of the staging of patients with NHL as much to establish a baseline for evaluating the response to treatment as for determining the actual extent of disease. In HL, involved nodes are often small and may be missed by CT scanning. However, in NHL, retroperitoneal masses, if present, are often large and easily detected by CT scans. In addition, whereas mesenteric nodes are rarely involved in HL, they are involved in most cases of nodular NHL and can be detected by CT scan.
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With the advent of positron emission tomography (PET) scans, gallium scans have essentially become obsolete in the staging of lymphoma. Although PET scans may be negative in sites involved by low-grade lymphoma, they are generally positive in other histologic types of NHL. Additionally, studies have suggested that PET scans may be extremely well suited to evaluating residual masses detected by CT scanning as PET scans may reliably separate scar from active disease. In a recent study of patients with HL and NHL, 75 patients were studied with PET scans and CT scans following treatment; biopsies were obtained of areas that were suspicious for persistent or recurrent lymphoma. With a follow-up of 14 months, PET scans were far superior to CT scans in predicting relapse. If the PET scan is going to be used upon completion of therapy in a patient with a residual mass, it is rational to get a baseline PET scan to document that the tumor is PET positive. The optimal interval between posttreatment PET scans has not been determined.
Peripheral blood counts are an insensitive measure of bone marrow involvement. Most patients with small cleaved cell lymphoma (follicular lymphoma grade I) have focal marrow involvement, and almost all of these patients have normal peripheral blood counts. Abnormal blood counts may suggest marrow infiltration by lymphoma but may also occur when the spleen is infiltrated by lymphoma and extensively enlarged. As most patients with NHL will receive chemotherapy, evaluation of the blood counts is a basic part of staging of NHL. Serum LDH is an important prognostic indicator and is one of the variables considered in the IPI. Other molecular markers such as bcl-2, bcl-6, p53, ALK (anaplastic lymphoma kinase) in ALCL, and cyclin D-1 in mantle cell lymphoma as well as markers for multidrug resistance are under active investigation as prognostic indicators but are not part of standard staging systems.
IV. Radiation therapy of non Hodgkin's lymphoma
Because most patients with NHL have disseminated disease, radiation therapy plays a limited role in NHL. However, the value of radiation therapy should not be overlooked. With most histologic types of follicular lymphoma, doses of 44 Gy can achieve control of local disease. Because disease occurs outside of treatment fields, such as in the bone marrow, radiation therapy is rarely curative. However, when patients with follicular lymphoma have large masses, local radiation therapy may be the most effective means of palliation. A dose response curve for radiation therapy of large cell lymphoma is less well established, although radiation therapy may play a role in palliating patients with large cell lymphoma who have become refractory to chemotherapy.
Although 30% of patients with large cell lymphoma have stage I or II disease, the role of radiation therapy, as the sole treatment in these patients, has not been supported by clinical studies. Radiation therapy has been associated with cure rates exceeding 80% in stage I large cell lymphoma only when patients have been staged by laparotomy. Rather than subjecting these patients to a laparotomy, the usual approach is to treat clinical stage I and II intermediate-grade NHL patients with either six cycles of a chemotherapy regimen such as CHOP-Rituxan or three cycles of CHOP-Rituxan in conjunction with involved-field radiation therapy. In a randomized clinical trial, combined-modality
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therapy (chemotherapy plus radiotherapy) was associated with a projected 5-year progression-free survival of 77% as compared with a projected 5-year progression-free survival of 64% in patients receiving chemotherapy alone. However, with further follow-up, the survival curves have become almost overlapping, putting in doubt the superior value of combined-modality therapy in limited-stage patients.
V. Therapy of low-grade NHL
As follicular small cleaved cell lymphoma (follicular lymphoma grade I) represents most cases of low-grade lymphoma, the following discussion relates to the management of that disease entity. Although the terms follicular small cleaved cell lymphoma and low-grade lymphoma are used somewhat interchangeably in the medical literature, it must be recognized that other disorders are included in the category low-grade lymphoma, including small B-cell lymphoma (the nodal counterpart of chronic lymphocytic leukemia) and nodal marginal zone lymphoma. Most studies of low-grade lymphoma involve patient populations in which follicular small cleaved cell lymphomas are a majority, but not the totality, of the cases.
