- Email: [email protected]
The case of a diffuse large B-cell lymphoma (DLBCL) in a course of HIV
hiv & aids r e v i e w
volume 9 • number 1 • 2010
title
The case of a diffuse large B-cell lymphoma (DLBCL) in a course of HIV
authors Jacek Czepiel • Urszula Kluba-Wojewoda • Grażyna Biesiada • Tomasz Mach • Aleksander Garlicki Department of Infectious Diseases, Chair of Gastroenterology, Hepatology and Infectious Diseases, Jagiellonian University Medical College, Krakow, Poland
summary Background Lymphomas develop in approximately 6% of HIV-positive patients, who are estimated to have a 100-200-fold higher risk of lymphoma and as much as a 1000-fold higher risk of primary cerebral lymphoma. Case report Patient T.R., age 33, HIV positive – diagnosis 3 years before, CD4 = 120/ul, he didn’t agree to continue HAART. Two months before present hospitalization developed an enlarged lymph node in the left axilla, substantially increased in diameter reaching 12 cm, and an infiltration of the chest skin. The enlarged lymph node was sampled, and in a microscopic evaluation it was diagnosed as diffuse large B-cell lymphoma (DLBCL). After establishing the diagnosis, the patient received antiretroviral therapy (tenofovir, lamivudine, lopinavir, ritonavir) and courses of chemotherapy according to the CHOP regimen (cyclophosphamide, vincristine, doxorubicin, prednisone) combined with rituximab. The treatment resulted in a marked local tumor regression in the chest and left axilla. During the lymphoma therapy numerous complications were observed. Psychologically, the patient was very optimistic until the last chemotherapy cycle. He died after the fifth cycle. Conclusion The decision to start chemotherapy and HAART should be taken individually for every patient. Unfortunately, despite the recent advances in therapy, the prognosis in HIV-positive patients with lymphomas remain poor.
key words HIV, HAART, diffuse large B-cell lymphoma
address Jacek Czepiel Department of Infectious Diseases, Chair of Gastroenterology, Hepatology and Infectious Diseases Medical College, Jagiellonian University Śniadeckich 5 Str • 31-501 Krakow • Poland tel: 048124247349; fax: 048124247380 e-mail: [email protected] 22
We report no conflicts of interest.
HIV&AIDS R E V I E W
Background Advances in HIV therapy have resulted in the prolonged survival of HIV-positive patients and also in an increased prevalence of HIV-associated diseases, such as lymphomas. Lymphomas develop in approximately 6% of HIVpositive patients, who are estimated to have a 100-200-fold higher risk of lymphoma and as much as a 1000-fold higher risk of primary cerebral lymphoma (PCL). Lymphoma is the second most prevalent malignancy related to the HIV infection. It usually develops in the later phase of the HIV infection, when CD4 levels fall below 200 cells/ul. The risk of lymphoma increases with the duration of the infection. Three years after contracting the infection it is estimated to be 0.8% per year, while 8 years on it can reach as much as 2.6% per year. Clinical manifestation of lymphomas in HIV-positive patients is variable and may range from small lesions, through fever, to rapidly enlarging lymph nodes. Over 90% of patients have extranodal lesions and virtually every organ can be affected by lymphoma. The most frequent extranodal locations include the central nervous system (CNS), which is affected in approximately 30% of patients. The progression of PCL is associated with rapid development of neurological signs and symptoms, most often headaches, behavioral abnormalities and focal symptoms (1, 2). Diagnosis is based on histological examination of the affected lymph node or organ. According to the WHO, lymphomas in HIV-positive patients are classified into 3 main categories. The first category includes lymphomas, which may also be present in immunocompetent patients, such as Burkitt’s lymphoma, or a diffuse large B-cell lymphoma (DLBCL). The second category comprises lymphomas typical for HIV-positive patients, such as primary effusion lymphoma (PEL) or plasmablastic lymphoma. The third category includes lymphomas prevalent in immunosuppressed patients regardless of the cause of decreased immunity, such as B-cell lymphomas. The most prevalent lymphoma in HIV-positive patients is DLBCL (1, 2).
