QJM Advance Access originally published online on November 3, 2006
QJM 2006 99(12):811-826; doi:10.1093/qjmed/hcl115
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AIDS-related non-Hodgkin's lymphoma in the first decade of highly active antiretroviral therapy
From the Department of Oncology, Chelsea & Westminster Hospital, London, UK
Address correspondence to Dr M. Bower, Department of Oncology, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. email: m.bower{at}ic.ac.uk
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Summary |
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Top
Summary
IntroductionHighly active antiretroviral therapy (HAART) has had a dramatic effect on the natural history of HIV disease, reducing the incidence of opportunistic infections and Kaposi's sarcoma, and improving overall survival. Since HAART became available in 1996, the incidence of AIDS-related non-Hodgkin's lymphoma (NHL) has fallen, and although there has been no change in the clinical features at presentation, the overall survival of patients with AIDS-related NHL has improved. Prognosis is now determined chiefly by lymphoma-associated factors similar to those in the general population (the International Prognostic Index), although serum CD4 count at lymphoma diagnosis is an additional independent prognostic factor. The management of patients with AIDS-related NHL with either infusional chemotherapy or CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine and prednisolone) achieves response and survival rates approaching those observed in the general population. However, careful attention should be paid to central nervous system chemoprophylaxis, opportunistic infection prophylaxis and potential drug interactions between cytotoxic and antiretroviral therapies. In the era of HAART, the goal of therapy for these patients is now complete remission rather than palliation.
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Introduction |
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Acquired immunodeficiency syndrome (AIDS) following infection with human immunodeficiency virus (HIV), was brought to the world's attention in 1981 with the first case reports of Pneumocystis carinii (now known as P. jirovecii) pneumonia in homosexual men in Los Angeles.1 These reports were quickly followed by descriptions of Kaposi's sarcoma in similar patient groups.2,3 There followed a cornucopia of opportunistic infections and isolated reports of high-grade B-cell non-Hodgkin's lymphomas (NHL), both primary cerebral lymphomas and systemic NHL. By 1985, high-grade B-cell NHL was included along with Kaposi's sarcoma as an AIDS-defining illness by the Centre for Disease Control (CDC) following the publication of a series of 90 homosexual men with NHL.4–8 A final AIDS-defining malignancy, invasive cervical cancer, was added as an AIDS-defining illness in 1993, although the incidence of this malignancy is not increased as dramatically in HIV-seropositive women.9 A number of other cancers occur at an increased frequency in people with HIV infection but are not AIDS-defining; these include Hodgkin's disease, anal cancer, lung cancer10 and testicular seminoma.11 In Africa, and particularly Sub-Saharan Africa where the burden of HIV infection is the greatest, AIDS-related lymphoma is an increasing cause of morbidity and mortality.12 In these economically developing countries, the diagnosis and management of AIDS-related lymphoma presents particular challenges and problems for clinicians given the ‘environment of extreme scarcity‘.13 These clinical challenges include access to HAART, drugs for the prevention and management of opportunistic infection, access to intravenous chemotherapy and the availability of supportive therapy required during chemotherapy such blood transfusion.14
This review deals with HIV-associated non-Hodgkin's lymphoma and the changes that have occurred in its management in the first decade of highly active antiretroviral therapy (HAART).
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Highly active antiretroviral therapy (HAART) |
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The introduction of highly active antiretroviral therapy (HAART) during the mid-1990s in developed market economies has altered the natural history of HIV infection, and has resulted in a fall in the incidence of both opportunistic infection and AIDS-associated malignancies.
The development of effective antiretroviral therapies commenced with the introduction of nucleoside reverse transcriptase inhibitors starting with zidovudine in 1987. Since then, three new classes of antiretroviral agents have been introduced: protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, atazanavir), non-nucleoside reverse transcriptase inhibitors (nevirapine, delaviridine, efavirenz) and fusion inhibitors (enfurvirtide). The introduction of the first two classes in the late 1990s led to the use of combination highly active antiretroviral treatment (HAART). HAART has had an enormous impact on the treatment of HIV in terms of overall survival, incidence of opportunistic infections and quality of life. In randomized studies HAART leads to a dramatic decline in the mortality and morbidity of HIV.15 However, only 1 million of the estimated 42 million people infected with HIV worldwide are receiving HAART, as the majority of affected people live in developing countries.16 In addition, even in the established market economies with access to medical treatment, many individuals remain undiagnosed and consequently do not receive HAART. For the commonest AIDS-defining malignancy, Kaposi's sarcoma, HAART remains an effective therapy,17 although its effect on lymphoma is more controversial.18,19
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Epidemiology of AIDS-related systemic non-Hodgkin's lymphoma in era of HAART |
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Given the known association between NHL and both congenital and iatrogenic immunosuppression, the documentation of an increase in the incidence of NHL in the HIV-seropositive population was not surprising. Registry linkage studies in the pre-HAART era found that the incidence of NHL in HIV-positive individuals was 60–200 times higher than in a matched HIV-negative population,20,21 and the relative risk was even greater for primary cerebral lymphomas.22 There has been a significant fall in the incidence of both Kaposi's sarcoma and primary cerebral lymphoma following the introduction of HAART,23–25 which is believed to be secondary to the immune reconstitution produced by HAART.26,27 In contrast, the effects of HAART on systemic NHL are less clear,28,29 although some cohort studies suggest a modest non-significant decline in the incidence,30 including in the haemophilia population.31 An international meta-analysis of 20 cohort studies compared the incidences of systemic NHL between 1992–6 and 1997–9. There was an overall reduction in the incidence of both primary cerebral lymphoma (rate ratio 0.42) and systemic immunoblastic lymphoma (rate ratio 0.57) but not Burkitt's lymphoma (rate ratio 1.18).28 A further European epidemiological study found a significant decrease in the incidence of AIDS-defining conditions from 30.7 per 100 patient years in 1994 to 2.5 per 100 patient years in 1998. However NHL as the AIDS-defining diagnosis increased from 4% to 16% during the same time period.32
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Predictors of AIDS-related lymphoma |
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An analysis of a cohort of 7840 HIV-positive patients identified three factors in a multivariate analysis that were significantly associated with the development of systemic NHL: age, nadir CD4 cell count and no prior HAART.18 As the CD4 count falls, the development of lymphoma becomes more likely, and this may explain why there has been a decline in the incidence of NHL since the introduction of HAART. It therefore appears that the immune restoration that accompanies HAART protects against the development of HIV-related lymphoma. An update of this data using 9621 HIV-1-infected patients again found that the use of HAART protected against NHL development. Moreover, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART was found to be as protective as protease inhibitor (PI)-based HAART, and these were significantly more protective than nucleoside analogues alone (rate ratio 0.5, 95%CI 0.4–0.7) or no antiretrovirals (p < 0.001).30 With regard to other possible therapeutic interventions which might prevent HIV-related NHL, in one case-control study, administration of high-dose acyclovir (
800 mg/day), which has mild activity against Epstein Barr in vivo, for 1 year was associated with a significant reduction in the incidence of NHL.33 However, there is controversy concerning the association between serum Epstein Barr viral DNA loads and the risk of developing lymphoma.34,35 |
Clinical presentation of AIDS-related non-Hodgkin's lymphoma |
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Systemic AIDS-related lymphomas have a number of differences from NHL in the HIV-seronegative population, including: (i) presentation with advanced stage disease and B symptoms, (ii) extranodal, bone marrow and leptomeningeal involvement, (iii) plasmacellular differentiation and (iv) association with Epstein Barr virus (EBV). Central nervous system involvement is frequent in systemic AIDS-associated NHL. Leptomeningeal disease is present at diagnosis in 3–10%, and is significantly associated with Burkitt's lymphoma and both bone marrow and paraspinal or paranasal involvement.36–38 The administration of intra-thecal chemotherapy is an integral part of the management of such patients.