Follicular small cleaved cell lymphomas are associated with widespread disease at presentation. Bone marrow involvement is the most easily demonstrated site of advanced disease as it is found in 55% to 65% of cases on routine bone marrow biopsy. In patients whose bone marrow is negative by light microscopy, sensitive molecular techniques have often shown bone marrow involvement. This suggests that the true incidence of bone marrow involvement is at least 90% and may actually be close to 100%.
A. Watchful waiting
Despite the advanced stage of disease at presentation, median survival in most series of patients with low-grade NHL ranges from 5 to 12 years. Patients are often treated initially with watchful waiting, a strategy of watching the patient until the tumor burden is substantial or until symptoms develop. This is, in essence, the strategy used in chronic lymphocytic leukemia, when patients with elevated white blood cell counts and moderate adenopathy are simply observed until the disease becomes more advanced, as indicated by the development of anemia and/or thrombocytopenia. Often, patients can be followed for years without treatment. In a randomized trial, overall survival was similar for patients initially receiving aggressive combination chemotherapy as compared with those receiving no initial treatment. Although aggressive therapy led to patients spending more time in complete remission, the occurrence of myelodysplasia in the aggressively treated group prevented such therapy from achieving a therapeutic advantage.
B. Chemotherapy
Alternatively, patients may be treated with single-agent chlorambucil, single-agent fludarabine, antibody therapy (such as rituximab), combination chemotherapy, or a combination of chemotherapy and rituximab.
Chlorambucil is generally employed at a dose of 2 to 4 mg PO daily or 30 to 60 mg PO every 2 weeks.
Fludarabine is generally administered at a dose of 25mg/m2 IV daily for 5 days every 4 weeks.
Combination chemotherapy regimens have produced complete remissions in up to 80% of patients. However, such
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remissions are not durable, and the administration of combination chemotherapy may be associated with myelotoxicity, nausea, vomiting, and neurotoxicity. In general, clinicians tend to avoid anthracyclines as part of initial chemotherapy in these patients. As therapy is palliative, in view of the age of the patients, the toxicity of anthracyclines may be disproportionate to the relative benefit of using a regimen such as CVP (see Table 23.5 for a description of individual regimens). Although combination chemotherapy is associated with higher response rates, it must be recognized that aggressive therapy has not been proved to produce superior overall survival in these patients.
For patients who relapse following initial therapy, several options are available. If initial therapy has been low-dose chlorambucil, a regimen such as CHOP, CNOP, or FND (see Table 23.5) would be reasonable. These regimens can be administered with or without the inclusion of rituximab. Another alternative for patients relapsing after initial treatment, or failing to respond to initial therapy, is the use of one of the salvage regimens designed for use in intermediate-grade lymphoma, that is, a regimen such as DHAP, ESHAP, MINT, or ICE (Table 23.6). As low-grade lymphomas are associated with prolonged survival despite multiple recurrences, there is no single clinical algorithm to be applied to all patients. Palliative treatments should be individualized on the basis of extent of disease, clinical pace of disease, and age of the patient.
C. Antibody therapy
Rituximab is an antibody to CD20, an antigen generally found on B lymphocytes. A dose of 375 mg/m2/week x 4 to 8 weeks has become a popular choice for the therapy of low-grade lymphoma as the drug is effective in approximately half of the patients treated and has
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minimal toxicity. Although maintenance rituximab therapy can increase disease-free survival, there is no proof that such maintenance therapy produces better long-term results than can be obtained by simply waiting to use rituximab until the patient experiences a relapse.
Table 23.5. Initial combination chemotherapy regimens for non Hodgkin's lymphoma | |||||||||||||||||
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Table 23.6. Combination chemotherapy regimens useful as salvage regimens in non Hodgkin's lymphoma | ||
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Iodine-131 labeled tositumomab (Bexxar) andyttrium-90-labeled ibritumomab tiuxetan (Zevalin) have entered the clinical arena in the last 5 years. Both these radioimmunoconjugates employ antibodies to CD20. However, the presence of radioactivitymeans that the drugs can be effective not only in cells that are CD20 positive but in nearby cells that lack CD20. Because of potential marrow toxicity, such therapy has been employed only when marrow involvement by tumor is less than 25%. Using Bexxar, response rates of 47% to 68%, with complete responses of 20% to 38% have been reported in patients relapsing after chemotherapy or refractory to rituximab; 30% of patients experienced long remissions (1 10 years). When used
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as initial therapy, Bexxar produced an overall response rate of 95% with 75% complete responses. By life-table estimate, 77% of patients with a complete remission are disease free at 5 years. However, considering that low-grade lymphoma is considered an incurable disease in which aggressive combination chemotherapy has not been shown to improve overall survival, the role of radioimmunoconjugates as initial therapy of low-grade lymphoma has yet to be established.
