HIV-associated non-Hodgkin Lymphoma Research Articles

Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated non-Hodgkin lymphoma: pooled results from 3 phase 2 trials

AbstractEvidence suggests that infusional therapy is a more effective means for administering cytotoxic therapy than intravenous bolus therapy for lymphoma and offers greater potential for therapeutic synergy with rituximab, which has a long half-life. We pooled the results of 3 prospective phase 2 trials evaluating rituximab in combination with 96-hour infusion of cyclophosphamide (187.5-200 mg/m2 per day), doxorubicin (12.5 mg/m2 per day), and etoposide (60 mg/m2 per day) (R-CDE) plus granulocyte–colony-stimulating factor (G-CSF) in 74 patients with HIV-associated, B-cell non-Hodgkin lymphoma, of whom 56 (76%) patients received concurrent highly active antiretroviral therapy (HAART). The complete remission (CR) rate was 70% (95% confidence interval [CI], 59%-81%), and the estimated 2-year failure-free survival and overall survival rates were 59% (95% CI, 47%-71%) and 64% (95% CI, 52%-76%), respectively. Ten (14%) patients had opportunistic infections during or within 3 months of the end of R-CDE, and 17 (23%) patients developed nonopportunistic infections after that time. Six (8%) patients died because of infection; 2 (3%) of those infections were bacterial sepsis during R-CDE, and 4 (5%) were opportunistic infections that occurred between 2 and 8 months after the completion of R-CDE. R-CDE produced a 70% CR rate and a 59% 2-year failure-free survival rate in patients with HIV-associated lymphoma. Consistent with other reports, adding rituximab to cytotoxic therapy in this population may increase the risk for life-threatening infection. Further studies evaluating rituximab in combination with infusional chemotherapy are warranted, but caution is advised.

Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas

AbstractThe treatment of HIV-associated lymphoma has changed since the widespread use of highly active antiretroviral therapy. HIV-infected individuals can tolerate more intensive chemotherapy, as they have better hematologic reserves and fewer infections. This has led to higher response rates in patients with HIV-associated Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) treated with chemotherapy in conjunction with antiretroviral therapy. However, for patients with refractory or relapsed disease, salvage chemotherapy still offers little chance of long-term survival. In the non-HIV setting, patients with relapsed Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) have a better chance of long-term remission with high-dose chemotherapy with autologous stem cell rescue (ASCT) compared with conventional salvage chemotherapy. In a prior report we demonstrated that this approach is well tolerated in patients with underlying immunodeficiency from HIV infection. Furthermore, similar engraftment to the non-HIV setting and low infectious risks have been observed. Herein, we expand upon this early experience with the largest single institution series of 20 patients. With long-term follow-up we demonstrate that ASCT can lead to an 85% progression-free survival, which suggests that this approach may be potentially curative in select patients with relapsed HIV-associated HD or NHL.

Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma

We demonstrated that highly active antiretroviral therapy (HAART) increases the toxic effect of cyclophosphamide, vincristine, doxorubicin (DOX) and prednisone (CHOP) in HIV-patients with non-Hodgkin's lymphoma (NHL). To ascertain the cause of increased toxicity, we investigated the pharmacokinetics of DOX in HIV-patients with NHL treated with CHOP with and without HAART. Complete pharmacokinetics and pharmacodynamic analysis was determined in 19 patients during 38 cycles of chemotherapy: 19 cycles with CHOP and 19 CHOP + HAART in a crossover-designed study. HAART included protease inhibitors indinavir (IDV) in nine patients, saquinavir (SQV) hard gel in six patients and nelfinavir (NFV) in four patients. No significant effects of HAART on pharmacokinetics parameters of DOX were observed. Similarly, no differential effect on DOX pharmacokinetics among IDV, SQV, and NFV was evidenced. Significant associations (P=0.012) were observed between DOX AUC0-infinity (area under the concentration curve) and G3-G4 WHO haematologic toxicity, in patients treated with CHOP alone, but not in those treated with CHOP + HAART (P = not significant). We demonstrated that HAART therapy has no significant effect on DOX pharmacokinetics. DOX AUC appears to be a predictor of toxicity only in patients treated with CHOP alone. Other factors beside DOX plasma levels are detrimental for toxicity after CHOP + HAART. Therefore, pharmacodynamic interactions between HAART and DOX should be considered.

