© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 101-105,
1998
© 1998 Oxford University Press
Clinical Management of Human Immunodeficiency Virus-Associated Non-Hodgkin's Lymphoma
* Affiliations of author: Department of Medicine, San Francisco General Hospital, and Department of Medicine, University of California.
Correspondence to: Lawrence D. Kaplan, M.D., University of California, San Francisco, San Francisco General Hospital/AIDS Program, Oncology Division, Ward 84, 995 Potrero Ave., San Francisco, CA 941110.
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Introduction |
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 Top Introduction Primary CNS LymphomasSystemic LymphomasPrimary Effusion LymphomasReferences |
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The human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphomas are best divided into three categories: 1) primary central nervous system (CNS) lymphomas, 2) systemic lymphomas, and 3) primary effusion lymphomas. As described elsewhere in this monograph, these lymphomas differ in many of their molecular characteristics and presumed mechanisms of pathogenesis. These factors may be relevant in terms of development of future therapeutic approaches that take advantage of some of these unique molecular characteristics. However, of more immediate relevance is the fact that these lymphomas occur in different patient populations and are associated with different clinical outcomes. Systemic lymphomas are observed across a broad range of levels of immune function, with a median CD4+ cell count of approximately 100/mm3 (1,2). The median survival among patients with systemic lymphoma is approximately 5-8 months, and 10%-20% survive disease free for longer than 2 years (2-4). In contrast, primary CNS lymphoma occurs in the most severely immunocompromised group, 75% of whom have CD4 counts less than 50/mm3 (1). CNS lymphoma in the setting of this profound immunosuppression is associated with a median survival of only 3 months. The diagnosis and management of primary CNS lymphoma therefore present unique clinical management problems, and it is here that I will begin the discussion of clinical management.
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Primary CNS Lymphomas |
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Diagnosis
The difficulty in diagnosing primary CNS lymphoma is related to the fact that lymphoma in the brain is difficult to distinguish from intercerebral toxoplasmosis, a common opportunistic infection in patients with HIV disease. Although the radiographic appearance on computed tomography or magnetic resonance imaging scan may provide clues as to the diagnosis, these studies are rarely diagnostic in acquired immunodeficiency syndrome (AIDS) patients with CNS lesions. Since magnetic resonance scanning in individuals with toxoplasmosis reveals a solitary lesion in only 21% of cases (5), the finding of a solitary lesion is more suggestive of a diagnosis of lymphoma. However, magnetic resonance scanning in individuals with CNS lymphoma demonstrates multiple lesions in 50% of cases (5), and this finding is less likely to be helpful. The diagnosis of lymphoma may also be suggested by a periventricular location or a lesion that crosses the midline. However, these "classic" radiographic findings occur infrequently in HIV-associated CNS lymphoma.
Recently, thallium-201 single-photon emission computed tomography (SPECT) scanning has been used to distinguish between these two entities. In one study (6), all 24 individuals with toxoplasmosis had negative scans, whereas all 12 with CNS lymphoma had positive scans. In another study (7), nine patients with CNS lymphoma were all positive on thallium-201 SPECT scanning. Of concern, however, was the fact that three of 10 patients with toxoplasmosis also had positive scans. Although these series of patients are small and data from larger numbers of patients are needed, these observations do suggest a potential utility for this nuclear medicine study in the diagnosis of CNS lymphoma.
Of even greater interest are observations made with the use of polymerase chain reaction (PCR) for detecting Epstein-Barr virus (EBV) DNA sequences in cerebrospinal fluid. De Luca et al. (8) showed that seven of eight individuals with documented CNS lymphoma had positive PCR for EBV in cerebrospinal fluid. All 11 patients with brain lesions and no lymphoma were negative, and 21 individuals with AIDS but no CNS lesions were also negative. In a second series (9), all 17 individuals with CNS lymphoma were positive for EBV by PCR and 67 of 68 individuals with HIV and no lymphoma were negative. Data from a much larger series of patients have been reported elsewhere in this monograph and confirm these results. These data strongly suggest that this technique is a useful means of noninvasive diagnosis of primary CNS lymphoma in patients with HIV disease. This may be particularly powerful when used in conjunction with thallium-201 SPECT scanning and the results of Toxoplasma serologic studies.
At the present time, the standard of care for diagnosis of CNS lymphoma is brain biopsy. Since treatment outcome strongly depends on early diagnosis and institution of therapy, it is strongly recommended that individuals who are Toxoplasma seronegative, and therefore unlikely to have a diagnosis of toxoplasmosis, be referred for early brain biopsy if cerebrospinal fluid cytology is negative.