D. High-dose chemotherapy with stem cell transplantation
Another approach to low-grade NHL involves the use of very high dose chemotherapy, with or without total-body radiation therapy, in conjunction with autologous bone marrow or stem cell transplantation. This approach is limited by the fact that the bone marrow and presumably the peripheral blood are frequently involved in low-grade lymphoma. Even when genetic markers such as bcl-2 are used to confirm successful purging of tumor cells, lymphoma may not be completely removed from the reinfused stem cell product. Autologous transplantation has produced long-term disease-free survival in patients whose disease remains sensitive to chemotherapy at the time of transplantation. However, as with other therapies for low-grade lymphoma, there is no evidence that these results represent cures. Additionally, the optimal timing of such therapy (after one, two, or three chemotherapy regimens), the optimal preparative regimen (with or without total-body irradiation), and the value of purging are issues that have not been resolved. The best results have been obtained in patients with sensitive disease who have received minimal therapy. However, as lead-time and selection bias confound these observations, autologous transplantation has not been established as part of standard therapy for low-grade lymphoma. Although allogeneic transplantation eliminates the risk of reinfusing tumor cells, it is associated with intrinsic risks such as graft-versus-host disease. Clinical results using allogeneic transplantation in this disorder have been highly variable, and the role of allogeneic transplantation in low-grade lymphoma (with either full intensity or reduced intensity preparative regimens) requires further evaluation. Nevertheless, it appears that allogeneic transplantation is the one approach to low-grade lymphoma that has a potential to achieve cure.
VI. Therapy of intermediate-grade NHL
The most common intermediate-grade lymphoma is large B-cell lymphoma. Also included in this category are diffuse mixed cell lymphomas, diffuse small cleaved cell lymphoma, mantle cell lymphoma, immunoblastic lymphoma of B-cell origin, T-cell rich B-cell lymphoma, ALCL (generally a T-cell disease), and peripheral T-cell lymphoma. Although recommendations can be made for intermediate-grade lymphomas as if they were a single entity, one must recognize that some of the entities behave in a distinct manner. Specifically, although it is said that intermediate-grade lymphomas have a response rate between 70% and 80% and a cure rate between 40% and 50%, patients with peripheral T-cell lymphoma have a slightly lower response rate and are rarely cured (with the exception of ALK-positive ALCL and the small minority of peripheral T-cell lymphoma patients with low IPI). Additionally, patients with mantle cell lymphoma have a high
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response rate but almost always have a relapse and die within a few years of diagnosis.
The clinical progress in treating intermediate-grade lymphoma not only represents one of the major success stories of modern oncology, but also represents a major caution regarding the problems associated with overinterpreting uncontrolled clinical observations. In the 1960s, patients with these lymphomas were routinely treated with single-agent therapy, usually chlorambucil. The median survival was 6 months; the 2-year survival rate was only 5% to 10%; cures were rare. In the early 1970s, parallel to the observation that MOPP (nitrogen mustard, Oncovin, procarbazine, and prednisone) could cure HL, workers at the National Cancer Institute reported that COPP (a regimen that substituted cyclophosphamide for nitrogen mustard) could produce complete remissions in 41% of patients with histiocytic lymphoma and long-term disease-free survival in 35%. This result was confirmed and slightly improved with investigators who used the CHOP regimen, a regimen that substituted doxorubicin (hydroxydaunorubicin, Adriamycin) for procarbazine.
