Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin lymphoma.
Vaccher E, Spina M, di Gennaro G, Talamini R, Nasti G, Schioppa O, Vultaggio G, Tirelli U.
Division of Medical Oncology A, National Cancer Institute, Aviano, Italy.
BACKGROUND: The feasibility and efficacy of concomitant chemotherapy and highly active antiretroviral therapy (HAART) is still unknown in patients with human immunodeficiency virus (HIV)-related malignancies. To evaluate the impact of chemotherapy plus HAART on the clinical course of patients with HIV-related, systemic, non-Hodgkin lymphoma (HIV-NHL), the authors compared retrospectively a group of 24 patients with HIV-NHL who were treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen plus HAART with a group of 80 patients who were treated with CHOP chemotherapy or a CHOP-like regimen (i.e., cyclophosphamide, doxorubicin, teniposide, and prednisone with vincristine plus bleomycin) without receiving antiretroviral therapy. METHODS: All patients were enrolled in two sequential trials performed at the Aviano Cancer Center, Italy, from April 1988 to December 1998. HAART was included with combination therapy from January 1997. Antiretroviral regimens consisted of two reverse transcriptase inhibitors and one protease inhibitor. RESULTS: The two treatment groups were well matched with regard to patient demographics, NHL characteristics, HIV status, and treatment, i.e., the number of cycles and chemotherapy dose. The response rates were similar between the two groups. Severe anemia (Grade 3-4 according to the World Health Organization criteria) was significantly greater in the patients who received CHOP-HAART compared with the patients who received CHOP alone (33% vs. 7%, respectively; P = 0.001). Leukopenia was similar between the two groups, but colony stimulating factor support was significantly greater in the CHOP-HAART group than in the control group (92% vs. 66%, respectively; P = 0.03). Seventeen percent of CHOP-HAART patients developed severe autonomic neurotoxicity, whereas none of the CHOP patients developed neurotoxicity (P = 0.002). At similar median follow-up, opportunistic infection (OI) rates and mortality were significantly lower in the CHOP-HAART patients than in the CHOP patients (18% vs. 52%, respectively; P = 0.05; and 38% vs. 85%, respectively; P = 0.001). The median survival for CHOP-HAART patients was not reached, whereas the medial survival of CHOP patients was 7 months (P = 0.03). CONCLUSIONS: The combination of CHOP plus HAART is feasible and may reduce the morbidity from OIs in HIV-NHL patients. However, careful attention must be directed to cross toxicity and possible pharmacokinetic interactions between antiretroviral and antineoplastic drugs. The impact of the combined chemotherapy plus HAART treatment on patient survival needs urgently to be evaluated in prospective studies. Copyright 2001 American Cancer Society.
Epidemiological, biological and clinical features of HIV-related lymphomas in the era of highly active antiretroviral therapy.
Tirelli U, Spina M, Gaidano G, Vaccher E, Franceschi S, Carbone A.
Publication Types:
- Editorial
- Review
- Review, Tutorial
Hodgkin's disease: clinical presentation and treatment.
Tirelli U, Vaccher E, Spina M, Carbone A.
Aviano Cancer Center.
Publication Types:
- Review
- Review, Tutorial
A 20-year experience on malignant lymphomas in patients aged 70 and older at a single institute.
Tirelli U, Carbone A, Monfardini S, Zagonel V.
Division of Medical Oncology A, National Cancer Institute, Via Pedemontana Occ.le 12, 33081, Aviano, PN, Italy. oma@ets
We have evaluated the clinico-pathological and therepeutical outcome of patients aged 70 and older with malignant lymphomas treated at a single institute over a 20-year period of time. Among the several studies evaluated, the most important is a prospective randomized study comparing a new regimen, VMP (VP 16, Mitoxantrone and Prednimustine) vs the goal standard CHOP in unfavorable non-Hodgkin's lymphoma (NHL), showing that CHOP is significantly better than VMP in terms of objective response rate, progression free and overall survival. Therefore CHOP remains the standard regimen also for patients of over 70 years of age and stage II--IV intermediate and high grade NHL.
Discordant HHV8 detection in a young HIV-negative patient with Kaposi's sarcoma and sarcoidosis.
di Gennaro G, Canzonieri V, Schioppa O, Nasti G, Carbone A, Tirelli U.