Once the diagnosis of CNS lymphoma has been established, all patients should undergo a slit lamp examination before initiation of therapy to rule out the presence of ocular lymphoma.
Treatment
In most series reported in the literature, patients have been treated with a course of whole-brain radiotherapy. In three series reporting the occurrence of clinical improvement with therapy (10-12), 62%-79% had improvement in their neurologic symptoms. Overall response rates of 52%-70% have been reported, with complete response rates of 40%-50% (1,10-14). Median survival has been 2-4.8 months, with most patients dying as a result of nonlymphoma complications from their HIV disease (1,10-14). However, the proportion of treated patients dying as a result of lymphoma progression ranged from 13% to 55%, suggesting that improvement in treatment of the lymphoma itself is clearly needed (1,10-14).
Two small pilot studies (15,16) have investigated the use of combined modality therapy with chemotherapy and radiotherapy being administered. In one series (15), 10 individuals treated in this fashion had a complete response rate of 88%, and none of these patients died as a result of their CNS lymphoma. However, the reported median survival of 3.5 months was no better than that reported in studies using whole-brain radiotherapy alone. It is clear then that improvement in the management of CNS lymphoma will require not only improvement in management of the lymphoma, but also better treatment for the underlying HIV disease. The current use of multiagent antiretroviral therapies, which have been shown to be highly effective, may prolong survival from the underlying immunodeficiency disease long enough so that better management of the lymphoma may soon become a more critical factor.
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Systemic Lymphomas |
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Although primary CNS involvement is associated with the worst prognosis of all presentations of AIDS-associated lymphoma, a number of factors have been associated with clinical outcome in systemic disease. Early retrospective studies (1,3) demonstrated factors associated with the underlying immunodeficiency disorder such as CD4 count, presence or absence of a prior AIDS-defining diagnosis, and performance status to be the most important predictors of outcome. Presence or absence of extranodal disease, particularly bone marrow involvement, was the only tumor-related factor associated with prognosis.
Data from more recent studies, such as the prospective data on 192 patients enrolled in the ACTG 142 study (17), a study of low-dose versus standard-dose chemotherapy, more closely resemble those factors identified in the International Prognostic Index (18) for non-immunodeficiency-associated aggressive non-Hodgkin's lymphomas. In this study (17), factors associated with poor prognosis included age older than 35 years, CD4 count of less than 100/mm3, history of intravenous drug use, and, for the first time, tumor bulk as measured by stage of disease. Advanced stage III or IV disease was associated with a poor outcome. Similarly, a recent retrospective review of 96 patients treated for aggressive HIV-associated lymphomas (19) indicated that bulky tumor, as measured by elevation of serum lactate dehydrogenase levels, was again associated with a poor clinical outcome.
Treatment
A number of therapeutic approaches have been utilized in the management of AIDS-associated lymphoma. Initially, dose-intensive regimens were used in an effort to improve outcome. These regimens included high-dose methotrexate and high-dose cytarabine (20) or regimens containing high-dose cyclophosphamide (3). In general, these treatments were associated with a high risk of death due to opportunistic infection and survival times of 5-6 months, which were not better than those seen with more standard-dose therapy. Patients treated in these studies had median CD4 counts in the mid-100 range.
A large clinical trial of the aggressive LNH-84 regimen (21) targeted individuals with higher CD4 counts (median count, 227/mm3) and was associated with a high complete remission rate, a median survival time of 9 months, and a 2-year disease-free survival of 42%. However, it cannot be demonstrated in this trial whether the improved clinical outcome is due to the aggressive chemotherapy regimen or to the fact that patients with higher CD4 counts are more likely to survive longer.
Because of the disappointing results initially observed with higher dose regimens, studies of dose-reduced chemotherapy regimens were subsequently conducted. The AIDS Clinical Trials Group (22) utilized an mBACOD regimen (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) in which the dosages of cyclophosphamide and doxorubicin were reduced by approximately 50% in 35 patients who had aggressive AIDS-associated lymphomas. The complete response rate of 46% and the median survival of 5.6 months were not significantly different from those observed in previous trials of standard-dose chemotherapy, but they were achieved at the expense of significantly less hematologic toxicity. In this study (22), the median CD4 count was 150/mm3. Subsequently, an Italian study of a similar low-dose regimen in 37 patients with lymphoma and a median CD4 count of 25/mm3 (23) achieved only a 14% complete remission rate and a median survival of only 3.5 months. Taken together, these data imply a more important effect of immune function on survival than choice of therapeutic regimen.