The studies with COPP and CHOP established the basic principles regarding the chemotherapy of intermediate-grade lymphoma. First, the studies established that some patients within this group of lymphomas are curable with combination chemotherapy, although, with further data collection, we have come to realize that some subsets of patients, such as those with peripheral T-cell lymphoma, may be less curable than other subsets of intermediate-grade lymphoma. Second, the studies demonstrated that depending on how a complete remission is defined, from 60% to 80% of complete remissions represent cures. Many patients with lymphoma have residual masses upon completion of therapy. These residual masses may represent scar or may represent persistent disease. If the term complete remission is used only for patients who have no progression of residual masses for 3 months following completion of therapy, up to 80% of complete remissions may represent cures. Third, although complete remissions do not necessarily represent cures, complete remissions that persist for 2 years represent cures almost 95% of the time; that is, relapses after 2 years of remission are uncommon, although they do occur.
In the decade following the publication of the results of the CHOP regimen, a number of more intense combination chemotherapy regimens were studied in uncontrolled, single-institution, phase II studies. These regimens, shown in Table 23.7, suggested that long-term complete remission might be achieved in up to 75% of patients as compared with the 40% to 45% range observed with CHOP. However, even before randomized trials were conducted, there were several reasons to suspect that the improvement might be less than was suggested by uncontrolled phase II studies. First, as regimens became more dose intense, older patients, who generally do worse than younger patients, were selectively excluded on the grounds that they would be unable to tolerate the more intense therapy. The median age in the early CHOP study was 58 years; the median age in the MACOP-B study was 44 years. Second, with the demonstration that stage II disease was not routinely curable with radiation therapy, stage II patients became eligible for new
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chemotherapy regimens. By contrast, the early CHOP study contained only stage III and IV patients. As patients with lesser stages of disease would be expected to do better, including them in studies of newer regimens would favorably bias the results achieved with those regimens.
Table 23.7. Combination chemotherapy regimens used as primary treatment of intermediate-grade lymphoma | ||
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The key study regarding the role of chemotherapy in intermediate-grade lymphoma was the Intergroup Study, which randomly assigned patients with intermediate-grade lymphoma to CHOP, m-BACOD, MACOP-B, and ProMACE-CYtaBOM. Contrary to the expectations of clinicians who felt that these regimens were clearly better than CHOP, there were no significant differences among the regimens with respect to survival or disease-free survival. For all regimens, actuarial survival was between 40% and 45%.
A. Initial chemotherapy
Thus, until recently, CHOP remained the standard-of-care chemotherapy regimen for patients with intermediate-grade lymphoma. Randomized clinical trials have found higher remission rates to be associated with addition of rituximab to CHOP chemotherapy and CHOP-rituximab has become a standard approach for treating these patients. A population study has been reported from the Canadian province of British Columbia looking at all patients treated between 1999 and 2002; approximately half the number of patients were treated before rituximab became part of standard therapy and the other half were treated with rituximab as part of the initial combination regimen. Two-year progression-free survival increased significantly from 51% to 69% with the addition of rituximab; 2-year overall survival increased significantly from 52% to 78%.
B. Secondary chemotherapy
The fact that only 40% to 45% of patients with intermediate-grade lymphoma are cured with standard combination chemotherapy (at least before rituximab) means that most patients eventually become candidates for second-line treatment. Salvage chemotherapy regimens (see Table 23.6) can produce responses in 50% to 60% of patients, with 20% to 30% of patients achieving complete remission. However, cures with salvage chemotherapy are uncommon and occur in approximately 5% of patients.
C. High-dose chemotherapy with stem cell transplantation
As salvage chemotherapy rarely produces a cure, the standard approach to patients with relapsed or refractory intermediate-grade lymphoma has been to initiate salvage chemotherapy and to proceed to autologous stem cell transplantation in patients who respond to salvage therapy. The optimal preparative regimen for autologous transplantation has not been determined. Although some studies have suggested that results are equivalent whether total-body irradiation is included in the preparative regimen or not, even this point has not been firmly established.