Division of Medical Oncology A, National Cancer Institute, Aviano, Italy.
Human herpesvirus 8 (HHV8), which has been suggested as the causal agent of Kaposi's sarcoma (KS), has also been implicated in the pathogenesis of sarcoidosis. We describe a patient affected concomitantly by sarcoidosis and KS. HHV8 sequences were detected with PCR only on KS lesions, whereas sarcoid tissues did not harbor HHV8 DNA. Immune dysfunction related to sarcoidosis may have facilitated the oncogenic role of HHV8 and the development of KS.
Chronic hepatitis C in HIV-coinfected patients: feasibility and efficacy of interferon-alpha2b and ribavirin combination therapy.
Nasti G, di Gennaro G, Rizzardini G, Cadorin L, Tirelli U.
Publication Types:
- Letter
Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study.
Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, Bron D, Roozendaal KJ, Noordijk EM, Musson H, Teodorovic I, Maes B, Carbone A, Carde P, Thomas J.
Department of Hematology, Leiden University Medical Center, The Netherlands. J.C.Kluin-Nelemans@int.azg.nl
BACKGROUND: The long-term outcome for patients with aggressive non-Hodgkin's lymphoma (NHL) is poor. Consequently, the European Organization for Research and Treatment of Cancer Lymphoma Group designed a prospective randomized trial to investigate whether high-dose chemotherapy plus autologous bone marrow transplantation (ABMT) after standard combination chemotherapy improves long-term survival. METHODS: Patients aged 15-65 years with aggressive NHL received three cycles of CHVmP/BV polychemotherapy (i.e., a combination of cyclophosphamide, doxorubicin, teniposide, and prednisone, with bleomycin and vincristine added at mid-cycle). After these three cycles, patients with a complete or partial remission and at that time no lymphoma involvement in the bone marrow were randomly assigned to the ABMT arm (a further three cycles of CHVmP/BV followed by BEAC [i.e., a combination of carmustine, etoposide, cytarabine, and cyclophosphamide] chemotherapy and ABMT) or to the control arm (five more cycles of CHVmP/BV). All statistical tests are two-sided. RESULTS: From December 1990 through October 1998, 311 patients (median age = 44 years) were registered and received the first three cycles of CHVmP/BV, and 194 patients were randomly assigned to the treatment arms. Approximately 70% (140 patients) of these patients were of low or low-intermediate International Prognostic Index (IPI) risk. After a median follow-up of 53 months, an intention-to-treat analysis showed a time to disease progression and overall survival at 5 years of 61% (95% confidence interval [CI] = 51% to 72%) and 68% (95% CI = 57% to 79%), respectively, for the ABMT arm and 56% (95% CI = 45% to 67%) and 77% (95% CI = 67% to 86%), respectively, for the control arm. Differences between arms were not statistically significant. A subset analysis on IPI risk groups, although too small for reliable statistical analysis, yielded similar results. CONCLUSIONS: Standard combination therapies remain the best choice for most patients with aggressive NHL. We recommend that patients with IPI low or low-intermediate risk not be subjected to high-dose chemotherapy and ABMT as a first-line therapy.
Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas.
Carbone A, Gloghini A, Larocca LM, Capello D, Pierconti F, Canzonieri V, Tirelli U, Dalla-Favera R, Gaidano G.
Divisions of Pathology and Medical Oncology A, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano, Italy.