Case report Patient T.R., age 33, was admitted to our Department because of lymphoma that developed in the course of an HIV infection. The HIV infection had been diagnosed 3 years before the current hospitalization, and the CD4 level was 120 cells/ul at that time. At the time of the initial diagnosis the patient started antiretroviral therapy, but then decided to stop after 6 months during the period of effective immunological reconstitution. For the subsequent 3 years the patient did not report to a physician. Two months before his current hospitalization he developed an enlarged lymph node in the left axilla, which then substantially increased in diameter reaching 12 cm. Subsequently he developed an infiltrate of the chest skin. The enlarged lymph node was sampled, and in a microscopic evaluation it was diagnosed as high-grade DLBCL, IHC: CD20 (+), CD3 (-), bcl 2 (-), Ki67 (+) > 95 cells. Chest CT scans revealed a very large pathological mass, most probably emerging from the lymph nodes, located on the level of the left axilla, associated with lymphatic retention in the upper half of the chest and upper part of the left arm and pleural effusion on the right. In the abdomen, conglomerates of the enlarged
lymph nodes up to 20 mm in diameter were found, together with signs of mesenteric infiltrates and a substantial thickening of soft tissues (photos 1 and 2). After establishing the diagnosis, the patient received antiretroviral therapy (tenofovir, lamivudine, lopinavir, ritonavir) and courses of chemotherapy according to the CHOP regimen (cyclophosphamide, vincristine, doxorubicin, prednisone) combined with rituximab. Before chemotherapy the CD4 level was 3956 cells/mm3, which was 30% of CD3 cells; the high CD4 level being associated with the malignant process. The patient received five chemotherapy cycles. The treatment resulted in a marked local tumor regression in the chest and left axilla (photo 3). During the lymphoma therapy numerous complications were observed, including skin ulcerations over the tumor surface, diarrhea and stomatitis. Myelosuppression developed after each chemotherapy cycle. The suppression was most marked in the lymphocyte counts, and on days 7–9 after the cycle they reached 100-300 cells/mm3, although anemia and thrombocytopenia were less marked. Leukopenia was treated with filgrastim whilst antibiotic (ceftriaxone) and antifungal (fluconazole) therapy was also instituted. The erythrocyte and platelet counts improved spontaneously to satisfactory levels after approximately 7 days, and the stomatitis was treated with chlorhexidine. The patient’s reaction to every subsequent chemotherapy cycle became worse and he developed cachexia and asthenia. Psychologically, the patient was very optimistic until the last chemotherapy cycle. He died after the fifth cycle.
Discussion Pathogenesis of lymphoma development in the course of an HIV infection is complex and not fully understood. Key risk factors are low CD4 levels, a high HIV load and advanced age. The main factor enhancing the development of malignancy is clonal B-cell proliferation, which is a consequence of stimulation with viral antigens. The duration of the HIV infection is directly related to the increased risk of lymphoma. The prognosis of patients with AIDS-related lymphoma (ARL) is generally poor, although some patients have markedly better treatment outcomes. CD4 levels at diagnosis seem to be the main prognostic factor and higher counts are associated with a better prognosis (1, 3). In the case of our patient, a most notable feature was his willful interruption of antiretroviral treatment, which must be categorically implicated in shortening his chances of survival. Properly instituted antiretroviral therapy decreases the patient’s HIV load and enables immunological reconstitution. Patients with low viral load and high CD4 counts have a lower risk of lymphoma than persons with high HIV loads and low CD4 levels. ART discontinuation in our patient was not caused by poor tolerance of treatment. His reaction to treatment was indeed very good, which fostered his opinion that the disease was not dangerous and could be easily controlled. The patient willfully decided to stop the treatment and planned to start it again if the disease progressed further. It must be noted, that many clinicians taking care of HIV-positive patients also describe such patient attitudes. This issue is another challenge to the efforts being made to achieve good treatment results for HIV infections. An optimal method of treatment of lymphomas in HIVpositive patients has not been established so far. Many regimens are used in these patients (Kaplan et al., 1989; volume 9 • number 1 • 2010
23