A number of published series have compared the clinical characteristics of AIDS-related lymphomas presenting in the pre-HAART era with those presenting in the post-HAART era. In a comparison of the clinical characteristics of 99 AIDS-related NHL patients presenting prior to 1996 with 55 cases presenting between 1996–1999, there were no differences between the two groups with regard to stage at presentation, presence of B symptoms, bone marrow infiltration or performance status.18 A French study of 145 cases reported similar results, with no significant differences at presentation with regard to gender, stage, histology, or proportion with elevated serum lactate dehydrogenase (LDH) and extranodal disease.39
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Treatment of AIDS-related non-Hodgkin's lymphoma in the era of HAART |
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In the 1980s, conventional chemotherapy schedules were used at full dosages for patients with better prognostic factors. However, the marked toxicity, in particular myelosuppression and the increased incidence of opportunistic infections, led to modifications of the standard lymphoma regimens. The subsequent development and introduction of haematopoetic growth factors allowed the introduction of more myelotoxic schedules. The appreciable death rate from opportunistic infections generally offset any decline in NHL-related deaths, and most centres persisted with either dose-reduced chemotherapy schedules or prognostic stratification that reserved full-dose therapy for only patients with the best prognostic factors.
With the advent of HAART, groups began combining HAART with cytotoxic chemotherapy; Table 1 summarizes the outcome for such regimens. However, initial reports either had HAART as optional therapy and did not report the number of patients on such treatment, or only had a proportion of patients on HAART.40,41 The first report of a series including patients treated with chemotherapy and HAART described an alternating weekly chemotherapy regime using bleomycin, etoposide, vincristine, methotrexate, prednisolone/cyclophosphamide, doxorubicin (BEMOP/CA) in patients with a good prognosis. Half were receiving HAART, and the overall 2-year survival rate was 46% (95%CI 27%–65%), with a 2-year lymphoma-specific survival of 59% (95%CI 27%–65%).41
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The feasibility of combining chemotherapy with HAART therapy was formally explored in the AIDS Malignancy Consortium 005 (AMC 005) trial, which compared CHOP chemotherapy at a reduced dose (mCHOP) or full-dose CHOP, with concomitant HAART therapy (stavudine, lamivudine, and indinavir) being given to all patients.42 This was not a randomized comparative trial, but rather two successive treatment arms. They reported overall response rates for mCHOP and full-dose CHOP of 60% (95%CI 45%–75%) and 57% (95%CI 38%–77%), respectively (p = 0.79), although the complete response rate was significantly higher in the full-dose CHOP arm (48%, as compared to 30% in mCHOP). No long-term outcome data have been reported for this group of patients. There were no significant differences in grade 3 and 4 toxicities observed in the two groups. Furthermore, HIV viral loads declined and CD4 counts increased significantly despite the concurrent use of chemotherapy, and only one opportunistic infection was reported during the trial and its follow-up period, in contrast with previous trials.40,43
These data were supported by a further study which looked at the effect of HAART on the response to treatment and survival in patients with HIV-associated NHL treated with CHOP chemotherapy, using historical controls. This revealed that patients treated with CHOP plus HAART had a higher response rate than those treated with CHOP alone (75% vs. 34%; p = 0.003). The median overall survival for those treated with CHOP alone was 7 months (range 3–10.8 months), whereas the median time was not reached in the HAART plus CHOP group (p = 0.0015). Under multivariate analysis, HAART treatment was an independent prognostic factor for complete response and overall survival.44
The authors therefore suggested that the addition of HAART to CHOP might improve the efficacy of chemotherapy, and appeared to be safe and effective. Other studies involving CHOP given with HAART have reported response rates of 47–75%, with median survival of up to 27 months and overall survivals of 58% and 55% being reported at 1 and 2 years, respectively.45–47 The substitution of liposome-encapsulated doxorubicin for conventional doxorubicin in the CHOP regimen does not appear to affect the efficacy of this treatment.46
A prospective observational study of 44 patients included 34 treated with CHOP and the remaining 10 with either m-BACOD, modified m-BACOD, methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, bleomycin (MA-COP-B) or adriamycin, cyclophosphamide, vinblastine, and bleomycin (ACVB). Eight patients in this cohort did not take HAART. The study reported a complete response in 52% of patients, with a complete response more frequently seen in those who had a virological response to HAART (70% as opposed to 30% in non-responders: OR 5.67, 95%CI 1.54–20.78). Multivariate analysis revealed that virological response to HAART was the only variable associated with tumour response (OR 6.36, 95%CI 1.56–25.81).48 This finding could be related to the fact that those who had a virological response received a significantly higher dose intensity of chemotherapy, compared to those who did not respond to HAART, due to the possible improvement in haematopoiesis given the inhibition of HIV. This enabled a greater dose density of chemotherapy to be delivered, which is a known factor in the outcome of NHL. The estimated overall survival for all patients was 360 days (95%CI 81–639), with a 1 year cumulative survival probability of 0.49; however. in the HAART-treated patients, estimated overall survival was 425 days (95%CI 241–609), with a 1 year cumulative probability of 0.51, increasing to 0.78 in those with a virological response to HAART.48
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Infusional chemotherapy: the CDE regimen |
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Preclinical data suggested that infusional schedules of cytotoxic agents might have a therapeutic advantage,49 and this is supported by clinical data such as the response of chemotherapy refractory multiple myeloma to infusional doxorubicin and vincristine,50 and the higher response rates seen in small-cell lung cancer with 5-day infusions of etoposide, as compared with a one-day regimen of the same dose.51 Two infusional chemotherapy regimens have been investigated in AIDS-related NHL, namely: cyclophosphamide, doxorubicin and etoposide (CDE) administered as a 96-h continuous infusion, and cyclophosphamide, doxorubicin, etoposide, vincristine and prednisolone (EPOCH), which will be discussed later. CDE was first found to be highly active and capable of producing durable remissions in HIV-related NHL in a small pre-HAART era study, in which CDE was administered to 12 HIV-seropositive and two HTLV-1-seropositive patients, with a complete response rate of 71% and a partial response rate of 21%. Median survival was estimated at 17.4 months, with 7 of the 12 HIV-positive patients alive and disease-free at a median follow-up of 15 months.52 A subsequent report of 25 patients with AIDS-related lymphomas treated with CDE plus didanosine produced a complete response rate of 58% (95%CI 38–78%) and a median survival of 18.4 months; this was seen as a major advance in the treatment of HIV related NHL.53 The same schedule combined with saquinavir produced similar results, although there was more mucositis with the protease inhibitor.54 A multicentre phase II trial of infusional CDE plus concurrent HAART produced far less impressive results than the earlier trials. with a reported complete response rate of 45% (95%CI 35–55%) and 2-year survival of 44% (95%CI 33–53%).55 A comparison of patients treated with CDE revealed improved overall survival with the concurrent use of HAART as compared to those in the pre-HAART group, namely those patients treated with didanosine (p = 0.039).55 Complete response rates of 50%, with a 2-year survival of 61% and median survival of 26 months, have been reported by others using this regimen.56
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Treatment of HIV-associated NHL with omission of HAART |
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The omission of HAART for the duration of chemotherapy for HIV-related NHL was examined in a trial involving a dose-adjusted chemotherapy schedule developed at the National Cancer Institute named DA-EPOCH (dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin). DA-EPOCH had previously shown a high degree of activity in HIV-negative patients with diffuse large B-cell lymphoma.57 The rationale behind interrupting HAART was to try to avert adverse drug reactions that could reduce the chance of cure. In addition, it was felt firstly that HAART would not prevent chemotherapy-induced lymphocyte depletion, secondly that the predicted HIV-dependent CD4+ cell loss during the 16-week period of HAART would be relatively small, and thirdly there was concern that HAART could inhibit lymphocyte apoptosis, and hence impact on the efficacy of chemotherapy.58 Other potential reasons to consider omission of HAART for patients receiving chemotherapy included compliance issues in the setting of polypharmacy, as well as problems with chemotherapy-induced nausea, vomiting and mucositis which may reduce ability to comply with treatment.
