AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 May 31, 1996 Opportunistic Infections (Part XXV) AIDS-Related Lymphoma - Physician Information CancerNet from the National Cancer Institute Information from PDQ for Physicians May 7, 1996 PROGNOSIS The Acquired Immune Deficiency Syndrome (AIDS) was first described in 1981, and the first definitions included certain opportunistic infections, Kaposi's sarcoma, and central nervous system (CNS) lymphomas. In 1984, a multicentered study described the clinical spectrum of non-Hodgkin's lymphomas in the populations at risk for AIDS.[1] In 1985, the Centers for Disease Control (CDC) revised the definition of AIDS to include patients with high-grade B-cell non-Hodgkin's lymphoma in human immunodeficiency virus (HIV) infected patients. In 1987, intermediate-grade B-cell lymphomas were added to the definition of AIDS after several reports noted an increased incidence of large-cell lymphoma in patients with AIDS and HIV infection. The incidence of non-Hodgkin's lymphoma has increased in an almost parallel course with the AIDS epidemic and accounts for 3.3% of newly diagnosed AIDS cases. Over 200,000 cases of AIDS have been reported to the CDC. Of these, 2% were large-cell or immunoblastic lymphomas, 0.7% were small-noncleaved lymphomas, and 0.6% were primary CNS lymphomas. In addition, there appears to be a marked increase in the incidence of lymphoma in patients with diagnosed AIDS which, because these are secondary diagnoses, are not included in the CDC statistics. Reports from the National Cancer Institute have estimated the probability of developing a high-grade non-Hodgkin's B-cell lymphoma in this group of patients to be as high as 19.4% by 36 months after starting antiretroviral therapy. Other reports suggest a relatively constant rate of risk for the development of non-Hodgkin's lymphoma of 1.6%-2.0% per year in a population with AIDS or ARC.[2-4] The diagnosis of AIDS precedes the onset of non-Hodgkin's lymphoma in approximately 57% of the patients, but in 30% the diagnosis of AIDS is made at the time of the diagnosis of non-Hodgkin's lymphoma and HIV positivity.[5] The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike Kaposi's sarcoma, which has a predilection for homosexual men and appears to be on the decline in incidence, all risk groups appear to have an excess number of non-Hodgkin's lymphoma, including intravenous drug users and children of HIV-positive individuals. In general, the clinical setting and response to treatment of patients with AIDS-related lymphoma is very different from the non-HIV patient with lymphoma. The HIV-infected individual with intermediate- or high-grade lymphoma usually presents with advanced stage disease that is frequently extranodal. The clinical course is more aggressive, and the disease both more extensive and less responsive to chemotherapy. Immunodeficiency and cytopenias, common in these patients at the time of initial presentation, are exacerbated by the administration of chemotherapy. Therefore, treatment of the malignancy increases the risk of opportunistic infections, which in turn further compromise the delivery of adequate treatment. Prognosis of patients with AIDS-related lymphoma has been associated with stage (extent of disease, extranodal involvement, bone marrow involvement), severity of the underlying immunodeficiency (measured by CD4 lymphocyte count in peripheral blood), performance status, and prior AIDS diagnosis (history of opportunistic infection or Kaposi's sarcoma). Patients with AIDS-related primary CNS lymphoma appear to have more severe underlying HIV-related disease than do patients with systemic lymphoma. In one report, this was evidenced by patients with primary CNS lymphoma having a higher incidence of a prior AIDS diagnosis (73% vs. 37%), lower median number of CD4 lymphocytes (30/dL vs. 189/dL), and a worse median survival (2.5 months vs. 6.0 months).[6] This same report showed that patients with poor risk factors (defined as Karnofsky performance status <70%, history of prior AIDS diagnosis, and bone marrow involvement) had a median survival of 4.0 months as compared to a "good prognosis" group without any of these risk factors with a median survival of 11.3 months. HIV-Associated Hodgkin's Disease Since 1984, several series of cases of Hodgkin's disease occurring in patients at risk for AIDS have been published.[7-9] However, Hodgkin's disease is still not part of the CDC definition of AIDS because there has been no clear demonstration yet of its increased incidence in conjunction with HIV, as is the case for aggressive non-Hodgkin's lymphoma. Recently, the CDC in conjunction with the San Francisco Department of Public Health reported a cohort study in which HIV-infected men had an excess risk attributable to the HIV infection of 19.3 cases of Hodgkin's disease per 100,000 person-years and 224.9 cases of non-Hodgkin's lymphoma per 100,000 person-years and 224.9 cases of non-Hodgkin's lymphoma per 100,000 person-years. Although an excess incidence of Hodgkin's disease was found in HIV-infected homosexual men in this report, additional epidemiologic studies will be needed before the CDC will reconsider Hodgkin's disease as an HIV-associated malignancy.