In view of these observations, the AIDS Clinical Trials Group
designed a clinical trial to compare directly the importance of
chemotherapy dose intensity for clinical outcome in
AIDS-associated lymphoma. In this trial, patients were randomly
assigned to receive either standard-dose mBACOD chemotherapy with
granulocyte-macrophage colony-stimulating factor (GM-CSF) support
or reduced-dose mBACOD with GM-CSF administered only as required
for neutropenia (2). The results (Table 1)
demonstrated no significant difference in
complete response rate, response duration, time to progression,
and overall or disease-free survival. And the difference for
response duration very nearly reached statistical significance in
favor of the low-dose regimen. When subjects were divided into
those with greater than or equal to or less than 100 CD4 cells/mm3, those with better immune function did survive
longer than those with poor immune function. However, within each
of these two CD4 cohorts, no significant differences were
observed with respect to treatment assignment, indicating that
these results may apply to the majority of individuals with
HIV-associated lymphoma and that the most appropriate choice of
chemotherapy regimens for most individuals with AIDS-associated
lymphoma should be a dose-reduced treatment regimen. However, an
insufficient number of individuals with CD4 counts greater than
or equal to 200/mm3 were enrolled in this clinical
trial to determine whether some of those patients may have
benefited from the use of a standard-dose regimen. For this
reason, it is recommended that some patients with relatively
intact immune function (CD4
200/mm3) be considered
for standard-dose therapy.
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Recently, the use of continuous infusion of cyclophosphamide, doxorubicin, and etoposide has been studied for the management of AIDS-associated lymphoma (24). This treatment approach, piloted by Sparano et al., used a 96-hour continuous infusion of these three agents with granulocyte colony-stimulating factor. Patients assigned to group A received adjunctive therapy with didanosine in cycles 1, 2, 5, and 6; those assigned to group B received this antiretroviral agent in cycles 3, 4, 5, and 6. The complete response rate observed in this study of 56% was not significantly different from that observed in previous trials; however, the median survival time of 18.4 months reported in this study appeared to be significantly longer than that previously reported. It remains to be seen whether this longer survival time is due to improvement in antiviral therapy, more recent improvement in the overall management of HIV disease, or a regimen that truly produces more durable responses. A large phase II study of this chemotherapy regimen is currently under way by the Eastern Cooperative Oncology Group.
For those individuals who have refractory lymphoma, treatment outcome is particularly poor. Little data have been reported in the literature. Tirelli et al. (25) recently reported on the use of a combination of etoposide, mitoxantrone, and prednimustine in 21 patients with either primary resistance or relapse after having complete responses. In this study group, the complete response rate was 26%, and the median survival time was only 2 months; the majority of patients ultimately died of refractory lymphoma.
Data from San Francisco General Hospital (Kaplan LD: unpublished data), in which 14 patients were treated with escalating doses of infusional ifosfamide and etoposide, demonstrated a relatively similar outcome. The overall complete response rate in this series of patients was 43% with a relatively short median response duration of only 79 days.
Levine et al. (26) recently reported on the treatment of 35 patients with refractory AIDS-associated lymphoma with the single agent mitoguazone; although this agent appeared to be extremely well tolerated and non-myelosuppressive, the overall response rate of 23% suggests that mitoguazone may be better suited for use in combination regimens than as a single agent.
Meningeal Lymphomas
The reported incidence of lymphomatous meningitis at the time of diagnosis of systemic lymphoma ranges from 3% to 25%. Most of these cases are reported from relatively small retrospective series of patients. In the largest prospective series reported, the ACTG 142 study of 192 patients, the incidence of meningeal lymphoma at diagnosis was only 3%, suggesting that the frequency of this complication may be lower than initially suspected (2). The frequency of meningeal relapse is a much more difficult number to determine because most reported series in the literature routinely treat their patients prophylactically with the use of intrathecal chemotherapy. However, in one small, early study, Gill et al. (20) treated 22 patients with a high-dose methotrexate, high-dose cytarabine treatment regimen. Despite the fact that these are agents that should have adequate CNS penetration, the frequency of meningeal relapse was very high (35%). However, it is noteworthy that seven of the eight relapses occurred in individuals who had bone marrow involvement at the time of their initial diagnosis of lymphoma. Similarly, in the series by Lowenthal et al. (27), two of three individuals developing meningeal relapse had bone marrow involvement at diagnosis.
At the San Francisco General Hospital, we no longer routinely treat prophylactically all patients with systemic AIDS-associated lymphoma for meningeal recurrence. Rather, we target those individuals with risk factors for meningeal disease identified in the non-immunodeficiency-associated lymphoma population. These risk factors include bone marrow involvement, epidural disease, paranasal sinus involvement, and small, non-cleaved histologic pattern.