In 39 newly-diagnosed HIV-associated lymphomas, the reported complete remission rate was 74% (95%CI; 58–87) and at a median follow-up of 53 months, disease-free and overall survival rates were 73% and 60%, respectively. A low CD4 count (<101/mm3) and CNS involvement were associated with reduced survival.59 During treatment, patients received G-CSF support as well as prophylaxis against Pneumocystis jervecii pneumonia and Mycobacterium avium complex. Neutropenic sepsis was reported in 13% of cycles, and no new opportunistic infections were reported on chemotherapy; however, two cases of cytomegalovirus retinitis and one of Mycobacterium avium complex were reported 5–13 weeks post-treatment. There were no direct treatment-related deaths reported. Currently, EPOCH is under investigation in a multicentre study. Given that to date there have been no comparative studies, and hence there is no optimal gold-standard therapy, there are advocates of conventional CHOP, as well as supporters of infusional therapies such as CDE and EPOCH.
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Role of rituximab in the treatment of HIV-associated NHL |
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Rituximab is a chimeric monclonal antibody directed against CD20 (B1), a B-cell-specific cell-surface molecule that is involved in B cell activation and differentiation, and that is present on mature B-cells and nearly all B-cell lymphomas.60,61 Studies in immunocompetent patients with diffuse large B-cell lymphoma (DLBCL) have shown improved outcome in those receiving rituximab.62,63 Following these studies, and since 60–70% of HIV-related NHL are DLBCL, the addition of rituximab to chemotherapy has been investigated in a number of trials. The AMC Trial 010 found no significant difference between rituximab plus CHOP (R-CHOP) vs. CHOP alone for either complete response rates (57% vs. 47%; p = 0.147) or overall survival (139 weeks vs. 110 weeks; p = 0.76).47 The addition of rituximab to CDE in a Phase I/II trial involving 29 patients found a complete response rate of 86% and a partial response in a further 4%. Actuarial survival at 2 years was 80%, with median overall survival not reached at a median follow-up of 9 months.64 A subsequent pooled analysis of three prospective phase II trials involving 79 patients found a complete response of 70% (95%CI 58–81%) and an overall survival of 64% (95%CI 52–76%).65 It therefore appears that the addition of rituximab could enhance the efficacy of CDE, but there remain concerns over additional toxicity.
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Interaction between HAART and chemotherapy |
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Both NNRTIs and PIs are extensively metabolized by the cytochrome p450 system, so there is the potential for competitive drug interactions when they are administered concomitantly with other drugs metabolized through this pathway. PIs can modify the metabolism of cytotoxic drugs by inhibiting the CYP3A4 enzyme. A pharmacokinetic study of modified-dose and full-dose CHOP given with HAART (which consisted of stavudine, lamivudine and indinavir) revealed that the clearance of cyclophosphamide was reduced. This is consistent with an effect of indinavir. In contrast, no effect of mCHOP or CHOP on indinavir levels was observed.42 Another potential interaction occurs because PIs are substrates and inhibitors of the drug transporter P-glycoprotein, an efflux pump that transports a wide range of structurally unrelated drugs such as PIs and anthracyclines.66–68 Other published studies have confirmed interactions between PI containing HAART and chemotherapy. For example, CDE combined with the PI saquinavir resulted in 67% of patients developing mucositis,40 while this only occurred in 12% when CDE was administered with the nucleoside analogue didanosine.39 In addition, neutrophil counts 10 and 14 days after CDE chemotherapy were significantly lower in patients receiving PIs as compared to non-PI HAART regimens.56 The reduced hepatic metabolism of cyclophosphamide and doxorubicin due to inhibition of P450,69 and/or the increased intracellular concentration of cytotoxic agents as a result of inhibition of p-glycoprotein70,71 by PIs, probably account for the increased incidence of neutropenia seen with this group of anti-retrovirals. Despite the increase neutropenia, there is no observed increase in response with PI-based HAART, suggesting that there is no significant dose-response gradient, even if there is a significant dose-toxicity relationship.56 Thus consideration should be given where possible to the use of non-PI-based HAART in patients receiving chemotherapy for HIV-related NHL, particularly since data indicate that NNRTI-based therapy is as potent and provides durable virological control. Within the setting of high-dose chemotherapy, the pharmacokinetic effects and potential clinical ramifications of the concomitant administration of HAART need particular attention and consideration.
Certain other anti-retrovirals are best avoided in combination with chemotherapy, such as zidovudine, which significantly adds to the myelosuppression of chemotherapy, and didanosine, which may worsen the peripheral neuropathy caused by taxanes and vinca alkaloids.