Anatomical site predilections of non-Hodgkin's lymphoma in Human Immunodeficiency Virus infection: A report on 54 cases

To identify and describe the primary anatomic sites of non-Hodgkin's lymphoma arising in the setting of Human Immunodeficiency Virus infection. Prospective (ongoing) study. Kenyatta National Hospital a referral and teaching hospital in Kenya. Patients (n=54) with human immunodeficiency virus with associated non-Hodgkin's lymphoma managed at the Kenyatta National hospital from January 2001 to December 2003. Relevant clinical information obtained by medical history, physical examination and investigations. Of the 54 patients studied 29(54%) were males and 25(46%) females with median age 36 and range 20 to 61 years. Fifty (93%) had high grade and four (7%) intermediate grade lymphoma, the former had 15 (30%) Burkitt's and the rest large cell lymphoma. The stages at diagnosis were IV 35(65%), III 14(26%) and II 5(9%) and all had B symptoms. The primary sites at presentation to the hospital were peripheral nodes 16(30%), abdominal 15(28%), pectoral/chest wall 11(20%), central nervous system eight (15%) and systemic/generalised, four (7%). This study demonstrates that there were preferred anatomical sites of involvement by HIV associated non-Hodgkin's lymphomas and the finding of pectoral/ chest involvement in this series may not be coincidental. Further, this study suggests that anatomical sites predilection may be due to the tendency of viral associated malignancies to home to specific anatomic sites and also due to the anatomy of the lymphoreticular system. Studying virus pathogenesis in malignancies should consider also the anatomic sites involved.

Plasmablastic lymphoma in an HIV-negative patient: a case report and review of the literature

Plasmablastic lymphoma is an HIV-associated non-Hodgkin's lymphoma primarily affecting the oral cavity and jaws. The purpose of this study is to report a case of plasmablastic lymphoma occurring in a 49-year-old HIV-negative African-American male. The patient presented with pain and swelling of the right mandible of 2 weeks duration, with a single enlarged lymph node. A computerized tomography scan revealed a destructive mass centered on the right posterior mandible. Histopathologic examination of an incisional biopsy revealed a dense diffuse lymphocytic infiltrate of noncohesive large lymphocytes with plasmacytoid features. Immunohistochemical analysis revealed positivity for the B-cell marker CD79a, Epstein-Barr virus latent membrane protein (LMP), and lambda light chain restriction; in contrast, the neoplastic cells were negative for leukocyte common antigen, CD20, CD3, CD10, Bcl-2, desmin, actin, EMA, S-100, HMB45, and cytokeratins. The final diagnosis of plasmablastic lymphoma was made with a recommendation for HIV testing, which was negative. There are 6 previously reported cases of plasmablastic lymphoma in HIV-negative patients, including 3 immunosuppressed, 2 immunocompetent, and 1 of unknown immune status. The present case represents the first reported oral plasmablastic lymphoma in an HIV-negative as well as nonimmunocompromised individual. The features of this rare disease are summarized based on a comprehensive review of the epidemiologic, clinical and immunohistochemical findings of previously reported cases.

Pathogenesis of HIV-associated non-Hodgkin lymphoma.

In the current era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated non-Hodgkin lymphoma (H-NHL) is not as high as in the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, but still remains above that of non-HIV-infected individuals. Therefore, the epidemiology suggests that the pathogenesis of H-NHL may be multifactoral, involving the interaction of the immune system with HIV or other pathogens. Although HIV is a retrovirus, it is not characterized with the typical oncogenic potential associated with insertional mutagenesis. HIV integration occurs as a necessary step in the life cycle allowing for replication and transcription of the viral genome to take place. While HIV is thought to integrate randomly, more recent studies have suggested that integration occasionally occurs in a less random fashion. While the majority of H-NHL may be secondary to immune dysfunction, this non-random integration may be a factor leading to pathogenesis of a small subset of H-NHL since the pathways involved in malignancies usually require an accumulation of abnormalities leading to proliferation and transformation. A common element among lymphomas in this setting of immune dysfunction is the inability to control a pathogen that acts as an ongoing immune activator. Thus, an increased risk of H-NHL emerges from the combination of immunodeficiency, increased immune activation and possible HIV insertional mutagenesis. The focus of this review will be on the role viral pathogenesis plays in oncogenic transformation.