HIV&AIDS R E V I E W Gisselbrecht et al, 1993; Fischer et al, 1993, Costello et al, 2004; Sparano et al, 2004) and the CHOP regimen (cyclophosphamide, vincristine, doxorubicin, prednisone), used as a standard therapy in HIV-positive patients, seems to be the most promising of them. Clinicians treating lymphomas in HIV-positive patients encounter two major challenges. The first is the unsatisfactory complete remission (CR) rates, which result from the aggressive course of lymphoma, and the second is chemotherapy toxicity, which is higher than in HIV-negative patients. Higher toxicity results from the concomitant use of ART as well as from advanced AIDS (4–8). As the use of standard CHOP doses in HIV-positive patients caused numerous side effects, some authors attempted to use lower doses of chemotherapy (Tirelli et al, 1992; Kaplan et al, 1997). Positive effects of such therapy were observed in the early stages of AIDS. Kaplan compared the use of the m-BACOD regimen (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with standard and reduced drug doses and achieved similar CR rates (42% vs 41%), as well as lower toxicity levels associated with reduced doses (9, 10). However, Ratner et al., 2001, observed, that the use of lower drug doses in the CHOP regimen resulted not only in lower CR rates (30% vs 48%) but also in a shorter CR duration (11). The GELA-GICAT Group conducted a study including 485 HIV-positive patients with lymphomas. They compared CHOP, low dose CHOP (Ld-CHOP) and ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimens. The results of treatment were better in the CHOP group compared to the Ld-CHOP (49% vs 32%). Notably, the 5-year overall survival rate (OS) was slightly higher in the CHOP group compared to Ld-CHOP (28% vs 24%) (12). In view of the aggressive course of lymphomas in the course of an HIV infection and unsatisfactory CR rates after standard regimens, more intensive therapy has been considered. Several studies reported the beneficial effects of using higher drug doses in the CHOP regimen (Tilly et al, 2003; Mounier et al, 2007; Reyes et al, 2005), but in view of the high toxicity of such therapy it is still being debated. In a treatment of our patient we used standard CHOP doses. Despite the young age of the patient and lack of comorbidities except for the HIV infection and lymphoma, the drug toxicities could not be avoided. The use of higher chemotherapy doses in this patient would probably have led to even more toxicities. Perhaps the end result of lymphoma treatment would be better if the patient had had less advanced AIDS, which would have enabled us to use more intensive lymphoma therapy (13–15). In recent years, based on results of lymphoma treatment in HIV-negative patients and because the majority of lymphomas in HIV-positive patients are CD20-positive, rituximab has been used in such patients. Rituximab is a chimeric murine/human monoclonal antibody which blocks lymphocyte CD20 surface receptors. Studies completed to date have reported the beneficial results of treatment with this agent. In the study by Spina et al., 70% of patients achieved CR, the 2-year OS was 64% and 2-year event-free survival (EFS) was 52%. In the study by Boue et al., 67% of patients achieved CR, 10% achieved partial remission (PR), the 2-year OS was 75%, and 2-year EFS was 65%. The only randomized study completed so far (Kaplan et al. 2005); compared the efficacy of CHOP and R-CHOP regimens. CR in the R-CHOP group was 57%, and in the CHOP group it was 47% (16–18). HAART (highly active antiretroviral therapy) is an important element of therapy of HIV-positive patients with 24
volume 9 • number 1 • 2010
lymphoma and results in marked benefits (Gabarre et al. 1995, Retner et al. 2001, Powles et al. 2002) (11, 19, 20). Baiocchi et al. reported six-fold longer survival times in the group of patients with ARL, receiving HAART compared to the group in which HAART was not used (21). However, antiviral drugs which may cause myelosuppression, and particularly AZT, should be avoided (11, 19, 20). Little et al. assessed the effects of withholding HAART until the end of chemotherapy treatment. Such an approach was beneficial and resulted in lower toxicity rates in patients with CD4 levels >100 cells/ul, while in patients with CD4 levels < 100 cells/ul, the course of AIDS worsened and opportunistic infections developed. In summarizing the above reports, one can say that the risk of increased toxicities in patients treated for lymphomas and who are receiving HAART is slightly higher than in HIV-negative patients, and delayed introduction of HAART may only be considered in the early phase of AIDS. In patients with very low CD4 levels (< 100 cells/ul), delayed HAART negatively affects the prognosis. Although the use of HAART increases the toxicities of therapy and mandates close monitoring, its concomitant use with chemotherapy seems indispensable in HIV-positive patients (22).