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CD4 cell dynamics, viral load and chemotherapy |
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The effect of chemotherapy on CD4 count and plasma HIV viral load has been investigated in some clinical trials. The results reported vary: some studies have found an increase in the CD4 count on treatment (e.g. from a median baseline value of 138 (CHOP) and 122 (mCHOP) cells/mm3 to a median of 216 cells/mm3 after treatment42), but two other trials of chemotherapy alone found a decrease in CD4 cell count with treatment, with a mean change between commencement and completion of –47 cells/mm3,48 and a 50% decrease in another.72 With regard to viral load, two trials found significant decreases (from a median baseline of 29 000 copies/ml to a median of 500 copies/ml;42 and a change of –1.61 log10 copies/ml48) by the time of completion of chemotherapy. In the CHOP and mCHOP trial, there were no differences in the CD4 and VL dynamics between the two chemotherapy arms.42 With DA-EPOCH where HAART is discontinued, the viral load increased a median of 0.83 log10 (range –0.28 to 4.12 log10), while the CD4 count decreased by a median of 189 cells/mm3 (range +19 to –973) by the sixth cycle of treatment.59
For those trials that reported either a decrease in CD4 or increase in viral load, some information is available on recovery times. With concomitant HAART, a normalization of CD4 count occurred within 1 month,72 while the drop reported by Antinori48 had recovered to greater than baseline when re-measured at 6 months post chemotherapy (+25 cells/mm3, p = 0.19) and was significantly higher by 9 months (+131 cells/mm3, p = 0.001).48 With DA-EPOCH, the viral load returned to baseline levels at 3 months, but CD4+ cells took 6–12 months to recovery to baseline values.59
Only one trial that combined chemotherapy and rituximab has described CD4 and viral load changes. It showed a small drop in the median CD4 count between baseline and 1 month post-treatment, from 161/mm3 to 108/mm3. Viral load, which was detectable in 40% of patients at start of treatment, became undetectable in all patients a month after completing treatment.65
The maintenance of virological response with the administration of both R-CDE and CHOP chemotherapy has been confirmed by others;73 in this study, 68% and 84%, respectively, of patients maintained a virological response while receiving chemotherapy.73 HIV genotype and virtual phenotype analysis was carried out on all those patients who suffered virological failure. While different mutations were present in the reverse transcriptase and protease genes, there were no significant changes in the resistance profiles in the majority of non-responders, suggesting that chemotherapy does not significantly increase the occurrence of new resistance patterns.73
The possible relationship between response to HAART and response to chemotherapy was investigated in a univariate analysis of R-CDE. A detectable viral load at the completion of treatment was associated with significantly increased risks of treatment failure (HR 1.97, 95%CI 0.99–3.91, p = 0.03) and death (HR 2.39, 95%CI 1.10–5.18; p = 0.03).65 In a separate multivariate analysis, virological response was the only factor associated with tumour response.48 In contrast, Little and colleges found tumour responses in the face of worsening viral and immunological parameters,59 and Levine found no relationship between virological control and response to chemotherapy, although relapses tended to occur more frequently in those without virological control.46
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CNS involvement |
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The high rate of leptomeningeal disease at presentation, which may be asymptomatic, has resulted in the widespread use of staging lumbar punctures and prophylactic intrathecal chemotherapy for patients considered to be at high risk of relapse from the cerebrospinal fluid results. Based on published data from 12 studies in the post-HAART era, only two of which were prospective or randomized (Table 1), information regarding the rate of CNS disease is somewhat variable (Table 2). Some trials did not formally report the rate of CNS involvement at the time of initiation of systemic treatment, even though lumbar puncture was reported as being part of the initial assessment,44,45,47 and one formally excluded any patient with meningeal disease.42 In the seven studies where the rate of CNS involvement was reported, it varied between 0% and 20%.40,41,46,55,56,59,65,74 With regard to CNS relapse during treatment, the data are again highly variable and often no formal report or comment is made (Table 2). In the publications where data on CNS relapse was reported, it varied between 3 and 13%; the number of patients in these studies varying between 24 and 198.40,41,46,59,75 One study that compared patients in the pre-and post-HAART era reported a 4% rate of meningeal involvement, but did not comment on any difference between the pre- and post-HAART groups.55 Two additional reports that compared patients in the pre-and post-HAART eras made no comment on CNS involvement.18,44
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In the pre-HAART era, some trials made no comment on CNS involvement,76 while Sparano77 reported no CNS involvement at initiation of therapy in 12 patients treated with infusional CDE; however 2/6 patients receiving intrathecal methotrexate developed meningeal disease after the second cycle of treatment. An 8% rate of meningeal involvement at initiation of therapy was reported in a subsequent group of 25 patients treated with the same regime and didanosine.53 Updated results from both these papers were subsequently included in a review of CNS involvement in 62 patients treated with infusional CDE.78 In this review of patients with HIV-related NHL treated using CDE between 1990 and 1996, 13 patients (21%) presented with or developed CNS involvement; five of these had meningeal involvement and six had parenchymal disease. Furthermore, in this series, two patients (7%) receiving prophylactic intrathecal chemotherapy developed meningeal disease. At presentation, five patients (8%) had CNS involvement, of whom four had clinical signs or symptoms, three had positive CSF cytology, and two of the latter also had parenchymal brain involvement on radiology. Of the three patients with meningeal involvement, two (67%) had a complete response and survived for a year. On follow-up, only one was alive at 68 months from diagnosis.78
In contrast, of the 57 patients without clinical, radiological or CSF evidence of lymphatomatous involvement, 26 (46%) did not meet the criteria for CNS prophylaxis, and none developed an isolated meningeal recurrence, although four developed parenchymal disease. Thirty-one patients (54%) met the criteria for CNS prophylaxis, three of whom refused it. Of the eight CNS recurrences, four met CNS prophylaxis criteria. One refused, two received intrathecal methotrexate and one intrathecal cytarabine. Of these four patients, two developed cytology-proved meningeal disease within 3 months of diagnosis (both were receiving prophylaxis with methotrexate) and the other two developed presumed parenchymal disease at 7 months, both having failed to achieve a complete response with CDE. In the two meningeal recurrences, CSF cytology cleared after continued IT methorexate and whole-brain radiotherapy, and both achieved complete response. The other four recurrences, who did not meet CNS prophylaxis criteria, developed parenchymal brain recurrence with no evidence of meningeal disease. Of the two meningeal recurrences, one subsequently died of pneumonia at 50 months; the other was alive and disease-free at 48 months. Of the six who developed parenchymal disease, all died of systemic NHL (n = 5) or a CNS recurrence (n = 1), with a median survival of 7.5 months (range 7–21 months).
In an analysis of a prospective database, 18/176 patients with ARL had leptomeningeal involvement.75 In this cohort, Burkitt lymphoma histology and paraspinal or paranasal disease were associated with leptomeningeal disease, but (unlike other series) bone-marrow involvement was not. Overall survival was not significantly affected by leptomeningeal involvement at presentation. Of 21 high-risk patients given prophylactic intrathecal chemotherapy, only four (19%) developed meningeal disease. Thus the prophylactic administration of intrathecal chemotherapy to patients with risk factors but without meningeal disease at presentation prevented meningeal relapse in 81%. Given that the data was collected over a period that spans both the pre- and post-HAART era, the results could now vary in the post-HAART era. Based on the available data, it is difficult to make a direct comparison of the rate of CNS disease between pre- and post-HAART eras, but there does not appear to be any great change in the frequency or nature of the CNS disease.