Successful Treatment of Aggressive HIV-associated Non-Hodgkin's Lymphoma with Combination Chemotherapy, Biotherapy with Rituximab and HAART: Presentation of a Therapeutic Option

The incidence of non-Hodgkin's lymphoma (NHL) in individuals infected with human immunodeficiency virus (HIV) is more than 60 times higher than in matched controls. In the vast majority of cases aggressive pathological subtypes and advanced stages prevail, extranodal sites are involved and systemic symptoms are present. The prognosis of HIV-NHL remains poor and the optimal therapeutic approach has yet to be defined. We report a 48-year-old Ethiopian woman with advanced-stage HIV infection, who developed diffuse large cell, immunoblastic type B-cell NHL and was treated with a modified CHOP-like chemotherapy combined with Rituximab and supported with growth factor. Highly active antiretroviral therapy (HAART) and opportunistic infections prophylaxis were administered concomitantly. The patient completed 6 cycles of therapy and currently, 76 weeks after diagnosis, is in complete clinical remission. Despite the fact that there was a transient decrease in the CD4-positive cell number and a 1.5 log increase in plasma viral load there were no opportunistic infections, nor was life-threatening toxicity seen. Rituximab seems a well-tolerable and advantageous adjunct to chemotherapy and HAART in the treatment of aggressive HIV-associated NHL and should be investigated in large trials in the future.

Lymphocyte subsets and viral load in patients with HIV-associated non-Hodgkin's lymphoma treated with anti-CD20 monoclonal antibody and chemotherapy.

The anti-CD20 monoclonal antibody Rituximab is a novel antitumor agent used in association with chemotherapy (CT) for the treatment of high-grade/intermediate non-Hodgkin's lymphomas (NHL) in HIV-negative populations. This therapeutic combination is currently also being explored in HIV-positive patients with NHL (HIV-NHL). The objective of our study was to determine CD4 and CD8T cell counts, HIV plasma viremia and proviral load in patients with CD20-positive HIV-NHL treated with Rituximab plus CT and highly active antiretroviral therapy (HAART). We studied eight patients with HIV-NHL treated by anti-CD20 and CT before, after three, and after six cycles of therapy; CD4, CD8 and CD19 lymphocyte subsets were measured by monoclonal antibodies and flow cytometry. HIV plasma viremia was determined by the b-DNA assay, and proviral load by a quantitative competitive PCR. CD4T cell counts remained stable after three cycles of therapy, while a significant reduction of this subset was present at the end of therapy. HIV plasma viremia was significantly reduced after the third cycle, but returned to pretreatment levels at the end of therapy; we also observed individual fluctuations of proviral load during therapy, this marker being increased in two out of three patients at the end of therapy. These observations suggest that Rituximab plus CT accelerated the rate of CD4 depletion and of HIV replication in the peripheral blood of HIV-NHL patients and that HAART may be able to delay these effects.

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide (CDE) plus the anti-CD20 monoclonal antibody (rituximab) in HIV-associated non-Hodgkin's lymphoma (NHL). Preliminary results of an international multicentre trial

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide (CDE) plus the anti-CD20 monoclonal antibody (rituximab) in HIV-associated non-Hodgkin's lymphoma (NHL). Preliminary results of an international multicentre trial

No Increased Human Herpesvirus 8 Seroprevalence in Patients With HIV-Associated Non-Hodgkin's Lymphoma

No Increased Human Herpesvirus 8 Seroprevalence in Patients With HIV-Associated Non-Hodgkin's Lymphoma

Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-related non-Hodgkin lymphoma.