HIV&AIDS R E V I E W
Conclusion The decision to start chemotherapy and HAART should be taken individually for every patient. The patient’s performance status, age, phase of HIV infection and stage of lymphoma should be considered. Such an individualized approach allows one to achieve the best possible CR with the minimum adverse effects. Unfortunately, despite the recent advances in therapy, the prognosis in HIV-positive patients with lymphomas remains poor.
References 1. Grogg KL, Miller RF, Dogan A. HIV infection and lymphoma. J Clin Pathol 2007; 60: 1365–72. 2. Lim F, Abdalla SH. Interactions between HIV infection and lymphoplasmacytoid lymphoma: Leukemia & Lymphoma 2006; 47: 163–6. 3. Bower M, Gazzard B, Mandalia S, Newsom-Davis T, Thirlwell C, Dhillon T et al. A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of Highly Active Antiretroviral Therapy. Ann Intern Med 2005; 143: 265–73. 4. Kaplan LD, Abrams DI, Feigal E, McGrath M, Kahn J, Neville P. AIDS-associated non-Hodgkin’s lymphoma in San Francisco. JAMA 1989; 261: 719–24. 5. Gisselbrecht C, Oksenhendler E, Tirelli U, Lepage E, Gabarre J, Farcet JP et al. Human immunodeficiency virus-related lymphoma treatment with intensive combination chemotherapy. French-Italian Cooperative Group. Am J Med 1993; 95: 188–96. 6. Fischer RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. NEJM 1993; 328: 1002–6. 7. Costello RT, Zerazhi H, Charbonnier A, de Colella JM, Alzieu C, Poizot-Martin I et al. Intensive sequential chemotherapy with hematopoietic growth factor support for nonHodgkin lymphoma in patients infected with the human immunodeficiency virus. Cancer 2004; 100: 667–76.
8. Sparano JA, Lee S, Chen MG, Nazeer T, Einzig A, Ambinder RF et al. Phase II trial of infusional cyclophosphamide, doxorubicin and etoposide in patients with HIV-associated nonHodgkin’s lymphoma: an Eastern Cooperative Oncology Group Trial. J Clin Onc 2004; 22: 1491–500. 9. Tirelli U, Errante D, Oksenhendler E, Spina M, Vaccher E, Serraino D et al.: Prospective study with combined low-dose chemotherapy and zidovudine in 37 patients with poorprognosis AIDS-related non-Hodgkin’s lymphoma. FrenchItalian Cooperative Study Group. Ann Oncol 1992; 3: 843– 7. 10. Kaplan LD, Straus DJ, Testa MA, Von Roenn J, Dezube BJ, Cooley TP et al.: Low-dose compared with standard-dose mBACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. NEJM 1997; 336: 1641–8. 11. Ratner L, Lee J, Tang S, Redden D, Hamzeh F, Herndier B et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Onc 2001; 19: 2171–8. 12. Mounnier N, Gisselbrecht C, Briere J. Prognostic factors in patients with aggressive non-Hodgkin’s lymphoma treated by front line autotransplantation after complete remission: a cohort study by the Group d’Etude des Lymphomes de l’Adulte. J Clin Onc 2004; 22: 2826–34. 13. Mounier N, Spina M, Gisselbrecht Ch. Modern management of non-Hodgkin lymphoma in HIV-infected patients. Br J Haematol 2007; 136: 685–98. 14. Tilly H, Lepage E, Coiffier B. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 2003; 102: 4284–9. 15. Reyes F, Lepage E, Ganem G. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. NEJM 2005; 352: 1197–205. 16. Spina M, Jaeger U, Sparano JA, Talamini R, Simonelli C, Michieli M et al. Rituximab plus infusional cyclophosphamide, doxorubicin and etoposide (R-CDE) in HIV-associated non-Hodgkin’s lymphoma: pooled results from three phase II trials. Blood 2005; 705: 1891–7. 