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Prophylactic management of the CNS |
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All the published trials involved staging lumbar puncture and some form of CNS prophylaxis, but CNS prophylaxis protocols have varied widely, both in terms of which patient groups receive prophylaxis, and in terms of the drugs used and the frequency of administration. In some trials all patients received prophylaxis;40,44,48 others limited prophylaxis to patients at high risk (such as those with Burkitt's histology);41,55 and in one trial, it was limited to the last 17 patients entering the trial.59 In terms of drugs and frequency, this varied from 2-weekly intrathecal methotrexate41 to intrathecal methotrexate, cytrabine and hydrocortisone with each cycle of CHOP.44 In some multicentre trials, recommendations were made for CNS prophylaxis but it was ultimately left to the discretion of the local investigators42,47 (Table 3). Clinical experience has also resulted in evolution of the prophylactic regimen used, with a move away from whole-brain radiotherapy in responders, the use of cytarabine rather than methotrexate in one US centre,78 and the use of intrathecal liposomal cytarabine.79
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The wide variation in the published CNS prophylaxis protocols reflects the lack of trial data in this area of management of ARL: given the small number in the trials and the lack of head-to-head comparisons, it is difficult to make a recommendation based on the published protocols within these trials. With regard to the treatment of CNS involvement with NHL, this again varied, but generally involved whole-brain radiotherapy and intrathecal chemotherapy, which was given for up to a year from cytological clearance,40,47,55 to intrathecal chemotherapy alone, with cranial irradiation reserved for when chemotherapy failed.59
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Prophylactic management of opportunistic infection and neutropenia |
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The administration of cytotoxic chemotherapy to both immunocompetent and immunocompromised patients results in a decline in CD4 cell counts. In light of this, prophylaxis to prevent opportunistic infections in HIV-seropositive patients is particularly important. It is well established that prophylaxis against Pneumocystis jirovecii pneumonia (PCP) should commence when the CD4 cell count falls below 200/mm3, and against Mycobacterium avium complex when it falls below 50/mm3.80,81 However, many consider immediate concurrent PCP prophylaxis regardless of the CD4+ count as the standard of care for individuals commencing chemotherapy for AIDS-related lymphoma, given the potential rapid effects of chemotherapy on CD4+ lymphocyte count, and this has been the strategy adopted in many of the AIDS-related lymphoma trials.
The dramatic and prolonged T-cell depletion following the administration of the EPOCH regimen was demonstrated for patients receiving chemotherapy in the pre-HAART era.82 As discussed above, the concomitant use of chemotherapy and HAART ameliorates this decline in CD4 count. To prevent opportunistic infections, most of the published trials have involved prophylaxis and again this has varied widely, but has generally included PCP prophylaxis, with the inclusion of anti-mycobacterial, anti-fungal, anti-herpetic and anti-bacterial prophylaxis in some trials. In addition to the risk of opportunistic infections, neutropenia and neutropenic sepsis can be life-threatening and are a danger with many chemotherapy regimens in the immunocompetent population. However, in those with AIDS-related NHL, in addition to the myelotoxicity of cytotoxic chemotherapy, there are a number of issues which result in a particularly poor haematological reserves. These include: (i) HIV infection, which itself is associated with tri-lineage abnormalities of haematopoiesis;83 (ii) increased frequency of bone marrow involvement in ARL; and (iii) the use of PI-based HAART.56 In light of this, granulocyte or granulocyte-macrophage colony stimulating factor (G-CSF or GM-CSF) has been incorporated into many of the chemotherapy regimes, but again the exact circumstances under which they have been used have varied from trial to trial (Table 3). G-CSF is the preferred agent, given that GM-CSF has the potential risk of enhancing HIV replication macrophages.84
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Toxicity associated with chemotherapy |
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In a prospective study, low CD4 count was associated with increased risk of bacterial infection in HIV-seropositive patients,85 and others have reported that a CD4 count of <450/mm3 is an independent risk factor for febrile neutropenia and early death from infection in patients receiving chemotherapy.86
The addition of rituximab to infusional CDE may increase the risk of life-threatening infections, with 14% of patients developing opportunistic infections and 8% of patients deaths attributable to treatment-related infections in a pooled analysis of three trials.65 Similarly, a significantly higher rate of deaths from treatment-related infections was seen when CHOP was combined with rituximab, compared to CHOP alone (14% vs. 2%; p = 0.035). There was also a trend to more neutropenia in the R-CHOP arm (p = 0.11).47 This increase in infections may be in part related to the effect of rituximab on mature B cells, which also express CD20, resulting in depletion and further immunosuppression in a group of patients already immunocompromised by HIV. This is borne out by a report of persistent panhypogammaglobulinaemia after R-CHOP treatment, with IgM, IgG and IgA levels being undetectable or below normal limits for over 3 years.87 Data on immunoglobulin levels from the AMC010 trial appear to support this initial observation, with severe hypogammaglobulinemia only seen in the R-CHOP group.47 The increased risk of death from infection with R-CHOP is probably due to a combination of impaired innate immunity, with diminished neutrophil-mediated immunity and reduced adaptive T- and B-cell function.
Data from clinical trials suggest that concurrent HAART with cytotoxic chemotherapy can have a bone-marrow-sparing effect. Concurrent treatment with the nucleoside analogue didanosine has been reported to blunt the myelosuppression of infusional-CDE chemotherapy.53 In the AMC005 trial of CHOP combined with HAART, 25% of patients receiving mCHOP and 13% of patients receiving CHOP developed grade 3 or higher neutropenia, and only one patient (1.6%) in the study (receiving mCHOP) developed febrile neutropenia.42 This degree of myelosuppression in AMC005 contrasts sharply with that reported in the pre-HAART era trial ACTG 142. In this study, 69% of patients receiving SD m-BACOD developed grade 4 neutropenia, and 8% developed febrile neutropenia.40 The reduced myelotoxicity reported in AMC005 suggests that the concurrent use of HAART may be important for the administration of full dosages of chemotherapy with less myelosuppression.
The improved survival since the introduction of HAART and the preservation of immune function suggests that the combination of chemotherapy with HAART is an important step forward in the management of AIDS-related lymphomas. However, there appear to be both toxicity-related and pharmacokinetic drawbacks to the concomitant administration of chemotherapy and HAART, although they may have a beneficial sparing effect on the bone marrow.
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Outcomes in the era of HAART |
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Improvements in outcome have been reported for those treated in the post-HAART era. An analysis by the Eastern Cooperative Oncology Group of the outcome of patients treated with infusional-CDE chemotherapy in the pre- and post-HAART era found that the median survival (8.2 vs. 17.8 months), and the 1-year survival rate (48% vs. 55%) were superior for those treated in the post-HAART era.52 A further study showed an improvement in the survival of patients treated for HIV-related NHL treated in the post-HAART era, with an increase in median survival from 3 to 16 months.88 In addition, the complete remission rates for regimens using the combination of chemotherapy and HAART are 48–92% and the published 2-year overall survivals are 48–60%.42,45,74,89 These response rates and survival duration statistics are starting to approach those seen in the general population with advanced-stage high-grade lymphoma. Indeed, whereas the prognostic factors for survival in the pre-HAART era were predominantly immunological (prior AIDS-defining illness and CD4 cell count), in a more recent analysis, prognostic factors in AIDS-related lymphoma closely resembled those for the general population, with the international prognostic index (IPI) being an equally valuable guide in both groups.90 A recent study of prognostic factors in the post-HAART era confirms that an accurate scoring system can be based on the IPI rating and CD4 cell count alone.91 The goal of therapy is now clearly complete remission, not palliation. However, in some series there has been no change in the lymphoma response rates, and the improvements in survival duration may be related to reduced deaths from opportunistic infections amongst patients who achieve durable tumour remissions. Nonetheless, these encouraging findings have led to a more aggressive approach to the management of AIDS-associated NHL.