Salvage chemotherapy and autologous transplantation. In a randomized clinical trial, patients with intermediate-grade lymphoma who were responding to salvage chemotherapy were randomized to continue on salvage chemotherapy or to switch over to high-dose therapy in conjunction with stem cell transplantation. Five-year event-free survival was significantly
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higher in the group that switched to autologous transplantation (46%) as compared with 5-year event-free survival in the patients who continued on salvage chemotherapy (12%) (p = 0.001). Survival was also significantly better in the patients who switched to autologous transplantation as compared to survival in patients who continued to receive conventional salvage chemotherapy (53% vs. 32%, respectively; p < 0.05).Autologous therapy as consolidation chemotherapy. With autologous transplantation being shown to be effective as salvage treatment in intermediate-grade NHL, a logical issue to pursue is whether such therapy might be effective for consolidation of complete remission. However, results using high-dose therapy as part of initial therapy have not consistently shown a clinical benefit and the role of this approach needs to be clarified by further clinical trials. Although this approach has the potential for increasing cures, it obviously subjects patients who can be cured by standard chemotherapy to unnecessary risks.
D. Advanced age and comorbid disease
The incidence of lymphoma increases with age. Thus, a common clinical problem involves the selection of appropriate therapy for a patient with intermediate-grade NHL over the age of 70 or older than 60 with significant comorbid disease. Clearly, older patients should not be denied a chance of cure on the basis of age alone, and elderly patients with good performance status and well-controlled comorbid disease are good candidates for curative therapy. Despite considerable efforts to design less intensive, better-tolerated therapies for older patients, there is no firm evidence that any of these regimens is equivalent to CHOP. The best strategy, therefore, is to attempt to administer CHOP plus rituxan therapy and use growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) starting with cycle 1 to limit marrow toxicity.
VII. Therapy of high-grade NHL
The most commonly seen high-grade lymphomas are Burkitt's and Burkitt's-like lymphoma, lymphoblastic lymphoma, and peripheral T-cell lymphomas (excluding anaplastic large cell lymphoma [ALCL], which has a prognosis similar to other intermediate-grade lymphomas). Because these diseases have different clinical manifestations, it is most reasonable to consider them separately.
A. Burkitt's lymphoma and Burkitt's-like lymphoma
These diseases have similarmorphologic features and a similar prognosis. They are both B-cell lymphomas of small noncleaved cells, and both have been associated with a t(8;14) translocation. In the United States, Burkitt's lymphoma tends to occur in younger patients and to be associated with a higher incidence of gastrointestinal disease and a lower incidence of bone marrow involvement. Both diseases are relatively resistant to standard chemotherapy regimens such as CHOP as that therapy is generally associated with a median survival between 6 and 10 months. More intense therapy such as the highintensity brief-duration regimen, the hyper-CVAD regimen, and the CODOX-M/IVAC regimen presented in Table 23.8 have been associated with long-term disease-free survival in
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almost 50% of patients, but these results are dependent on stage. Patients with disease involving the CNS or bone marrow or with marked elevation of LDH levels have an especially poor prognosis. Salvage therapy with or without stem cell transplantation is less effective in high-grade lymphoma as compared with intermediate-grade lymphoma, especially when high-dose therapy is used as initial treatment. The role of stem cell transplantation in routine consolidation following initial high-dose therapy has not been established by clinical trials.
Table 23.8. Therapy for high-grade lymphoma | ||
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B. Lymphoblastic lymphoma
Lymphoblastic lymphoma is usually a T-cell malignancy that can be regarded as a variant of T-cell acute lymphoblastic leukemia (ALL). This disorder commonly presents with a mediastinal mass and bone marrow involvement. ALL-type therapy is most commonly employed to treat lymphoblastic lymphoma (see Chapter 19). However, excellent results have been reported with a regimen devised at Stanford University, which includes a CHOP-like induction, CNS prophylaxis, and consolidation that includes methotrexate and 6-mercaptopurine. In the initial report of this regimen, patients with marrow involvement, CNS involvement, and elevated LDH levels had a 5-year survival of only 19%, whereas patients without these features had a 5-year survival of 94%. Unfortunately, further studies of other regimens have not established that marrow involvement, CNS involvement, and LDH are the sole reliable prognostic factors in lymphoblastic lymphoma. As with Burkitt's lymphoma, high-dose therapy followed by stem cell transplantation as consolidation is a rational approach but one which has not been proven by randomized clinical trials.