Unlike aggressive non-Hodgkin lymphoma (NHL), Hodgkin disease (HD) develops rarely in patients who are infected by human immunodeficiency virus (HIV), and its characteristics are not well defined. The authors analyzed the clinicopathologic and prognostic features from a consecutive series of patients with HIV-associated HD who were observed at their institution and compared them with the features observed in a concurrent series of patients with systemic HIV-related NHL. Eighteen patients with HIV infection who were diagnosed and treated uniformly from 1985 to 1999 at a single primary referral center were analyzed. Their demographic, immunologic, and clinicopathologic features; responses to treatment; and outcomes were compared with those of 98 patients with systemic NHL of aggressive histology who were diagnosed during the same period and with 165 HIV negative patients with HD. HIV-associated HD and NHL occurred in patients with similar age, gender, HIV risk factors, degree of immunodeficiency, and incidence of previous acquired immunodeficiency syndrome. The clinical presentation of HIV-associated HD was atypical and was more aggressive than in HIV negative patients (mediastinal involvement, 11%; Stage III-IV, 84%; B symptoms, 83%). It was similar to HIV-related NHL, except for the frequency of extralymph node disease, which was seen less frequently in patients who had HD (56%) compared with patients who had NHL (82%; P = 0.025), and the frequency of bone marrow involvement, which was unexpectedly higher in patients who had HD (50%) compared with patients who had NHL (20%; P = 0.011). Potentially curative treatment was administered to 77% of patients with HD and 66% of patients with NHL. Complete remission and disease recurrence rates as well as disease free and overall survival rates did not differ significantly, with estimated overall survival at 5 years of 24% in patients with HD and 23% in patients with NHL. HIV-associated HD is an aggressive disease with demographic, clinical, and prognostic features nearly identical to those of HIV-related NHL.

Trends in non-Hodgkin lymphoma (NHL) and HIV-associated NHL deaths in the United States.

Since a significant number of lymphomas have been associated with the human immunodeficiency virus (HIV), the purpose of this study was to describe the impact of HIV infection on non-Hodgkin's lymphoma (NHL) mortality trends and demographics. Multiple-cause-of-death data for the United States from 1979 through 1996 were obtained from the National Center for Health Statistics, Centers for Disease Control and Prevention. Annual NHL deaths rates for the United States were calculated as the number of NHL deaths per 100,000 persons, based on estimates of the U.S. resident population. The time periods 1979-1982, 1986-1989, and 1993-1996 were examined for changes over time. To describe NHL and HIV infection mortality, the characteristics of NHL deaths with HIV infection listed anywhere on the death records were examined beginning in 1987. This study found that despite reports of a lower incidence rate of NHL among blacks with HIV/AIDS, death rates from lymphomas associated with HIV/AIDS have markedly increased in black males and females over time. It was also noted that in agreement with other studies, this study documented a decrease in NHL/HIV mortality in 1996.

High dose therapy and autologous stem cell transplantation for human immunodeficiency virus‐associated non‐Hodgkin lymphoma in the era of highly active antiretroviral therapy

BACKGROUND The advent of highly active antiretroviral therapy (HAART) has allowed the exploration of more dose-intensive therapy such as autologous stem cell transplantation (ASCT) in selected patients with human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL). METHODS The authors report on the use of myeloablative chemotherapy with ASCT in two HIV positive patients with NHL. The first patient underwent ASCT at the time of first disease remission for poor risk, diffuse, large cell NHL and the second patient had multiply recurrent, chemosensitive Burkitt lymphoma. ASCT was performed in both patients using a transplant conditioning regimen of high dose cyclophosphamide, carmustine, and etoposide (CBV). RESULTS The target dose of ≥ 5 × 106/kg CD34 positive peripheral blood stem cells (PBSC) utilized for ASCT was collected using granulocyte-colony stimulating factor (G-CSF) after chemotherapy for mobilization while both patients were receiving concomitant HAART for HIV infection. HAART was continued during CBV conditioning. Prompt hematopoietic recovery was observed after ASCT. Both patients remained in clinical disease remission from their lymphoma at 28 months and 20 months after transplant, respectively. CONCLUSIONS ASCT is feasible in patients with HIV-associated NHL. Adequate numbers of CD34 positive PBSC can be procured from patients receiving HAART and chemotherapy for NHL. Selected patients with HIV-related lymphoma can tolerate the high dose CBV myeloablative chemotherapy regimen without increased acute regimen-related toxicity. Reinfusion of G-CSF-mobilized PBSC can lead to rapid recovery of hematologic function and sustained engraftment after ASCT. Given the poor prognosis of patients with HIV-associated NHL treated with conventional chemotherapy, further investigation of this approach should be considered. Cancer 2000;89:680–9. © 2000 American Cancer Society.