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Search strategy |
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We reviewed articles published in English found using the PubMed and Medline search engines, with the search terms ‘HIV’, ‘AIDS’, ‘non-Hodgkin's lymphoma’, ‘antiretrovirals’ and ‘highly active antiretroviral therapy’. Papers reviewed were limited to those published since the introduction of highly active antiretroviral therapy, which was taken as the mid-1990s. Citations from papers were also reviewed, and where possible primary sources have been quoted.
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References |
|---|
1. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A. (1981) Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 305 1425–31.[Abstract]
2. Harris C, Small CB, Klein RS, Friedland GH, Moll B, Emeson EE, Spigland I, Steigbigel NH. (1983) Immunodeficiency in female sexual partners of men with the acquired immunodeficiency syndrome. N Engl J Med 308 1181–4.[Abstract]
3. Stebbing J and Bower M. (2003) What can oncologists learn from HIV? Lancet Oncol 4 438–45.[CrossRef][Web of Science][Medline]
4. Ziegler JL, Templeton AC, Vogel CL. (1984) Kaposi's sarcoma: a comparison of classical, endemic, and epidemic forms. Semin Oncol 11 47–52.[Web of Science][Medline]
5. Boring CC, Brynes RK, Chan WC, Causey N, Gregory HR, Nadel MR, Greenberg RS. (1985) Increase in high-grade lymphomas in young men. Lancet 1 857–9.[CrossRef][Web of Science][Medline]
6. Levine AM, Gill PS, Meyer PR, Burkes RL, Ross R, Dworsky RD, Krailo M, Parker JW, Lukes RJ, Rasheed S. (1985) Retrovirus and malignant lymphoma in homosexual men. JAMA 254 1921–5.
7. Stebbing J, Marvin V, Bower M. (2004) The evidence-based treatment of AIDS-related non-Hodgkin's lymphoma. Cancer Treat Rev 30 249–53.[CrossRef][Web of Science][Medline]
8. Thirlwell C, Sarker D, Stebbing J, Bower M. (2003) Acquired immunodeficiency syndrome-related lymphoma in the era of highly active antiretroviral therapy. Clin Lymphoma 4 86–92.[Web of Science][Medline]
9. Phelps RM, Smith DK, Heilig CM, Gardner LI, Carpenter CC, Klein RS, Jamieson DJ, Vlahov D, Schuman P, Holmberg SD. (2001) Cancer incidence in women with or at risk for HIV. Int J Cancer 94 753–7.[CrossRef][Web of Science][Medline]
10. Bower M, Powles T, Nelson M, Shah P, Cox S, Mandelia S, Gazzard B. (2003) HIV-related lung cancer in the era of highly active antiretroviral therapy. AIDS 17 371–5.[CrossRef][Web of Science][Medline]
11. Powles T, Bower M, Daugaard G, Shamash J, de Ruiter A, Johnson M, Fisher M, Anderson J, Mandalia S, Stebbing J, Nelson M, Gazzard B, Oliver T. (2003) Multicenter study of human immunodeficiency virus-related germ cell tumors. J Clin Oncol 21 1922–7.
12. Thomas JO. (2001) Acquired immunodeficiency syndrome-associated cancers in Sub-Saharan Africa. Semin Oncol 28 198–206.[CrossRef][Web of Science][Medline]
13. N'Galy B, Bertozzi S, Ryder RW. (1990) Obstacles to the optimal management of HIV infection/AIDS in Africa. J Acquir Immune Defic Syndr 3 430–7.
14. Otieno MW, Banura C, Katongole-Mbidde E, Johnson JL, Ghannoum M, Dowlati A, Renne R, Arts E, Whalen C, Lederman MM, Remick SC. (2002) Therapeutic challenges of AIDS-related non-Hodgkin's lymphoma in the United States and East Africa. J Natl Cancer Inst 94 718–32.
15. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338 853–60.
16. Stebbing J and Gazzard B. (2003) Stemming the epidemic: prevention and therapy go hand-in-hand. J HIV Ther 8 51–5.[Medline]
17. Jacobson L. (1998) Impact of highly effective anti-retroviral therapy on the incidence of malignancies among HIV infected individuals. J AIDS Hum Retrovirol 9 A39.
18. Matthews GV, Bower M, Mandalia S, Powles T, Nelson MR, Gazzard BG. (2000) Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood 96 2730–4.
19. Beral V, Newton R, Reeves G. collaborators. (2000) obotsa. International collaboration on HIV and cancer. J Acquir Immune Defic Syndr 23 A8.
20. Beral V, Peterman T, Berkelman R, Jaffe H. (1991) AIDS-associated non-Hodgkin lymphoma. Lancet 337 805–9.[CrossRef][Web of Science][Medline]
21. Biggar RJ, Rosenberg PS, Cote T. (1996) Kaposi's sarcoma and non-Hodgkin's lymphoma following the diagnosis of AIDS. Multistate AIDS/Cancer Match Study Group. Int J Cancer 68 754–8.[CrossRef][Web of Science][Medline]
22. Auperin I, Mikolt J, Oksenhendler E, Thiebaut JB, Brunet M, Dupont B, Morinet F. (1994) Primary central nervous system malignant non-Hodgkin's lymphomas from HIV-infected and non-infected patients: expression of cellular surface proteins and Epstein-Barr viral markers. Neuropathol Appl Neurobiol 20 243–52.[Web of Science][Medline]
23. Ledergerber B, Telenti A, Egger M. (1999) Risk of HIV related Kaposi's sarcoma and Non-Hodgkin's lymphoma with potent antiretroviral therapy: prospective cohort study. Swiss HIV Cohort Study. Br Med J 319 23–4.
24. Inungu J, Melendez MF, Montgomery JP. (2002) AIDS-related primary brain lymphoma in Michigan, January 1990 to December 2000. AIDS Patient Care STDS 16 107–12.[CrossRef][Web of Science][Medline]
25. Portsmouth S, Stebbing J, Gill J, Mandalia S, Bower M, Nelson M, Gazzard B. (2003) A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS 17 17–22.
26. Autran B, Carcelain G, Debre P. (2001) Immune reconstitution after highly active anti-retroviral treatment of HIV infection. Adv Exp Med Biol 495 205–12.[Web of Science][Medline]
27. Lederman M. (2001) Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 15Suppl. 2, S11–15.
28. International Collaboration on HIV and Cancer: Highly Active Antiretroviral Therapy and Incidence of Cancer in Human Immunodeficiency Virus-Infected Adults. J Natl Cancer Inst (2000) 92 1823–30.
29. Rabkin CS. (2001) AIDS and cancer in the era of highly active antiretroviral therapy (HAART). Eur J Cancer 37 1316–19.[CrossRef][Web of Science][Medline]
30. Stebbing J, Gazzard B, Mandalia S, Teague A, Waterston A, Marvin V, Nelson M, Bower M. (2004) Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 22 2177–83.