C. Peripheral T-cell lymphomas
For many years, controversy has existed over whether the T-cell lymphomas included in intermediate-grade lymphoma have a prognosis that is the same as or worse than that of the B-cell lymphomas that make up most intermediate-grade lymphomas. Over the last several years, clinical pathologic studies have shed some light on this important issue. First, the entity of T-cell rich B-cell lymphomas has been identified. These lymphomas are
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B-cell lymphomas and have a prognosis similar to that of other B-cell lymphomas. However, as most cells in the lymphoma are nonmalignant T cells, these lymphomas may have been included in studies of T-cell lymphoma, falsely improving the prognosis. Second, the category of T-cell lymphomas includes ALCL, a group of lymphomas that have a prognosis similar to that of B-cell lymphomas. Once these lymphomas are excluded, the remaining T-cell lymphomas have a prognosis that is worse than that of B-cell intermediate-grade lymphomas, and as a result, the category of peripheral T-cell lymphomas may be considered as high-grade lymphomas, although this is not accepted by all investigators and clinicians.
Peripheral T-cell lymphomas are a heterogeneous group of lymphomas that constitute approximately 5% to 7% of adult NHLs (see Table 23.3). CHOP therapy is generally associated with long-term survival in 0% to 20% of patients with these disorders. With the exception of infrequent cases of peripheral T-cell lymphoma with low IPI, which do relatively well with CHOP, no optimal therapy for these patients has been defined, and the most rational course seems to be the use of one of the regimens employed for Burkitt's or Burkitt's-like lymphoma (see Table 23.8), or to employ a strategy that includes early transplantation. Active single agents that are under investigation for future inclusion in combination chemotherapy regimens for T-cell lymphomas include nucleoside analogues (gemcitabine, pentostatin), histone deacetylators (depsipeptide), and monoclonal antibodies (denileukin diftitox and alemtuzumab).
VIII. Therapy of other lymphomas
The classification of NHL into low grade, intermediate grade, and high grade is an over of this complex group of disorders. While a consideration of every entity is beyond the scope of this chapter, a number of subtypes of lymphoma have specific features that are worth noting.
A.
Mantle cell lymphomas are composed of small B lymphocytes. The cell of origin is the mantle zone cell, which surrounds the lymphoid follicle and not the follicular center cell of follicular lymphoma. These lymphomas have a diffuse pattern, are generally CD5 positive and CD23 negative, are positive for cyclin D-1, and are associated with a t(11;14) chromosomal translocation. These lymphomas used to be included in low-grade lymphoma and were often regarded as diffuse forms of small cleaved cell follicular lymphoma. However, in contrast to small cleaved cell lymphoma, median survival in this type of lymphoma is between 3 and 4 years. Although responses are seen with CHOP, relapses are the rule rather than the exception, and cure is rarely, if ever, seen. The high incidence of marrow involvement limits the use of autologous stem cell transplantation, and early encouraging results using this approach as consolidation or salvage therapy have not been confirmed. This has led some investigators to advocate aggressive chemotherapy followed by allogeneic transplantation as consolidation therapy in this group of lymphomas. However, further data will be necessary to establish the role of that approach in mantle cell lymphoma.
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B.
Maltomas are mucosa-associated lymphoid tumors, which are low-grade B-cell lymphomas that can occur at a number of sites including conjunctiva, thyroid, salivary gland, and gastrointestinal tract. Maltomas tend to be localized and are associated with a better survival than other low-grade lymphomas. Maltomas of the stomach have been associated with infection by Helicobacter pylori, and cures have been achieved with eradication of H. pylori by the use of antibiotics. This suggests that certain lymphomas may require continued antigenic stimulation in order to persist.
C.
Anaplastic large cell lymphomas (ALCLs) are usually T-cell lymphomas, though null cell forms of ALCL exist. The lymphomas can be associated with a t(2;5) translocation and are generally CD30 positive. However, CD30 is not pathognomonic for ALCL as it may also be seen in HL, other B-cell and T-cell lymphomas, embryonal carcinoma, and seminoma. ALK-positive ALCL is commonly seen in young patients, usually is disseminated with nodal and extranodal sites (skin, bone), and has a prognosis similar to large B-cell lymphoma. ALK-negative ALCL involving lymph nodes is more resistant to chemotherapy. Additionally, there is a primary cutaneous form of ALK-negative ALCL, which is associated with a more indolent prognosis than node-based ALCL. The fact that ALCL limited to the skin is generally negative for t(2;5), i.e., ALK negative, suggests that these different forms of ALCL may have different etiologies.