17. Boue F, Gabarre J, Gisselbrecht C, Reynes J, Cheret A, Bonnet F et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin’s lymphoma. J Clin Onc 2006; 24: 4123–8. 18. Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A et. al. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood 2005; 106: 1538–43. 19. Gabarre J, Lepage E, Thyss A. Chemotherapy combined with zidovudine and GM-CSF in human immunodeficiency virus related non-Hodgkin’s lymphoma. Ann Onc 1995; 6: 1025– 32. 20. Powles T, Imami N, Nelson M. Effects of combination chemotherapy and highly active antiretroviral therapy on immune parameters in HIV-1 associated lymphoma. AIDS 2002; 16: 531–6. 21. Baiocchi OCG, Colleoni GWB, Navajas EV, Duarte LC, Alves AC, Andrade AL. Impact of Highly Active Antiretroviral Therapy in the treatment of HIV-infected patients with systemic non-Hodgkin’s lymphoma. Acta Oncol 2002; 41: 192–6. 22. Little RF, Pittaluga S, Grant N, Steinberg SM, Kavlick MF, Mitsuya H et al: Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with doseadjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 2003; 101: 4653–9.
volume 9 • number 1 • 2010
25
volume 9 • number 1 • 2010
title
The case of a diffuse large B-cell lymphoma (DLBCL) in a course of HIV
authors Jacek Czepiel • Urszula Kluba-Wojewoda • Grażyna Biesiada • Tomasz Mach • Aleksander Garlicki Department of Infectious Diseases, Chair of Gastroenterology, Hepatology and Infectious Diseases, Jagiellonian University Medical College, Krakow, Poland
summary Background Lymphomas develop in approximately 6% of HIV-positive patients, who are estimated to have a 100-200-fold higher risk of lymphoma and as much as a 1000-fold higher risk of primary cerebral lymphoma. Case report Patient T.R., age 33, HIV positive – diagnosis 3 years before, CD4 = 120/ul, he didn’t agree to continue HAART. Two months before present hospitalization developed an enlarged lymph node in the left axilla, substantially increased in diameter reaching 12 cm, and an infiltration of the chest skin. The enlarged lymph node was sampled, and in a microscopic evaluation it was diagnosed as diffuse large B-cell lymphoma (DLBCL). After establishing the diagnosis, the patient received antiretroviral therapy (tenofovir, lamivudine, lopinavir, ritonavir) and courses of chemotherapy according to the CHOP regimen (cyclophosphamide, vincristine, doxorubicin, prednisone) combined with rituximab. The treatment resulted in a marked local tumor regression in the chest and left axilla. During the lymphoma therapy numerous complications were observed. Psychologically, the patient was very optimistic until the last chemotherapy cycle. He died after the fifth cycle. Conclusion The decision to start chemotherapy and HAART should be taken individually for every patient. Unfortunately, despite the recent advances in therapy, the prognosis in HIV-positive patients with lymphomas remain poor.
key words HIV, HAART, diffuse large B-cell lymphoma
address Jacek Czepiel Department of Infectious Diseases, Chair of Gastroenterology, Hepatology and Infectious Diseases Medical College, Jagiellonian University Śniadeckich 5 Str • 31-501 Krakow • Poland tel: 048124247349; fax: 048124247380 e-mail: [email protected] 22
We report no conflicts of interest.