This study was aimed at defining the histogenesis of the pathologic spectrum of lymphoma arising in the context of human immunodeficiency virus (HIV) infection. Toward this aim, 87 AIDS-related non-Hodgkin lymphomas (AIDS-NHL) and 16 Hodgkin lymphomas arising in HIV+ patients (HIV-HL) were comparatively analyzed for the expression pattern of several B-cell histogenetic markers, including BCL-6 (expressed by centroblasts and centrocytes), MUM1/IRF4 (expressed by late centrocytes and post-germinal center [GC] B cells), and CD138/syn-1 (expressed by post-GC B cells). Expression of MUM1, BCL-6, and syn-1 segregated 3 major phenotypic patterns among AIDS-NHL and HIV-HL: (1) the BCL-6+/MUM1-/syn-1- pattern, selectively clustering with a large fraction of AIDS-Burkitt lymphoma (17 of 19) and of systemic AIDS-diffuse large cell lymphoma (12 of 16); (2) the BCL-6-/MUM1+/syn-1- pattern, associated with a fraction of AIDS-immunoblastic lymphoma (8 of 24); and (3) the BCL-6-/MUM1+/syn-1+ pattern, associated with systemic and primary central nervous system immunoblastic lymphoma (14 of 24) and with primary effusion lymphoma (10 of 10), plasmablastic lymphoma of the oral cavity (7 of 7), and HIV-HL (15 of 16). Analysis of nonneoplastic lymph nodes showed that the 3 phenotypic patterns detected in AIDS-NHL and HIV-HL correspond to distinct stages of physiologic B-cell development-centroblasts (BCL-6+/MUM1-/syn-1-), late GC/early post-GC B cells (BCL-6-/MUM1+/syn-1-), and post-GC B cells (BCL-6-/MUM1+/syn-1+). Expression of the Epstein-Barr virus-encoded latent membrane protein-1 clustered with the BCL-6-/MUM1+/syn-1+ profile throughout the clinicopathologic spectrum of AIDS-NHL and HIV-HL. Overall, these results define novel histogenetic subsets of AIDS-NHL and HIV-HL and may provide novel tools for refining the diagnosis of these disorders.
Incidence of invasive cervical cancer in a cohort of HIV-seropositive women before and after the introduction of highly active antiretroviral therapy.
Dorrucci M, Suligoi B, Serraino D, Tirelli U, Rezza G; Italian HIV-Seroconversion Study.
AIDS and STD Unit, Istituto Superiore di Sanita, Rome, Italy. maria.dorrucci@iss.it
To assess whether the incidence of invasive cervical cancer (ICC) has changed as a result of highly active antiretroviral therapy (HAART), we conducted a prospective cohort study on the incidence of ICC before and after the introduction of HAART among Italian women with a known duration of HIV infection. We estimated the incidence per 1000 person years of ICC as a first AIDS-defining disease for the periods 1981 through 1991, 1992 through 1995, and 1996 through 1998. We also estimated the incidence of other first AIDS-defining diseases. Kaplan-Meier and Cox models were applied to compare the periods 1981 through 1995 and 1996 through 1998 in terms of cumulative incidence and relative hazards (RHs). The analysis included 483 women (median follow-up: 7 years). In the period 1981 through 1995, a trend of increase was observed in the incidence of ICC and other AIDS-defining diseases; this trend has continued only for ICC, whereas the incidence of other AIDS-defining diseases has decreased since 1996. Compared with 1981 through 1995, the RH of ICC for 1996 through 1998 was 7.41 (95% confidence interval [CI]: 1.21--45.44); when adjusting for age at HIV seroconversion, the RH decreased to 4.75 (95% CI: 0.80--28.24). It remains to be determined whether the continued increase in ICC incidence after the introduction of HAART is attributable to a decreasing competitive mortality from other AIDS-defining diseases among HIV-infected women.
Response to highly active antiretroviral therapy according to duration of HIV infection.
Pezzotti P, Pappagallo M, Phillips AN, Boros S, Valdarchi C, Sinicco A, Zaccarelli M, Rezza G; The Italian Seroconversion Study.