IX. Special considerations
A. Central nervous system (CNS) prophylaxis
Involvement of the CNS by NHL is almost exclusively limited to small noncleaved cell lymphoma (Burkitt's and Burkitt's-like) and lymphoblastic lymphoma. As marrow involvement has been present in most cases with CNS involvement, a rational policy is to give intrathecal methotrexate and cranial irradiation to patients with these high-grade lymphomas and bone marrow involvement. Whether patients with intermediate-grade lymphoma and bone marrow involvement should receive CNS prophylaxis is not known. However, as testicular and nasopharyngeal involvement with intermediate-grade lymphoma is associated with an increased risk of CNS disease, such patients are rational candidates for CNS prophylaxis. As low-grade lymphomas do not involve the CNS unless transformation to intermediate-grade lymphoma has occurred, CNS prophylaxis is not needed for low-grade lymphoma despite the high incidence of bone marrow disease in these patients.
B. Lymphomas in patients with human immunodeficiency virus (HIV) infection
(Also see Chapter 26.) Among patients with HIV infection, 3% to 6% develop lymphoma. Lymphoma is an acquired immune deficiency syndrome (AIDS) defining illness, and it is estimated that approximately one-fourth of new cases of NHL occur in patients with HIV. The lymphomas are generally intermediate-grade lymphoma (diffuse large B-cell lymphoma) and high-grade lymphoma (small noncleaved cell lymphoma). Over the last 15 years, there has been a histopathologic shift, and large B-cell lymphoma is now the most common lymphoma seen in these patients. Additionally, with the use of highly active
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antiretroviral therapy (HAART), the incidence of primary CNS lymphoma has decreased.
With the introduction of HAART, the incidence of AIDS related lymphoma (ARL) decreased and the prognosis for patients with ARL has improved. Before HAART, median survival of patients with HIV who developed ARL was 5months to 8 months for systemic disease and 2 months for patients with CNS lymphoma. For patients with systemic ARL in the era of HAART, median survival approaches 20 months. In view of the poor prognosis of these patients and their underlying immunosuppression, chemotherapy regimens characterized by dose reductions (such as half-dose or three-fourths dose CHOP) have been investigated in patients with ARL. These regimens do not improve clinical results and standard dose regimens for lymphoma are recommended in patients with ARL. One caveat to this recommendation is that rituximab appears to augment the response to CHOP in patients without HIV infection, whereas in patients with HIV infection, the immunosuppression caused by rituximab appears to balance out an antitumor effect. As a result, the role of rituximab in therapy of ARL is not established and requires further investigation.
Patients with NHL and HIV infection should be evaluated for the presence of CNS disease including the presence of meningeal disease. If symptomatic CNS disease is present, therapy is indicated with an aim of improving quality, if not quantity, of life.
C. Extranodal lymphomas
NHLs arise at extranodal sites in approximately 10% to 20% of cases. In the past, these patients were often treated with radiation therapy alone. However, with extensive evidence that chemotherapy with or without radiation therapy can produce excellent results in patients with stage I lymphomas, these patients are rarely treated with radiation therapy alone. Certain extranodal sites present special considerations for which specific comments are needed.
Stomach. The most common site for extranodal lymphoma is the stomach. Approximately one half of all gastric lymphomas are maltomas, and the next most common histology is large B-cell lymphoma (intermediate-grade lymphoma). Approximately two-thirds of gastric maltomas respond to antibiotic therapy for H. pylori. For gastric lymphomas not related to H. pylori, therapy is dependent upon histology and stage and may include chemotherapy, rituximab, and/or radiation therapy; chemotherapy is the treatment modality of choice. In the past, surgery was part of the standard therapy for gastric lymphomas owing to the risk of perforation during therapy. However, with most tumors diagnosed by endoscopic biopsy, surgery is rarely a part of the management of this disease.
Primary central nervous system (CNS) lymphoma is commonly seen in patients with HIV but is also observed without HIV infection as a predisposition. All patients presenting with primary CNS lymphoma should be evaluated for possible HIV infection. In patients without HIV infection, the most common histologic types of lymphoma are large B-cell lymphoma and immunoblastic lymphoma.