HIV&AIDS R E V I E W
Background Advances in HIV therapy have resulted in the prolonged survival of HIV-positive patients and also in an increased prevalence of HIV-associated diseases, such as lymphomas. Lymphomas develop in approximately 6% of HIVpositive patients, who are estimated to have a 100-200-fold higher risk of lymphoma and as much as a 1000-fold higher risk of primary cerebral lymphoma (PCL). Lymphoma is the second most prevalent malignancy related to the HIV infection. It usually develops in the later phase of the HIV infection, when CD4 levels fall below 200 cells/ul. The risk of lymphoma increases with the duration of the infection. Three years after contracting the infection it is estimated to be 0.8% per year, while 8 years on it can reach as much as 2.6% per year. Clinical manifestation of lymphomas in HIV-positive patients is variable and may range from small lesions, through fever, to rapidly enlarging lymph nodes. Over 90% of patients have extranodal lesions and virtually every organ can be affected by lymphoma. The most frequent extranodal locations include the central nervous system (CNS), which is affected in approximately 30% of patients. The progression of PCL is associated with rapid development of neurological signs and symptoms, most often headaches, behavioral abnormalities and focal symptoms (1, 2). Diagnosis is based on histological examination of the affected lymph node or organ. According to the WHO, lymphomas in HIV-positive patients are classified into 3 main categories. The first category includes lymphomas, which may also be present in immunocompetent patients, such as Burkitt’s lymphoma, or a diffuse large B-cell lymphoma (DLBCL). The second category comprises lymphomas typical for HIV-positive patients, such as primary effusion lymphoma (PEL) or plasmablastic lymphoma. The third category includes lymphomas prevalent in immunosuppressed patients regardless of the cause of decreased immunity, such as B-cell lymphomas. The most prevalent lymphoma in HIV-positive patients is DLBCL (1, 2).
Case report Patient T.R., age 33, was admitted to our Department because of lymphoma that developed in the course of an HIV infection. The HIV infection had been diagnosed 3 years before the current hospitalization, and the CD4 level was 120 cells/ul at that time. At the time of the initial diagnosis the patient started antiretroviral therapy, but then decided to stop after 6 months during the period of effective immunological reconstitution. For the subsequent 3 years the patient did not report to a physician. Two months before his current hospitalization he developed an enlarged lymph node in the left axilla, which then substantially increased in diameter reaching 12 cm. Subsequently he developed an infiltrate of the chest skin. The enlarged lymph node was sampled, and in a microscopic evaluation it was diagnosed as high-grade DLBCL, IHC: CD20 (+), CD3 (-), bcl 2 (-), Ki67 (+) > 95 cells. Chest CT scans revealed a very large pathological mass, most probably emerging from the lymph nodes, located on the level of the left axilla, associated with lymphatic retention in the upper half of the chest and upper part of the left arm and pleural effusion on the right. In the abdomen, conglomerates of the enlarged
lymph nodes up to 20 mm in diameter were found, together with signs of mesenteric infiltrates and a substantial thickening of soft tissues (photos 1 and 2). After establishing the diagnosis, the patient received antiretroviral therapy (tenofovir, lamivudine, lopinavir, ritonavir) and courses of chemotherapy according to the CHOP regimen (cyclophosphamide, vincristine, doxorubicin, prednisone) combined with rituximab. Before chemotherapy the CD4 level was 3956 cells/mm3, which was 30% of CD3 cells; the high CD4 level being associated with the malignant process. The patient received five chemotherapy cycles. The treatment resulted in a marked local tumor regression in the chest and left axilla (photo 3). During the lymphoma therapy numerous complications were observed, including skin ulcerations over the tumor surface, diarrhea and stomatitis. Myelosuppression developed after each chemotherapy cycle. The suppression was most marked in the lymphocyte counts, and on days 7–9 after the cycle they reached 100-300 cells/mm3, although anemia and thrombocytopenia were less marked. Leukopenia was treated with filgrastim whilst antibiotic (ceftriaxone) and antifungal (fluconazole) therapy was also instituted. The erythrocyte and platelet counts improved spontaneously to satisfactory levels after approximately 7 days, and the stomatitis was treated with chlorhexidine. The patient’s reaction to every subsequent chemotherapy cycle became worse and he developed cachexia and asthenia. Psychologically, the patient was very optimistic until the last chemotherapy cycle. He died after the fifth cycle.