High dose therapy and autologous stem cell transplantation for human immunodeficiency virus-associated non-Hodgkin lymphoma in the era of highly active antiretroviral therapy

The advent of highly active antiretroviral therapy (HAART) has allowed the exploration of more dose-intensive therapy such as autologous stem cell transplantation (ASCT) in selected patients with human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL). The authors report on the use of myeloablative chemotherapy with ASCT in two HIV positive patients with NHL. The first patient underwent ASCT at the time of first disease remission for poor risk, diffuse, large cell NHL and the second patient had multiply recurrent, chemosensitive Burkitt lymphoma. ASCT was performed in both patients using a transplant conditioning regimen of high dose cyclophosphamide, carmustine, and etoposide (CBV). The target dose of >/= 5 x 10(6)/kg CD34 positive peripheral blood stem cells (PBSC) utilized for ASCT was collected using granulocyte-colony stimulating factor (G-CSF) after chemotherapy for mobilization while both patients were receiving concomitant HAART for HIV infection. HAART was continued during CBV conditioning. Prompt hematopoietic recovery was observed after ASCT. Both patients remained in clinical disease remission from their lymphoma at 28 months and 20 months after transplant, respectively. ASCT is feasible in patients with HIV-associated NHL. Adequate numbers of CD34 positive PBSC can be procured from patients receiving HAART and chemotherapy for NHL. Selected patients with HIV-related lymphoma can tolerate the high dose CBV myeloablative chemotherapy regimen without increased acute regimen-related toxicity. Reinfusion of G-CSF-mobilized PBSC can lead to rapid recovery of hematologic function and sustained engraftment after ASCT. Given the poor prognosis of patients with HIV-associated NHL treated with conventional chemotherapy, further investigation of this approach should be considered.

Intensive Chemotherapy (LNHIV-91 Regimen) and G-CSF for HIV Associated Non-Hodgkin's Lymphoma

The purpose of the study was to evaluate the safety and long-term efficacy of an intensive chemotherapy regimen associated with G-CSF in HIV-associated non-Hodgkin's lymphoma (NHL). Fifty two consecutive patients with HIV infection, agressive NHL and CD4+ cells ≥ 100 × 106/1 were included. The median CD4 cell count was 276 × 106/1. Nineteen tumors were of the Burkitt's type, 23 were large cells, 7 immunoblastic, and 3 anaplastic. Twenty-five patients had stage IV disease (bone marrow involvement in 7, and central nervous system in 9). Three cycles of ACVBP (doxorubicine, cyclophosphamide, vindesine, bleomycin, prednisolone) were given. A fourth cycle was delivered to patients in partial remission or with initial bulky disease. The induction was followed by three cycles of CVM (cyclophosphamide, etoposide, methotrexate). G-CSF 5 μ/kg was used at each cycle. Results showed that 37 patients (71%) achieved a complete remission. With a median follow-up of 74 months, 8 of them have relapsed. The median survival was 15 months and 34 patients have died (21 with NHL). The 4-year estimate survival was 33,9% (95% CI, 19,8%–47,4%). The Relative Dose-Intensity of the chemotherapy was 85% for doxorubicine and 87% for cyclophosphamide. In a multivariate analysis, homosexual men and patients with ECOG < 2 had a lower risk for death: RR = 0,32 (95% CI, 0,15–0,65) and RR = 0,36 (95% CI, 0,18–0,74), respectively. Achievement of complete remission was strongly associated with survival. In conclusion, it seems that in HIV-infected patients with NHL and a CD4 cell count above 100 × 106/1, high complete remission rate and prolonged survival can be achieved with the intensive LNHIV-91 regimen.

Advances in the epidemiology of HIV-associated non-Hodgkin's lymphoma and other lymphoid neoplasms.