31. Wilde JT, Lee CA, Darby SC, Kan SW, Giangrande P, Phillips AN, Winter M, Spooner R, Ludlam CA. (2002) The incidence of lymphoma in the UK haemophilia population between 1978 and 1999. AIDS 16 1803–7.[CrossRef][Web of Science][Medline]
32. Mocroft A, Katlama C, Johnson AM, Pradier C, Antunes F, Mulcahy F, Chiesi A, Phillips AN, Kirk O, Lundgren JD. (2000) AIDS across Europe, 1994–98: the EuroSIDA study. Lancet 356 291–6.[CrossRef][Web of Science][Medline]
33. Fong IW, Ho J, Toy C, Lo B, Fong MW. (2000) Value of long-term administration of acyclovir and similar agents for protecting against AIDS-related lymphoma: case-control and historical cohort studies. Clin Infect Dis 30 757–61.[CrossRef][Web of Science][Medline]
34. Bossolasco S, Cinque P, Ponzoni M, Vigano MG, Lazzarin A, Linde A, Falk KI. (2002) Epstein-Barr virus DNA load in cerebrospinal fluid and plasma of patients with AIDS-related lymphoma. J Neurovirol 8 432–8.[CrossRef][Web of Science][Medline]
35. Van Baarle D, Wolthers KC, Hovenkamp E, Niesters HG, Osterhaus AD, Miedema F, Van Oers MH. (2002) Absolute level of Epstein-Barr virus DNA in human immunodeficiency virus type 1 infection is not predictive of AIDS-related non-Hodgkin lymphoma. J Infect Dis 186 405–9.[CrossRef][Web of Science][Medline]
36. Sarker D, Thirlwell C, Nelson M, Gazzard B, Bower M. (2003) Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma. AIDS 17 861–5.[CrossRef][Web of Science][Medline]
37. Massarweh S, Udden MM, Shahab I, Kroll M, Sears DA, Lynch GR, Teh BS, Lu HH. (2003) HIV-related Hodgkin's disease with central nervous system involvement and association with Epstein-Barr virus. Am J Hematol 72 216–19.[CrossRef][Web of Science][Medline]
38. Desai J, Mitnick R, Henry D, Llena J, Sparano J. (1999) Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-Hodgkin lymphoma. Cancer 86 1840–7.[CrossRef][Web of Science][Medline]
39. Besson C, Goubar A, Gabarre J, et al. (2001) Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 98 2339–44.
40. Kaplan LD, Straus DJ, Testa MA, von Roenn J, Dezube BJ, Cooley TP, Herndier B, Northfelt DW, Huang J, Tulpule A, Levine AM. (1997) Low dose compared with standard dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. N Engl J Med 336 1641–8.
41. Bower M, Stern S, Fife K, Nelson M, Gazzard BG. (2000) Weekly alternating combination chemotherapy for good prognosis AIDS-related lymphoma. Eur J Cancer 36 363–7.[CrossRef][Web of Science][Medline]
42. Ratner L, Lee J, Tang S, Redden D, Hamzeh F, Herndier B, Scadden D, Kaplan L, Ambinder R, Levine A, Harrington W, Grochow L, Flexner C, Tan B, Straus D. (2001) Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 19 2171–8.
43. Gill PS, Levine AM, Krailo M, Rarick MU, Loureiro C, Deyton L, Meyer P, Rasheed S. (1987) AIDS-related malignant lymphoma: results of prospective treatment trials. J Clin Oncol 5 1322–8.
44. Navarro JT, Ribera JM, Oriol A, Vaquero M, Romeu J, Batlle M, Flores A, Milla F, Feliu E. (2001) Influence of highly active anti-retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone. Br J Haematol 112 909–15.[CrossRef][Web of Science][Medline]
45. Vaccher E, Spina M, di Gennaro G, Talamini R, Nasti G, Schioppa O, Vultaggio G, Tirelli U. (2001) Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin lymphoma. Cancer 91 155–63.[CrossRef][Medline]
46. Levine AM, Tulpule A, Espina B, Sherrod A, Boswell WD, Lieberman RD, Nathwani BN, Welles L. (2004) Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma: results of therapy and correlates of response. J Clin Oncol 22 2662–70.
47. Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. (2005) Rituximab does not improve clinical outcome in a randomized phase III trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin's lymphoma: AIDS-malignancies consortium trial 010. Blood 24 1538–43.
48. Antinori A, Cingolani A, Alba L, Ammassari A, Serraino D, Ciancio BC, Palmieri F, De Luca A, Larocca LM, Ruco L, Ippolito G, Cauda R. (2001) Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 15 1483–91.[CrossRef][Web of Science][Medline]
49. Matsushima Y, Kanzawa F, Hoshi A, Shimizu E, Nomori H, Sasaki Y, Saijo N. (1985) Time-schedule dependency of the inhibiting activity of various anticancer drugs in the clonogenic assay. Cancer Chemother Pharmacol 14 104–7.[CrossRef][Web of Science][Medline]
50. Barlogie B, Smith L, Alexanian R. (1984) Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310 1353–6.[Abstract]
51. Slevin ML, Clark PI, Joel SP, Malik S, Osborne RJ, Gregory WM, Lowe DG, Reznek RH, Wrigley PF. (1989) A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7 1333–40.[Abstract]
52. Sparano JA, Lee S, Henry DH, Ambinder RF, von Roenn J, Tirelli U. (2000) Infusional cyclophosphamide, doxorubicin and etoposide in HIV associated non-Hodgkin's lymphoma: A review of the Einstein, Aviano and ECOG experience in 182 patients. J Acquir Immune Defic Syndr 23 A11.[CrossRef]
53. Sparano JA, Wiernik PH, Hu X, Sarta C, Schwartz EL, Soeiro R, Henry DH, Mason B, Ratech H, Dutcher JP. (1996) Pilot trial of infusional cyclophosphamide, doxorubicin and etoposide plus didanosine and filgrastim in patients with HIV associated non-Hodgkin's lymphoma. Journal of Clinical Oncology 14 3026–35.[Abstract]
54. Sparano JA, Wiernik PH, Hu X, Sarta H, Henry DH, Ratech H. (1998) Saquinavir enhances the mucosal toxicity of infusional cyclophosphamide, doxorubicin and etoposide in patients with HIV-associated non-Hodgkin's lymphoma. Med Oncol 15 50–7.[Web of Science][Medline]
55. Sparano JA, Lee S, Chen MG, Nazeer T, Einzig A, Ambinder RF, Henry DH, Manalo J, Li T, Von Roenn JH. (2004) Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). J Clin Oncol 22 1491–500.
56. Bower M, McCall-Peat N, Ryan N, Davies L, Young AM, Gupta S, Nelson M, Gazzard B, Stebbing J. (2004) Protease inhibitors potentiate chemotherapy-induced neutropenia. Blood 104 2943–6.
57. Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F. (2002) Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood 99 2685–93.
58. Phenix BN, Lum JJ, Nie Z, Sanchez-Dardon J, Badley AD. (2001) Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss. Blood 98 1078–85.
59. Little RF, Pittaluga S, Grant N, Steinberg SM, Kavlick MF, Mitsuya H, Franchini G, Gutierrez M, Raffeld M, Jaffe ES, Shearer G, Yarchoan R, Wilson WH. (2003) Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 101 4653–9.