Discussion Pathogenesis of lymphoma development in the course of an HIV infection is complex and not fully understood. Key risk factors are low CD4 levels, a high HIV load and advanced age. The main factor enhancing the development of malignancy is clonal B-cell proliferation, which is a consequence of stimulation with viral antigens. The duration of the HIV infection is directly related to the increased risk of lymphoma. The prognosis of patients with AIDS-related lymphoma (ARL) is generally poor, although some patients have markedly better treatment outcomes. CD4 levels at diagnosis seem to be the main prognostic factor and higher counts are associated with a better prognosis (1, 3). In the case of our patient, a most notable feature was his willful interruption of antiretroviral treatment, which must be categorically implicated in shortening his chances of survival. Properly instituted antiretroviral therapy decreases the patient’s HIV load and enables immunological reconstitution. Patients with low viral load and high CD4 counts have a lower risk of lymphoma than persons with high HIV loads and low CD4 levels. ART discontinuation in our patient was not caused by poor tolerance of treatment. His reaction to treatment was indeed very good, which fostered his opinion that the disease was not dangerous and could be easily controlled. The patient willfully decided to stop the treatment and planned to start it again if the disease progressed further. It must be noted, that many clinicians taking care of HIV-positive patients also describe such patient attitudes. This issue is another challenge to the efforts being made to achieve good treatment results for HIV infections. An optimal method of treatment of lymphomas in HIVpositive patients has not been established so far. Many regimens are used in these patients (Kaplan et al., 1989; volume 9 • number 1 • 2010
23
HIV&AIDS R E V I E W Gisselbrecht et al, 1993; Fischer et al, 1993, Costello et al, 2004; Sparano et al, 2004) and the CHOP regimen (cyclophosphamide, vincristine, doxorubicin, prednisone), used as a standard therapy in HIV-positive patients, seems to be the most promising of them. Clinicians treating lymphomas in HIV-positive patients encounter two major challenges. The first is the unsatisfactory complete remission (CR) rates, which result from the aggressive course of lymphoma, and the second is chemotherapy toxicity, which is higher than in HIV-negative patients. Higher toxicity results from the concomitant use of ART as well as from advanced AIDS (4–8). As the use of standard CHOP doses in HIV-positive patients caused numerous side effects, some authors attempted to use lower doses of chemotherapy (Tirelli et al, 1992; Kaplan et al, 1997). Positive effects of such therapy were observed in the early stages of AIDS. Kaplan compared the use of the m-BACOD regimen (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with standard and reduced drug doses and achieved similar CR rates (42% vs 41%), as well as lower toxicity levels associated with reduced doses (9, 10). However, Ratner et al., 2001, observed, that the use of lower drug doses in the CHOP regimen resulted not only in lower CR rates (30% vs 48%) but also in a shorter CR duration (11). The GELA-GICAT Group conducted a study including 485 HIV-positive patients with lymphomas. They compared CHOP, low dose CHOP (Ld-CHOP) and ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimens. The results of treatment were better in the CHOP group compared to the Ld-CHOP (49% vs 32%). Notably, the 5-year overall survival rate (OS) was slightly higher in the CHOP group compared to Ld-CHOP (28% vs 24%) (12). In view of the aggressive course of lymphomas in the course of an HIV infection and unsatisfactory CR rates after standard regimens, more intensive therapy has been considered. Several studies reported the beneficial effects of using higher drug doses in the CHOP regimen (Tilly et al, 2003; Mounier et al, 2007; Reyes et al, 2005), but in view of the high toxicity of such therapy it is still being debated. In a treatment of our patient we used standard CHOP doses. Despite the young age of the patient and lack of comorbidities except for the HIV infection and lymphoma, the drug toxicities could not be