Reparto AIDS e MST, Istituto Superiore di Sanita, Rome, Italy. patrizio.pezzotti@iss.it
OBJECTIVE: To evaluate whether duration of HIV-1 infection influences the response to highly active antiretroviral therapy (HAART). DESIGN: Prospective study of individuals (Italian Seroconversion Study cohort) with well-estimated dates of HIV-1 seroconversion. METHODS: This analysis included 277 participants who began HAART (defined as three antiretroviral drugs used in combination). Cox regression models were used to evaluate the association between duration of infection (as categorical variable [</=3, 3-7.5, >7.5 years from seroconversion] or continuous variable) and an immunologic (rise in CD4 count >100 cells/mm3) and a virologic (decline in plasma HIV-RNA to unquantifiable levels) outcome. All analyses were stratified by center of recruitment and adjustment, when used, was for gender, age at inception of HAART, injection drug use, previous antiretroviral therapy, lag-time between positive and negative HIV test result, year of starting HAART, clinical stage, CD4 count, and HIV-RNA at time of HAART. RESULTS: HAART was initiated a median of 6.4 years after seroconversion. There was a median follow-up of 1.6 years after starting HAART to the calendar cut-off (November 1999). One-hundred-eighty-one (65.3%) patients experienced a decline in viral load to below quantifiable levels and 184 (66.4%) experienced a rise in CD4 >100 cells/mm3. In the Cox models, by 1-year increase in duration of infection, we estimated a lower crude hazard of achieving a CD4 count increase >100 cells (relative hazard [RH], 0.96; 95% confidence interval [CI], 0.92-1.01; p =.09), and a lower hazard of reaching an unquantifiable level of plasma HIV-RNA (RH, 0.97; 95%CI, 0.93-1.02; p =.20). After adjustment, these values became 0.99 (95%CI, 0.93-1.04; p =.62) and 0.98 (95%CI, 0.93-1.04; p =.48), respectively. When duration of HIV infection was considered as a categorical variable, the results were consistent with those already described. CONCLUSIONS: These results suggest that the duration of HIV infection does not seem to play an important independent role in determining the virologic and immunologic responses to HAART.
Lymphocyte subsets and viral load in patients with HIV-associated non-Hodgkin's lymphoma treated with anti-CD20 monoclonal antibody and chemotherapy.
De Paoli P, Vaccher E, Tedeschi R, Caffau C, Zanussi S, Bortolin MT, Crepaldi C, Spina M, Tirelli U.
Departments of Microbiology, Immunology and Virology, Centro di Riferimento Oncologico, IRCCS, via Pedemontana, 33081 Aviano, Italy. pdepaoli@cro.it
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.
Human immunodeficiency virus-related non-Hodgkin lymphoma: activity of infusional cyclophosphamide, doxorubicin, and etoposide as second-line chemotherapy in 40 patients.
Spina M, Vaccher E, Juzbasic S, Milan I, Nasti G, Talamini R, Fasan M, Antinori A, Nigra E, Tirelli U.
Division of Medical Oncology A, National Cancer Institute, Aviano (PN), Italy.
BACKGROUND: The prognosis of patients with human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) is poor. In fact, despite a high complete response (CR) rate, approximately 50% of these patients die from progressive lymphoma. METHODS: From November 1994 to April 2000, the authors treated 40 patients with resistant or recurrent HIV-related NHL with a 96-hour continuous intravenous infusion of cyclophosphamide (187.5 mg/m(2) per day), doxorubicin (12.5 mg/m(2) per day), and etoposide (60 mg/m(2) per day). RESULTS: The median number of cycles administered was two (range, one to six cycles). A CR was documented in 4 of 40 patients (10%), and a partial remission (PR) was documented in 7 of 40 patients (18%). The CR median duration was 6 months (range, 4--30+ months), whereas PRs lasted for 5 months (range, 2--8 months). The overall median survival was 4 months (range, < 1--33 months), and the median survival for responding patients was 10 months. CONCLUSIONS: The current data confirm that infusional cyclophosphamide, doxorubicin, and etoposide is active in patients with refractory or recurrent HIV-related NHL. However, the median survival of these patients remains poor, and the other innovative approaches should be used. Copyright 2001 American Cancer Society.
Impact of HAART on the clinical management of AIDS-related cancers.
Tirelli U, Bernardi D.
Division of Medical Oncology A, Centro di Riferimento Oncologico, IRCCS, Istituto Nazionale Tumori, Aviano, Italy. oma@cro.it
The development of HIV-related disease has changed dramatically since the introduction of highly active antiretroviral therapy (HAART) into clinical practice. Since the use of protease inhibitors became widespread, a 30-50% reduction in Kaposi's sarcoma (KS) has been observed. The results of recent studies indicate that HAART may be a useful alternative both to immune response modifiers during less aggressive stages of KS disease and to systemic cytotoxic drugs in the long-term maintenance therapy of advanced KS. The impact of HAART regimens on the incidence of systemic lymphoma (NHL-HIV) remains unclear, but it can be hypothesised that patients treated with HAART may survive longer with continued B cell stimulation and dysregulation resulting in an increased incidence of lymphoma over time. The impact of HAART on survival in patients affected by NHL-HIV has recently been evaluated and a positive correlation between HAART and outcome in these patients has been found. The spectrum of cancers in patients with HIV infection may develop further since these patients survive longer with HAART and with a better control of opportunistic infections. With the increasing use of HAART, the dilemma is whether to institute or continue protease inhibitors use during chemotherapy. Based on the advances in our understanding of HIV-related disease and the availability of new antiretroviral therapies, the choice for anti-HIV agents in patients receiving chemotherapy is important.