[10] The series referenced above are consistent in identifying several features of HIV-associated Hodgkin's disease. Specifically, HIV-associated Hodgkin's disease presents in a more aggressive fashion, often with extranodal or bone marrow involvement. Most patients in these series had either mixed cellularity or lymphocyte-depleted Hodgkin's disease, B symptoms, and a median CD4 count of 300 or less. Median survival is less than 1 year. However, death in these patients was not due to the Hodgkin's disease (most patients responded to standard treatment regimens) but rather to opportunistic infections or other HIV-related malignancies. References: 1. Ziegler JL, Beckstead JA, Volberding PA, et al.: Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. New England Journal of Medicine 311(9): 565-570, 1984. 2. Pluda JM, Yarchoan R, Jaffe ES, et al.: Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Annals of Internal Medicine 113(4): 276-282, 1990. 3. Gail MH, Pluda JM, Rabkin CS, et al.: Projections of the incidence of non-Hodgkin's lymphoma related to acquired immundeficiency syndrome. Journal of the National Cancer Institute 83(10): 695-701, 1991. 4. Pluda JM, Venzon DJ, Tosato G, et al.: Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. Journal of Clinical Oncology 11(6): 1099-1107, 1993. 5. Knowles DM, Chamulak GA, Subar M, et al.: Lymphoid neoplasia associated with the acquired immunodeficiency sydrome (AIDS): the New York University Medical Center experience with 105 patients. Annals of Internal Medicine 108(5): 744-753, 1988. 6. Levine AM, Sullivan-Halley J, Pike MC, et al.: Human immunodeficiency virus-related lymphoma: prognostic factors predictive of survival. Cancer 68(11): 2466-2472, 1991. 7. Ree HJ, Strauchen JA, Khan AA, et al.: Human immunodeficiency virus-associated Hodgkin's disease: clinicopathologic studies of 24 cases and preponderance of mixed cellularity type characterized by the occurrence of fibrohistiocytoid stromal cells. Cancer 67(6): 1614-1621, 1991. 8. Pelstring RJ, Zellmer RB, Sulak LE, et al.: Hodgkin's disease in association with human immunodeficiency virus infection. Cancer 67(7):1865-1873, 1991. 9. Ames ED, Conjalka MS, Goldberg AF, et al.: Hodgkin's disease and AIDS: twenty-three new cases and a review of the literature. Hematology/Oncology Clinics of North America 5(2): 343-356, 1991. 10. Hessol NA, Katz MH, Liu JY, et al.: Increased incidence of Hodgkin disease in homosexual men with HIV infection. Annals of Internal Medicine 117(4): 309-311, 1992. 11. Levine AM: Acquired immunodeficiency syndrome-related lymphoma. Blood 80(1): 8-20, 1992. CELLULAR CLASSIFICATION Almost all AIDS-related non-Hodgkin's lymphoma have been classified as B-cell, high or intermediate grade, according to the Working Formulation.[1] -- Working Formulation -- Low grade small lymphocytic, consistent with CLL (SL) follicular, predominately small cleaved cell (FSC) follicular, mixed small cleaved and large cell (FM) Intermediate grade follicular, predominately large cell (FL) diffuse, small cleaved cell (DSC) diffuse, mixed, small and large cell (DM) diffuse, large cleaved or noncleaved cell (DL) High Grade immunoblastic, large cell (IBL) lymphoblastic, convoluted or nonconvoluted cell (LL) small noncleaved cell, Burkitt's or non-Burkitt's (SNC) The majority of AIDS-related lymphomas are high grade. Approximately 34%-40% are small-noncleaved (Burkitt's and non-Burkitt's) lymphoma, 18%-43% are immunoblastic lymphomas, and 22%-36% are intermediate-grade, large-cell lymphomas.[2] AIDS-related lymphomas, although usually of B-cell origin as demonstrated by immunoglobulin heavy chain gene rearrangement studies, have also been shown to be oligoclonal and polyclonal, as well as monoclonal in origin. Chromosomal studies have shown predictive abnormalities as in other lymphomas of similar histology. Molecular genetic studies have shown c-myc translocation. Although HIV does not appear to have a direct etiologic role, HIV infection does lead to an altered immunologic milieu. HIV generally infects T-lymphocytes whose loss of regulation function leads to hypergammaglobulinemia and polyclonal B-cell hyperplasia. B cells are not the target of HIV infection. Instead, Epstein-Barr virus (EBV) is thought to be at least a cofactor in the etiology of some of these lymphomas. The EBV genome has been detected in varying numbers of patients with AIDS-related lymphomas with molecular analysis suggesting that the cells were infected before clonal proliferation began.[3] HIV-related T-cell lymphomas have also been identified and appear to be associated with EBV infection.[4] References: 1. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 49(10): 2112-2135, 1982. 2. Freter CE: Acquired immunodeficiency syndrome-associated lymphomas. Journal of the National Cancer Institute Monograph 10: 45-54, 1990. 3. Neri A, Barriga F, Inghirami G, et al.: Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma. Blood 77(5): 1092-1095, 1991. 4. Thomas JA, Cotter F, Hanby AM, et al.: Epstein-Barr Virus-related oral T-cell lymphoma associated with Human Immunodeficiency Virus immunosuppression. Blood 81(12): 3350-3356, 1993. STAGE INFORMATION Although stage is important in selecting the treatment for patients with non-AIDS-related non-Hodgkin's lymphoma, the majority of patients with AIDS-related lymphomas have far advanced disease. In general, the Ann Arbor staging system is used, identical to that for non--AIDS-related non-Hodgkin's lymphomas. Staging Classification System -- Stages I, II, III, and IV non-Hodgkin's disease can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without. The B designation is given to patients with any of the following: * unexplained loss of greater than 10% of body weight in the 6 months before diagnosis * unexplained fever with temperatures above 38 degrees C * drenching night sweats The designation "E" is used when extranodal lymphoid malignancies arise in tissues away from the major lymphatic aggregates. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Sites are identified by the following notation: N = nodes H = liver L = lung M = marrow S = spleen P = pleura O = bone D = skin -- Stage I -- Stage I non-Hodgkin's lymphoma means involvement of a single lymph node region (I), or localized involvement of a single extralymphatic organ or site (IE).[1,2] -- Stage II -- Stage II non-Hodgkin's lymphoma means involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE).[1,2] -- Stage III -- Stage III non-Hodgkin's lymphoma means involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), involvement of the spleen (IIIS), or both (IIIS+E).[1,2] -- Stage IV -- Stage IV non-Hodgkin's lymphoma means disseminated (multifocal) involvement of one or more extralymphatic sites with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.[1,2]] A number of factors important for determining prognosis are not included in the staging system for non-Hodgkin's lymphomas. All of these factors should be considered when selecting treatment. Prognosis is related to the severity of the underlying immune deficiency (CD4 lymphocyte count), the presence or history of opportunistic infections (prior AIDS-defining illness), bone marrow involvement, performance status, and presence of extranodal disease.[3] Typically, AIDS-related lymphomas are widespread with extranodal disease at the time of presentation. The most common extranodal sites are the gastrointestinal (GI) tract, central nervous system, bone marrow, and liver. In one series, the largest group of patients had both extranodal and nodal disease (43%), but one-third of the patients presented with extranodal disease only.[4] In a second series, 87% of the patients had extranodal disease at presentation.[5] Two-thirds of patients are stage IV at diagnosis. In addition, unusual presentations include involvement of the rectum, heart, pericardium, pulmonary parenchyma, bile ducts, mouth, and subcutaneous and soft tissues. The clinical features of AIDS-related lymphomas correlate with histopathology. The majority of small-noncleaved cell (Burkitt's) lymphomas present with Stage IV disease, mostly because of bone marrow involvement. This compares to approximately 40% stage IV presentation by the immunoblastic and large-cell lymphomas. A particular prevalence for GI involvement by immunoblastic and large-noncleaved cell lymphoma types has also been noted.[6] While high-risk behavior should be looked for in every patient, HIV testing should probably be done with any Burkitt's lymphoma or the atypical presentation of extranodal lymphoma involving rare sites, i.e., rectum, GI tract, bone, or orbit. Similarly, malignant lymphoma should be considered in any HIV-infected patient with progressive lymphadenopathy; tumors at any site; CNS symptoms; or unexplained wasting, fever, or abdominal pain. References: 1. American Joint Committee on Cancer: Manual for Staging of Cancer. Philadelphia: JB Lippincott Company, 3rd ed., 1988. 2. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 49(10): 2112-2135, 1982. 3. Levine AM, Sullivan-Halley J, Pike MC, et al.: Human immunodeficiency virus-related lymphoma: prognostic factors predictive of survival. Cancer 68(11): 2466-2472, 1991. 4. Kaplan LD, Abrams DI, Feigal E, et al.: AIDS-associated non-Hodgkin's lymphoma in San Francisco. Journal of the American Medical Association 261(5): 719-724, 1989. 5. Knowles DM, Chamulak GA, Subar M, et al.: Lymphoid neoplasia associated with the acquired immunodeficiency sydrome (AIDS): the New York University Medical Center experience with 105 patients. Annals of Internal Medicine 108(5): 744-753, 1988. 