The spectrum of HIV-related lymphoid malignancies certainly includes non-Hodgkin's lymphoma (NHL; i.e., chiefly large-cell lymphoma and Burkitt's lymphoma), primary lymphoma of the brain (PBL) and, possibly, Hodgkin's disease (HD). Since the mid-1990s, several epidemiological studies have led to better quantification of the burden of lymphomas in HIV-infected populations. AIDS surveillance data from 17 western European countries show that between 1988 and 1997 a total of 7,148 AIDS cases had NHL as the AIDS-defining illness. The yearly number of cases rose steadily from 1988 to 1995 but declined thereafter. As a percentage of AIDS-defining illnesses, NHL increased from 3.6% in 1994 to 4.9% in 1997. Percent increases were observed in different strata by area, age group, sex and HIV-transmission group. To estimate relative risk (RR) of NHL and other lymphoid neoplasms in unselected HIV-seropositive populations, records of population-based cancer registries and AIDS registries were linked in the United States, Italy and Australia. RRs for NHL in adults with HIV/AIDS ranged between 14 (for low-grade NHL) to over 300 (for high-grade NHL). For HD, the RR was approximately 10. Limited findings from studies based on death certificates and cohorts of HIV-seropositive persons were consistent with those from registry linkage studies. In developing countries, the risk of HIV-associated NHL appears to be much lower than in developed countries, but under-ascertainment and earlier death from other AIDS manifestations may explain the lack of HIV-associated lymphomas in Africa.

Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-Hodgkin lymphoma

Central nervous system involvement is a common manifestation of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)-infected individuals. The purpose of this study was to review the frequency and pattern of neurologic manifestation of lymphoma in a cohort of HIV-infected individuals with systemic NHL. Sixty-two patients with HIV-associated systemic NHL received infusional cyclophosphamide, doxorubicin, and etoposide. Five patients with lymphomatous meningitis at presentation received whole brain radiation therapy plus intrathecal chemotherapy (ITC). Of the remaining 57 patients, prophylactic ITC was recommended only for those patients with lymphomatous bone marrow involvement and/or high grade histology (N = 31). Thirteen patients (21%) had histologically documented (N = 6) or presumed (N = 7) central nervous system involvement, including 7 patients (11%) with meningeal lymphoma discovered either at presentation (N = 5) or soon after diagnosis (N = 2), and 6 patients (10%) with cerebral mass lesions at the time of disease recurrence consistent with parenchymal brain involvement. Five of six parenchymal brain recurrences occurred in the setting of progressive systemic disease. Four of 7 patients (57%) with meningeal lymphoma detected at presentation (N = 5) or within 3 months of presentation (N = 2) responded to therapy and survived >1 year. Of the 26 patients assigned to receive no prophylactic ITC, no patient developed an isolated meningeal recurrence and 1 patient developed an isolated parenchymal brain recurrence. The findings of the current study suggest that in patients with HIV-associated systemic lymphoma, meningeal lymphoma is potentially curable, parenchymal brain recurrence usually occurs in the setting of uncontrolled systemic disease, and prophylactic ITC may not be necessary for patients with intermediate grade histology and uninvolved bone marrow.

Dose-Adjusted EPOCH Chemotherapy (CT) in Previously Untreated HIV-Associated Non-Hodgkin's Lymphoma (HIV-NHL): Preliminary Report of Efficacy, Immune Reconstitution, and HIV Control Following Therapy.

Dose-Adjusted EPOCH Chemotherapy (CT) in Previously Untreated HIV-Associated Non-Hodgkin's Lymphoma (HIV-NHL): Preliminary Report of Efficacy, Immune Reconstitution, and HIV Control Following Therapy.

PILOT TRIAL OF SAQUINAVIR AND NUCLEOSIDE ANALGOGUES PLUS INFUSIONAL CYCLOPHOSPHAMIDE, DOXORUBICIN, AND ETOPOSIDE IN PATIENTS WITH HIV-ASSOCIATED NON-HODGKIN'S LYMPHOMA