Clinical aspects and management of Hodgkin's disease and other tumours in HIV-infected individuals.
Vaccher E, Spina M, Tirelli U.
Division of Medical Oncology A, Centro di Riferimento Oncologico, IRCCS, Istituto Nazionale Tumori, Via Pedemontana Occ. 12, 33081 (PN), Aviano, Italy. oma@cro.it
As the AIDS epidemic advances, the spectrum of malignancies encountered is expanding. Several non-AIDS defining cancers, i.e. Hodgkin's disease (HD), anal and testicular cancer, are increasing in incidence in HIV-infected patients. The widespread use of highly active antiretroviral therapy (HAART) in industrialised countries has resulted in substantial improvement in the survival of HIV-infected patients. It is likely that in the future, cancers associated with long-term mild immune suppression will occur at an increased rate in long-term survivors of HIV infection. The natural history of the majority of non-AIDS defining tumours differs from that of the general population. Unusual aspects of tumour localisation, growth behaviour and therapeutical responses distinguish tumours in patients with HIV infection from those without. This paper reviews the most relevant data on the epidemiology, pathology, clinical features and treatment of the most frequently reported non-AIDS defining tumours, i.e. HD, lung, testicular and skin cancers.
Chronic hepatitis C in HIV infection: feasibility and sustained efficacy of therapy with interferon alfa-2b and tribavirin.
Nasti G, Di Gennaro G, Tavio M, Cadorin L, Tedeschi RM, Talamini R, Carbone A, Tirelli U.
Division of Oncological Medicine A, National Cancer Institute, Aviano, Pordenone, Italy.
BACKGROUND: The role combination therapy with interferon alfa-2b and tribavirin (US: ribavirin) plays in producing sustained virological responses in patients with HIV and chronic hepatitis C (HCV) infection is still unknown. OBJECTIVES: To determine the feasibility and sustained response of interferon alfa-2b and tribavirin combination therapy. DESIGN: Phase II study. METHODS: Seventeen patients were enrolled at the National Cancer Institute, Aviano, Italy and received combination therapy with interferon alfa-2b 3 MIU subcutaneously three times a week plus tribavirin 1000-1200 mg/day for 24 weeks. Antiretroviral therapy was concomitantly given in all but one patient. RESULTS: At the end of treatment, five (31%) patients achieved clearance of HCV RNA and 11 (69%) showed normalized liver function enzyme levels. In three patients, serum HCV RNA concentration was still undetectable 24 weeks after treatment, with an overall sustained virological response rate of 19% The serum liver enzymes were still normal in 10 patients 24 weeks after treatment, the overall sustained biochemical response rate being 62% All patients with HCV RNA clearance at the end of treatment and 24 weeks after treatment had a concomitant biochemical response. Overall the combination treatment was well tolerated. CONCLUSIONS: Our data confirm that the combination of interferon alfa-2b and tribavirin is well tolerated and feasible in patients with HIV-HCV co-infection and it can be associated safely with highly active antiretroviral therapy. The sustained response achieved with the drug combination does not seem to be any better than that achieved with 12 months of monotherapy with interferon alfa-2b.
Cervical cancer in HIV.
Tirelli U, Bernardi D, Vaccher E.
Divisione di Oncologia Medica A, Istituto Nazionale Tumori, Aviano (PN).
Management of hematologic malignancies in the elderly: 15-year experience at the Aviano Cancer Center, Italy.
Zagonel V, Monfardini S, Tirelli U, Carbone A, Pinto A.