6. Raphael BG, Knowles DM: Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma. Seminars in Oncology 17(3): 361-366, 1990. TREATMENT OPTION OVERVIEW The treatment of AIDS-related lymphomas presents the challenge of integrating therapy appropriate for the stage and histologic subset of malignant lymphoma with the limitations imposed by HIV infection, to date an incurable illness. Patients with HIV positivity and underlying immunodeficiency have poor bone marrow reserve, thereby compromising the potential for dose intensity. There is a risk of intercurrent opportunistic infection, which may also lead to a decrease in drug delivery. Furthermore, chemotherapy itself compromises the immune system increasing the likelihood of opportunistic infection. In general, response rates are lower than for a non-HIV population. Complete responses occur but tend to be of shorter duration with frequent relapses. The question is whether the curative potential of high-dose chemotherapy is so compromised by the treatment-related morbidity and mortality, that low-dose chemotherapy should be used. Most studies have used a lower dose intensity, and delays in treatment have been common. In the initial reports of AIDS-related lymphomas approximately half of the evaluable patients achieved a complete remission with combination chemotherapy, but of these, approximately half subsequently relapsed. One-half of the deaths were from progressive lymphoma. Although the other half died of opportunistic infections, a significant percentage of this group had active lymphoma at the time of death. Since the initial studies, several investigators have attempted to use intensive chemotherapy regimens. In general, these have not improved survival. Median overall survival for treated patients is approximately 6 months. The patients with the more favorable outcomes and prolonged survival tend to have less disease (stage I or II), no systemic symptoms, good performance status, and no CNS or bone marrow involvement. Therefore, chemotherapy should be individualized for patients with good prognostic features who may tolerate more aggressive therapy than those with poor prognostic features. AIDS-RELATED PERIPHERAL/SYSTEMIC LYMPHOMA As noted above, the treatment of AIDS-related lymphomas involves overcoming several problems. These are all aggressive lymphomas, which by definition are diffuse large-cell/immunoblastic lymphoma or small-noncleaved cell lymphoma. These lymphomas frequently involve the bone marrow and central nervous system and therefore are usually in an advanced stage. In addition, the immunodeficiency of AIDS and the leukopenia commonly seen with HIV infection makes the use of immunosuppressive chemotherapy difficult. A large number of retrospective studies, and more recently several prospective studies, have been reported using regimens such as CHOP and m-BACOD as are commonly employed with non-AIDS aggressive lymphomas. In general, these studies have combined the various histologic subsets of AIDS-related systemic peripheral lymphomas. Unlike the non--HIV-related lymphomas, investigators have treated diffuse large-cell/immunoblastic lymphoma as they have small-noncleaved cell lymphoma. These studies have shown that complete remissions are possible, although the responses are often of short duration and relapses are frequent. The patients who go into remission are more likely to have less disease, no bone marrow or CNS involvement, no prior AIDS-defining illness, and a better performance status. Central nervous system relapses are common such that the use of prophylactic intrathecal chemotherapy is considered relatively standard.[1] Overall complete responses have been seen in approximately 50% of patients. The complete response rate and survival is higher in patients with diffuse large-cell lymphoma. Whether patients with small-noncleaved cell and immunoblastic lymphoma have a worse prognosis is unclear and varies from one series to another.[2] The most appropriate treatment regimen for patients with AIDS-related lymphoma is not known. Delays in therapy and dose reductions are often necessary, and some investigators have advocated using lower-dose chemotherapeutic regimens. In addition, more aggressive chemotherapy has been reported to be associated with a shortened survival for AIDS-related lymphomas.[3] Therefore, the prognostic features related to the underlying immune deficiency and marrow compromise seem to outweigh the lymphoma-specific related prognostic indicators. One recent report used a low dose modification of the m-BACOD regimen as well as intrathecal cytarabine. Pneumocystis prophylaxis was employed and zidovudine was instituted after completion of 4-6 cycles of chemotherapy. The results were comparable to the reports above.[4] Median duration of survival was 6.5 months in the patients evaluable for response and 15 months in the patients with complete response. Another report incorporated hematopoietic growth factor (GM-CSF) into a regimen using CHOP.