Antiviral Therapy
At this point in time, there is extensive experience in combining chemotherapy with nucleoside analogues. With the exception of concerns regarding overlapping myelosuppression when zidovudine (AZT) is used (and its use is therefore not recommended), there is little concern regarding the safety of these antiviral agents while chemotherapy is being administered. There are, however, little data concerning potential drug interactions between the protease inhibitors and agents such as cyclophosphamide and the anthracyclines. Clinical trials are currently investigating these potential drug interactions. Despite this lack of data, we believe that it is important to continue patients on their multiagent antiretroviral therapies while they are being administered chemotherapy. Physicians are urged to follow their patients closely for evidence of excessive toxicity when such combinations are used.
Future Therapeutic Approaches
There are undoubtedly a variety of mechanisms by which lymphoma arises in individuals with HIV disease. Lymphoma appears to arise out of a background of polyclonal B-cell hyperproliferation, which may arise through clonal integration of HIV in macrophages, resulting in overexpression of interleukin 6 or as a result of chronic antigenic stimulation from other sources (including viruses or other mitogens) (28). Overexpression of interleukin 10 also appears to be involved in an autocrine fashion (28,29). Other events that may involve viruses, such as EBV or human herpesvirus type 8 (HHV8), or genetic events, such as P53 mutations or c-myc gene rearrangements, may ultimately give rise to frank lymphoma.
At the same time, the cellular immune response to lymphoma may be blocked by a variety of mechanisms, including high concentrations of interleukin 6 and interleukin 10, which may prevent CD8 cytotoxic lymphocytes from becoming activated (28). The responsiveness of EBV-specific cytotoxic lymphocytes and natural killer (NK) cells appears to be blunted as well.
In vitro data as well as some preliminary in vivo data suggest that cytokines such as interleukin 2 (30) and interleukin 12 may be capable of improving CD8 and NK cell responses (31), and clinical trials investigating the use of each of these agents as potential therapeutic modalities or as an adjunct to standard chemotherapy are currently under way. In addition, expansion of EBV-specific cytotoxic lymphocytes used in adoptive immunotherapy is another therapeutic modality that is currently being explored.
Unique molecular characteristics of AIDS-associated lymphomas can also be taken advantage of with the use of monoclonal antibodies and immunotoxins. Substantial antitumor responses to an anti-CD22-ricin-A-chain immunotoxin have been reported (32), suggesting that this may be a potentially viable approach to therapy in some patients.
Anti-B4-blocked ricin has also been studied in individuals with refractory HIV-associated lymphoma with some observed responses, and clinical trials are currently in development for the use of anti-CD20 monoclonal antibodies, including the chimeric anti-CD20 antibody C2B8 which has been used successfully in the management of refractory low-grade lymphoma.
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Primary Effusion Lymphomas |
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The primary effusion lymphomas constitute only approximately 5% of all HIV-associated lymphomas. These lymphomas present as body cavity effusions (pleural, pericardial, or ascites) that are generally not associated with a contiguous mass lesion and tend to remain localized in the body cavity of origin (33). Morphologically, these lymphomas have a unique histologic pattern—one that is midway between that of large-cell immunoblastic and large-cell anaplastic lymphomas (33). These lymphomas are unique in their characteristic association with HHV8 (33,34). In addition, EBV genome was reported to be present in 100% of 15 tumors analyzed in one series (33) and in 50% of those evaluated in a second series of eight patients (35). Both B- and T-cell-associated antigens are usually absent (33).
Clinically, the majority of reported cases have occurred in homosexual or bisexual men (33). The median CD4 lymphocyte count in one study (n = 19) was 84/mm3; in a second study, it was 78/mm3 (35). Median survivals have been short (2-5 months), and no long-term disease-free survivors have been reported (33,35). However, the number of such cases reported in the medical literature is small, and there may be individuals whose clinical outcome is significantly better than those outcomes reported.
We are beginning to learn a great deal about the biology and pathogenesis of the HIV-associated non-Hodgkin's lymphomas. It is hoped that this new knowledge will lead to the development of more pathogenesis-based approaches to therapy and to a greater ability to take advantage of some of the unique molecular features of these lymphomas so that therapies can be identified but will allow us to reduce the amount of cytotoxic therapy required for the management of this disease.
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References |
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TopIntroductionPrimary CNS LymphomasSystemic LymphomasPrimary Effusion LymphomasReferences |
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