60. Stashenko P, Nadler LM, Hardy R, Schlossman SF. (1980) Characterization of a human B lymphocyte-specific antigen. J Immunol 125 1678–85.[Abstract]
61. Leget GA and Czuczman MS. (1998) Use of rituximab, the new FDA-approved antibody. Curr Opin Oncol 10 548–51.[Medline]
62. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16 2825–33.[Abstract]
63. Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feuring-Buske M, Radford JA, Capdeville R, Diehl V, Reyes F. (1998) Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92 1927–32.
64. Tirelli U, Spina M, Jaeger U, Nigra E, Blanc PL, Liberati AM, Benci A, Sparano JA. (2002) Infusional CDE with rituximab for the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma: preliminary results of a phase I/II study. Recent Results Cancer Res 159 149–53.[Medline]
65. Spina M, Jaeger U, Sparano JA, Talamini R, Simonelli C, Michieli M, Rossi G, Nigra E, Berretta M, Cattaneo C, Rieger AC, Vaccher E, Tirelli U. (2005) Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated non-Hodgkin lymphoma: pooled results from 3 phase 2 trials. Blood 105 1891–7.
66. Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP, Decosterd LA, Furrer H, Opravil M, Pantaleo G, Retelska D, Ruiz L, Schinkel AH, Vernazza P, Eap CB, Telenti A. (2002) Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359 30–6.[CrossRef][Web of Science][Medline]
67. Hochman JH, Chiba M, Nishime J, Yamazaki M, Lin JH. (2000) Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4. J Pharmacol Exp Ther 292 310–18.
68. Hochman JH, Yamazaki M, Ohe T, Lin JH. (2002) Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein. Curr Drug Metab 3 257–73.[CrossRef][Web of Science][Medline]
69. Chiba M, Nishime JA, Lin JH. (1995) Potent and selective inactivation of human liver microsomal cytochrome P-450 isoforms by L-754,394, an investigational human immune deficiency virus protease inhibitor. J Pharmacol Exp Ther 275 1527–34.
70. Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. (1999) HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 57 1147–52.[CrossRef][Web of Science][Medline]
71. Perloff MD, von Moltke LL, Fahey JM, Daily JP, Greenblatt DJ. (2000) Induction of P-glycoprotein expression by HIV protease inhibitors in cell culture. AIDS 14 1287–9.[CrossRef][Web of Science][Medline]
72. Powles T, Imami N, Nelson M, Gazzard BG, Bower M. (2002) Effects of combination chemotherapy and highly active antiretroviral therapy on immune parameters in HIV-1 associated lymphoma. AIDS 16 531–6.[CrossRef][Web of Science][Medline]
73. Simonelli C, Zanussi S, Cinelli R, Dal Maso L, Di Gennaro G, D'Andrea M, Nasti G, Spina M, Vaccher E, De Paoli P, Tirelli U. (2003) Impact of concomitant antiblastic chemotherapy and highly active antiretroviral therapy on human immunodeficiency virus (HIV) viremia and genotyping in HIV-infected patients with non-Hodgkin lymphoma. Clin Infect Dis 37 820–7.[CrossRef][Web of Science][Medline]
74. Lascaux AS, Hemery F, Goujard C, Lesprit P, Delfraissy JF, Sobel A, Lepage E, Levy Y. (2005) Beneficial effect of highly active antiretroviral therapy on the prognosis of AIDS-related systemic non-Hodgkin lymphomas. AIDS Res Hum Retroviruses 21 214–20.[CrossRef][Web of Science][Medline]
75. Sarker D, Thirlwell C, Nelson M, Gazzard B, Bower M. (2003) Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma. AIDS 17 861–5.[CrossRef][Web of Science][Medline]
76. Kaplan LD, Kahn JO, Crowe S, Northfelt D, Neville P, Grossberg H, Abrams DI, Tracey J, Mills J, Volberding PA. (1991) 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. J Clin Oncol 9 929–40.[Abstract]
77. Sparano JA, Wiernik PH, Strack M, Leaf A, Becker N, Valentine ES. (1993) Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin's lymphoma: a highly active regimen. Blood 81 2810–15.
78. Desai J, Mitnick RJ, Henry DH, Llena J, Sparano JA. (1999) Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-hodgkin lymphoma. Cancer 86 1840–7.[CrossRef][Web of Science][Medline]
79. Mazhar D, Stebbing J, Lewis R, Nelson M, Gazzard BG, Bower M. (2006) The management of meningeal lymphoma in patients with HIV in the era of HAART: intrathecal depot cytarabine is effective and safe. Blood 107 3412–14.
80. Kaplan JE, Masur H, Holmes KK. (2002) Guidelines for preventing opportunistic infections among HIV-infected persons–2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 51 1–52.[Medline]
81. Yeni PG, Hammer SM, Carpenter CC, et al. (2002) Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 288 222–35.
82. Zanussi S, Simonelli C, D'Andrea M, Comar M, Bidoli E, Giacca M, Tirelli U, Vaccher E, De Paoli P. (1996) The effects of antineoplastic chemotherapy on HIV disease. AIDS Res Hum Retroviruses 12 1703–7.[Web of Science][Medline]
83. Scadden DT, Zeira M, Woon A, Wang Z, Schieve L, Ikeuchi K, Lim B, Groopman JE. (1992) Human immunodeficiency virus infection of human bone marrow stromal fibroblasts. Blood 76 317–22.
84. Perno CF, Cooney DA, Gao WY, Hao Z, Johns DG, Foli A, Hartman NR, Calio R, Broder S, Yarchoan R. (1992) Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages. Blood 80 995–1003.
85. Moore DA, Benepal T, Portsmouth S, Gill J, Gazzard BG. (2001) Etiology and natural history of neutropenia in human immunodeficiency virus disease: a prospective study. Clin Infect Dis 32 469–75.[CrossRef][Web of Science][Medline]
86. Borg C, Ray-Coquard I, Philip I, Clapisson G, Bendriss-Vermare N, Menetrier-Caux C, Sebban C, Biron P, Blay JY. (2004) CD4 lymphopenia as a risk factor for febrile neutropenia and early death after cytotoxic chemotherapy in adult patients with cancer. Cancer 101 2675–80.[CrossRef][Web of Science][Medline]
87. Miles SA and McGratten M. (2005) Persistent panhypogammaglobulinemia after CHOP-rituximab for HIV-related lymphoma. J Clin Oncol 23 247–8.
88. Diamond C, Taylor TH, Im T, Miradi M, Anton-Culver H. (2006) Improved survival and chemotherapy response among patients with AIDS-related non-Hodgkin's lymphoma receiving highly active antiretroviral therapy. Hematol Oncol 10 10.
89. Cortes J, Thomas D, Rios A, Koller C, O'Brien S, Jeha S, Faderl S, Kantarjian H. (2002) Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia. Cancer 94 1492–9.[CrossRef][Web of Science][Medline]
90. Rossi G, Donisi A, Casari S, Re A, Cadeo G-P, Carosi G. (1999) The International Prognostic Index can be used as a guide to treatment decisions regarding patients with human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer 86 2391–7.[CrossRef][Web of Science][Medline]
91. Bower M, Gazzard B, Mandalia S, Newsom-Davis T, Thirlwell C, Dhillon T, Young AM, Powles T, Gaya A, Nelson M, Stebbing J. (2005) A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of highly active antiretroviral therapy. Ann Intern Med 143 265–73.
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