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Treatment with radiation therapy alone is generally associated with a median survival of less than 1 year and radiotherapy is no longer the treatment modality of choice for patients with primary CNS lymphoma. Recent trials employing chemotherapy, specifically high-dose methotrexate, as an alternative to radiation have produced superior results, with a median survival between 3 and 5 years. Although combined-modality therapy produces the best results, in patients over the age of 60, combined-modality therapy (chemotherapy plus radiotherapy) has been associated with clinical deterioration due to brain necrosis. Accordingly, an alternative approach is to give chemotherapy alone and reserve radiotherapy until the time of disease progression.3. Testicular lymphomas represent the most common testicular tumor seen in elderly men, with large B-cell lymphoma being the most common histologic type. Therapy consists of orchiectomy, chemotherapy, and irradiation of the contralateral testis. Additionally, as testicular lymphoma is associated with CNS disease, prophylactic treatment of the CNS is indicated.
Nasopharyngeal lymphomas are more commonly seen in Asia than in the United States. In the States, the most common type of NHL is large B-cell lymphoma. In contrast, the most common histologic type of NHL in Asia is angiocentric lymphoma of T-cell or natural killer (NK) cell origin. Formerly among the disorders included in the category lethal midline granuloma, this highly lethal lymphoma is often treated with radiation therapy and chemotherapy as well as with CNS prophylaxis. However, despite aggressive therapy, survival of greater than 1 year is uncommon.
Cutaneous lymphomas include a wide variety of diseases of both B-cell and T-cell origin. The most common cutaneous lymphoma is cutaneous or cerebriform T-cell lymphoma (CTCL), also known as mycosis fungoides. When there is generalized erythroderma and involvement of the peripheral blood, the syndrome is known as S zary syndrome. Prognosis in CTCL depends on stage of disease, and special staging systems for CTCL exist (Table 23.9). Clinical Stage IA disease is so indolent that it does not impact on normal life expectancy, while prognosis worsens with more advanced stage of disease. The disease may exist as plaques in the skin for many years before progressing to involve skin tumors, adenopathy, or visceral disease. Often, this clinical progression occurs in association with a pathologic transformation to a large cell lymphoma. If disease is limited to the skin, topical therapy such as topical nitrogen mustard, electron beam radiotherapy, or psoralen in conjunction with ultraviolet radiation may be employed. Combination chemotherapy as employed for intermediategrade lymphoma may be used for tumor stage of disease or for disease involving nodes or viscera. Unfortunately, such therapy may lead to simultaneous necrosis of skin tumors as well as the development of neutropenia, leading to fatal sepsis. Other approaches to this disease include the use of denileukin diftitox, an antibody to CD25, and bexarotene, a
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novel retinoid X receptor (RXR) selective retinoid, or rexinoid. Use of the latter agent is commonly associated with a syndrome of central hypothyroidism as well as abnormal lipid metabolism and patients must be monitored for these complications.Table 23.9. Staging system for cutaneous T-cell lymphoma
Stage I: limited or generalized plaques without adenopathy or histologic involvement of lymph nodes
Stage II: limited or generalized plaques with adenopathy, or cutaneous tumors without adenopathy; without histologic involvement of lymph nodes or viscera
Stage III: generalized erythroderma, with or without adenopathy; without histologic involvement of lymph nodes or viscera
Stage IV: histologic involvement of lymph nodes or viscera with any skin lesions; with or without adenopathy
X. Posttransplant lymphomas
Following organ transplantation and the associated immunosuppression, the most common tumors are skin cancer and NHL. Extranodal sites of disease including the CNS and gastrointestinal tract are commonly observed, and the histologic appearance is that of an intermediateor high-grade lymphoma. Many of these tumors are associated with Epstein-Barr virus (EBV), and if disease is limited in extent, one can employ therapy designed to increase the host response to EBV, such as withdrawing or decreasing immunosuppression, administering interferon, or giving lymphocytes from individuals who have had EBV infection. Such therapy is most effective in limited disease and in patients in whom the lymphocytes are polyclonal. Surgery or radiotherapy can be effective in localized disease. For more advanced disease and for disease in which the lymphocytes are monoclonal, chemotherapy is necessary, although rituximab has also been shown to be effective in this setting. Unfortunately, response rates are lower for transplant-associated lymphomas than for de novo lymphomas, and long-term survival is seen in less than 20% of patients.
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