avoided. The use of higher chemotherapy doses in this patient would probably have led to even more toxicities. Perhaps the end result of lymphoma treatment would be better if the patient had had less advanced AIDS, which would have enabled us to use more intensive lymphoma therapy (13–15). In recent years, based on results of lymphoma treatment in HIV-negative patients and because the majority of lymphomas in HIV-positive patients are CD20-positive, rituximab has been used in such patients. Rituximab is a chimeric murine/human monoclonal antibody which blocks lymphocyte CD20 surface receptors. Studies completed to date have reported the beneficial results of treatment with this agent. In the study by Spina et al., 70% of patients achieved CR, the 2-year OS was 64% and 2-year event-free survival (EFS) was 52%. In the study by Boue et al., 67% of patients achieved CR, 10% achieved partial remission (PR), the 2-year OS was 75%, and 2-year EFS was 65%. The only randomized study completed so far (Kaplan et al. 2005); compared the efficacy of CHOP and R-CHOP regimens. CR in the R-CHOP group was 57%, and in the CHOP group it was 47% (16–18). HAART (highly active antiretroviral therapy) is an important element of therapy of HIV-positive patients with 24
volume 9 • number 1 • 2010
lymphoma and results in marked benefits (Gabarre et al. 1995, Retner et al. 2001, Powles et al. 2002) (11, 19, 20). Baiocchi et al. reported six-fold longer survival times in the group of patients with ARL, receiving HAART compared to the group in which HAART was not used (21). However, antiviral drugs which may cause myelosuppression, and particularly AZT, should be avoided (11, 19, 20). Little et al. assessed the effects of withholding HAART until the end of chemotherapy treatment. Such an approach was beneficial and resulted in lower toxicity rates in patients with CD4 levels >100 cells/ul, while in patients with CD4 levels < 100 cells/ul, the course of AIDS worsened and opportunistic infections developed. In summarizing the above reports, one can say that the risk of increased toxicities in patients treated for lymphomas and who are receiving HAART is slightly higher than in HIV-negative patients, and delayed introduction of HAART may only be considered in the early phase of AIDS. In patients with very low CD4 levels (< 100 cells/ul), delayed HAART negatively affects the prognosis. Although the use of HAART increases the toxicities of therapy and mandates close monitoring, its concomitant use with chemotherapy seems indispensable in HIV-positive patients (22).
HIV&AIDS R E V I E W
Conclusion The decision to start chemotherapy and HAART should be taken individually for every patient. The patient’s performance status, age, phase of HIV infection and stage of lymphoma should be considered. Such an individualized approach allows one to achieve the best possible CR with the minimum adverse effects. Unfortunately, despite the recent advances in therapy, the prognosis in HIV-positive patients with lymphomas remains poor.
References 1. Grogg KL, Miller RF, Dogan A. HIV infection and lymphoma. J Clin Pathol 2007; 60: 1365–72. 2. Lim F, Abdalla SH. Interactions between HIV infection and lymphoplasmacytoid lymphoma: Leukemia & Lymphoma 2006; 47: 163–6. 3. Bower M, Gazzard B, Mandalia S, Newsom-Davis T, Thirlwell C, Dhillon T et al. A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of Highly Active Antiretroviral Therapy. Ann Intern Med 2005; 143: 265–73. 4. Kaplan LD, Abrams DI, Feigal E, McGrath M, Kahn J, Neville P. AIDS-associated non-Hodgkin’s lymphoma in San Francisco. JAMA 1989; 261: 719–24. 5. Gisselbrecht C, Oksenhendler E, Tirelli U, Lepage E, Gabarre J, Farcet JP et al. Human immunodeficiency virus-related lymphoma treatment with intensive combination chemotherapy. French-Italian Cooperative Group. Am J Med 1993; 95: 188–96. 6. Fischer RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. NEJM 1993; 328: 1002–6. 7. Costello RT, Zerazhi H, Charbonnier A, de Colella JM, Alzieu C, Poizot-Martin I et al. Intensive sequential chemotherapy with hematopoietic growth factor support for nonHodgkin lymphoma in patients infected with the human immunodeficiency virus. Cancer 2004; 100: 667–76.
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