78 Background: The purpose of our trial was to determine the feasibility of combining the PI saquinavir with a 96 hour continuous intravenous infusion of cyclophosphamide (800 mg/M2), doxorubicin (50 mg/M2), and etoposide (240 mg/M2) (CDE) plus filgrastim and nucleoside analogue therapy in patients with HIV-associated non-Hodgkin's lymphoma (NHL). Methods: Twelve patients with HIV-NHL received CDE every 28 or more days. All patients received saquinavir (600 mg PO TID), filgrastim and Pneumocystis carinli and fungal prophylaxis. Patients also received either stavudine (N = 2) or both stavudine and didanosine (N = 10). Toxicity was analyzed using the NCI Common Toxicity Criteria for each cycle and the data were compared with the data from our prior study of CDE plus didanosine (J Clin Oncol 1997; 14: 3026). Results: The characteristics of the patient population (including baseline renal function, liver function, and proportion with lymphomatous liver involvement) were comparable to our prior report of CDE without saquinavir. The median CD4 count was 45/uL (3-310/uL). Severe (grade 3 or 4) mucositis occurred in 8/12 patients (67%) treated with CDE plus saquinavir compared with 3/25 patients (12%) treated without saquinavir (P < 0.001). In logistic regression analysis, saquinavir use was the only factor associated with a significantly greater risk of severe mucositis (relative risk 7.9; P = 0.03), but had no effect on the incidence of febrile neutropenia, the neutrophil or platelet nadir, or the duration of severe neutropenia. The decrease in CD4 lymphocytes for patients treated with saquinavir (absolute decrease of 23/μL; 26% decrease from baseline) was significantly less than those treated without saquinavir (absolute decrease of 91/μL; 42% decrease [P = 0.05]). Four of 10 patients (40%) treated with saquinavir had an increase in CD4 count of ≥ 10/μL versus 0/25 (0%) treated without saquinavir (P < 0.001). Conclusions: Combination of the PI saquinavir with infusional CDE was associated with a significant increase in the incidence of severe mucositis, suggesting that the PIs may alter the metabolism of one of more of the cytotoxic agents in the CDE regimen. This effect may be specific for infusional therapy, and may not apply to more conventional lymphoma regimens given in as IV bolus injection. Further investigation regarding a potential pharmacokinetic interaction is warranted.

Opportunistic Infection and Immunologic Function in Patients with AIDS-Associated Lymphoma Treated with Chemotherapy

The incidence of systemic non-Hodgkin's lymphoma (NHL) is higher in the human immunodeficiency virus (HIV)-infected population than in the uninfected population. Standard treatment for this cancer involves the administration of systemic chemotherapy. Our objective was to determine the relative risk of opportunistic infection and the relative change in immunologic function in a cohort of patients who had HIV-associated non-Hodgkin's lymphoma(NHL) and who were treated with combination chemotherapy compared with a matched cohort of control subjects who had advanced HIV infection but no signs of NHL. We performed a case-control study in which the clinical course of each patient with HIV-associated NHL (N = 43; case subjects) treated with infusional cyclophosphamide, doxorubicin, and etoposide (CDE) was compared with that of two patients with HIV infection but without lymphoma that were matched for CD4 count and prior opportunistic infection (N = 86; control subjects). Univariate and multivariate analyses were performed to determine whether any of a number of confounding factors (e.g. age, sex, CD4 count, prior opportunistic infection, and prior antiretroviral therapy) could have influenced the risk of developing a first infectious event(defined as opportunistic infection or non-lymphoma death). In the multivariate analysis, being a case subject (RR 2.1, 95% CI = 1.2, 3.6;P <.01), having a low CD4 count (RR 2.1, 95% CI = 1.2, 3.9;P <.05), and being female (RR 3.0, 95% CI = 1.8, 5.6; P <.001) were the only characteristics associated with an increased risk of a first event. In the univariate analysis, other factors associated with an increased risk included prior Pneumocystis carinii pneumonia, any prior opportunistic infection, and prior antiretroviral therapy. When the mean CD4 lymphocyte count at one year was compared with baseline, there was a significantly greater decrease in the CD4 count among case subjects than among control subjects (mean decrease 99/uL ∟+ SD 138/uL| versus 29/uL∟+ SD 100/uL; P = .03). Treatment of HIV-associated NHL patients with a nonsteroid containing chemotherapy regimen was associated with a significant and sustained reduction in the CD4 lymphocyte count and a two-fold increase in the risk of developing opportunistic infection. Oncologists and other physicians who treat patients with HIV-associated NHL should be familiar with the prophylaxis, recognition, and management of opportunistic infection. In addition, there is a need to identify effective strategies for the amelioration of chemotherapy-induced immunosuppression in this population.