[5] Compared to a control group, patients receiving GM-CSF tolerated the chemotherapy better as evidenced by higher nadirs and fewer complications of neutropenia, fever, and hospitalization. In addition, fewer reductions in chemotherapy dosages and less frequent delays in chemotherapy administration were noted. Although complete responses were achieved in 70% of patients, the small numbers in the study did not allow for adequate comparison of prognostic factors to determine if dose intensity was useful. A phase I study of m-BACOD and GM-CSF has been recently reported in which the use of hematopoietic growth factor permitted administration of full doses of chemotherapy.[6] To determine if dose intensity is important in AIDS-related lymphoma, the AIDS clinical trial units (ACTG) are currently comparing low-dose to standard-dose chemotherapy in this group of patients. References: 1. Gill PS, Levine AM, Krailo M, et al.: Aids-related malignant lymphoma: results of prospective treatment trials. Journal of Clinical Oncology 5(9): 1322-1328, 1987. 2. Pedersen C, Gerstoft J, Lundgren JD, et al.: HIV-associated lymphoma: histopathology and association with Epstein-Barr virus genome related to clinical, immunological and prognostic features. European Journal of Cancer 27(11): 1416-1423, 1991. 3. Kaplan LD, Abrams DI, Feigal E, et al.: AIDS-associated non-Hodgkin's lymphoma in San Francisco. Journal of the American Medical Association 261(5): 719-724, 1989. 4. Levine AM, Wernz JC, Kaplan L, et al.: Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma: a prospective multi-institutional trial. Journal of the American Medical Association 266(1): 84-88, 1991. 5. Kaplan LD, Kahn JO, Crowe S, et al.: Clinical and virologic effects of recombinant human granulocyte-macrophage colony stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: results of a randomized trial. Journal of Clinical Oncology 9(6): 929-940, 1991. 6. C Walsh: Colony-stimulating factors in the treatment of HIV-associated non-Hodgkin's lymphoma. Oncology (Huntington NY) 3(10): 79-86, 1989. AIDS-RELATED PRIMARY CNS LYMPHOMA Until the 1980s, primary CNS lymphoma was a rare disease. Recently, there has been a dramatic increase in primary CNS lymphoma in association with AIDS.[1] Primary CNS lymphoma accounts for approximately 0.6% of initial AIDS diagnoses and is the second most frequent CNS mass lesion in adults with AIDS. As with other AIDS-related lymphomas, these are usually aggressive B-cell neoplasms, either diffuse large-cell or diffuse immunoblastic NHL. However, unlike AIDS-related systemic lymphomas in which 30%-50% of tumors are associated with EBV, AIDS-related primary CNS lymphoma has been reported to have a 100% association with EBV.[2] This indicates a pathogenetic role for EBV in this disease. These patients usually have evidence of far advanced AIDS, are severely debilitated, and present with focal neurologic symptoms such as seizures and paralysis. Computed tomography scans show contrast-enhancing mass lesions, which cannot be distinguished from other CNS diseases occurring in AIDS patients such as toxoplasmosis.[3] Diagnosis is made by biopsy. Primary CNS lymphoma is often identified as a terminal manifestation of AIDS or on postmortem examination. Radiation therapy alone has usually been used in this group of patients. With doses in the 3500-4000 cGy range, median survival has been only 72-119 days.[3-5] Survival is longer in patients with better performance status and absence of opportunistic infection. Most patients respond to treatment with partial improvement in neurologic symptoms. When autopsies have been performed, patients have been shown to die of opportunistic infections as well as tumor progression. Treatment of these patients is also complicated by other AIDS-related CNS infections including subacute AIDS encephalitis, CMV encephalitis, and toxoplasmosis encephalitis. References: 1. Ziegler JL, Beckstead JA, Volberding PA, et al.: Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. New England Journal of Medicine 311(9): 565-570, 1984. 2. MacMahon EM, Glass JD, Hayward SD, et al.: Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338(8773): 969-973, 1991. 3. Goldstein JD, Dickson DW, Moser FG, et al.: Primary central nervous system lymphoma in acquired immune deficiency syndrome: a clinical and pathologic study with results of treatment with radiation. Cancer 67(11): 2756-2765, 1991. 4. Baumgartner JE, Rachlin JR, Beckstead JH, et al.: Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. Journal of Neurosurgery 73(2): 206-211, 1990. 5. Remick SC, Diamond C, Migliozzi JA, et al.: Primary central nervous system lymphoma in patients with and without the acquired immune deficiency syndrome: a retrospective analysis and review of the literature. Medicine 69(6): 345-360, 1990. Date Last Modified: 05/96