Medical Oncology Department, Centro di Riberimento Oncologico, IRCCS, Aviano, Italy. vzagone@tin.it
The optimal management of hemopoietic malignancies in the elderly requires specific strategies targeted at the peculiar clinico-biologic features of such patients. In the time frame spanning from 1983 to 1998, several clinical trials have been performed at the Aviano Cancer Center, Italy, aimed at extending the knowledge of natural history of hemopoietic malignancies in the elderly and evaluating the efficacy and toxicity of different chemotherapy programs specifically devised for older subjects affected by acute myeloid leukemia, myelodysplasia, non-Hodgkin's lymphomas, or multiple myeloma. Here the most relevant results are summarized and information stemmed from such studies. The present report rather than provide a comprehensive review on hematologic neoplasms in the elderly, mainly reflects the 'philosophy' deriving from 15 years of studies of the group in the field of geriatric oncology/hematology. Elaboration of a 'consensus' view will represent the challenge for all the investigators involved in such an important field of research.
I linfomi non-Hodgkin-HIV sistemici nell'era dell'HAART. Storia naturale.
Juzbasic S, Spina M, Vaccher E, Tirelli U.
Divisione di Oncologia Medica A, Istituto Nazionale Tumori, Centro di Riferimento Oncologico, Aviano.
In the era of highly active antiretroviral therapy (HAART), systemic non-Hodgkin lymphoma (NHL) represented the most frequent cancer associated to HIV infection. In contrast to Kaposi's sarcoma and primary central nervous system lymphoma (PCNSL) which incidence have been declining after introduction of HAART, systemic NHL-HIV has relatively stable remained. Systemic HIV related NHL are markedly heterogeneous both histologically and clinically and this clinicophatological heterogenity reflects variability in the molecular lesions associated to these lymphomas and immunological status of these patients. The introduction of HAART has substantially modified the approach to HIV related lymphomas. The results of recent monoinstitutional study of Aviano Cancer's Institute on 235 patients have suggested that HAART would otherwise allow a long life expectancy with longer disease free survival and overall survival. In fact the reduced of morbidity of AIDS patients bought by HAART justified the use of aggressive antineoplastic therapies.
Low frequency of severe hepatotoxicity and association with HCV coinfection in HIV-positive patients treated with HAART.
Monforte Ade A, Bugarini R, Pezzotti P, De Luca A, Antinori A, Mussini C, Vigevani GM, Tirelli U, Bruno R, Gritti F, Piazza M, Chigiotti S, Chirianni A, De Stefano C, Pizzigallo E, Perrella O, Moroni M; The ICONA (Italian Cohort of Naive for Antiretrovirals) Study Group.
Institute of Infectious and Tropical Diseases, University of Milan, L Sacco H, Milan, Italy. adarmin@tin.it
BACKGROUND: Highly active antiretroviral therapy (HAART) is strongly effective in reducing morbidity and mortality in HIV-1-positive individuals. Its main drawback is the potential toxicity. Data on the frequency and determinants of severe hepatotoxicity in a clinical setting are still sparse. METHODS: This is a prospective study of HIV-1-positive individuals with known HBsAg and HCV-Ab serology. The study end point was progression to alanine aminotransferase (ALT) levels > or =200 IU/L after HAART initiation. Cumulative probability of progression to this end point was estimated by the Kaplan-Meier method. Crude and adjusted hazard ratios (HR) were estimated by proportional hazards regression model. RESULTS: One thousand two hundred fifty-five patients were included. HBsAg was found in 91 (7.2%), HCV-Ab in 578 (46.5%) patients; almost all injection drug users (451 of 482; 93.6%) were HCV-Ab positive. Sixty-one individuals progressed to the end point with a probability of 7.9% (95% confidence interval [CI], 5.6-10.0) of progression at 24 months from starting. Independent factors predicting progression to the end point were baseline ALT levels (HR, 5.29; 95% CI, 3.24-8.65; every 10 IU/L higher), HCV-Ab positivity (HR, 4.01; 95% CI, 1.48-10.85) or both HBsAg and HCV Ab positivity (HR, 3.85, 95% CI, 1.01-14.61), and previous non-HAART therapy (HR, 1.84, 95% CI, 1.04-3.42). Patients receiving stavudine-containing regimens had a lower risk than those receiving zidovudine-containing regimens (HR, 0.30, 95% CI, 0.12-0.71). CONCLUSIONS: There was a low risk of ALT > or =200 IU/L in our cohort. Hepatitis C coinfection and elevated ALT levels at HAART initiation are important predictors of progression to ALT > or =200 IU/L; stavudine-containing regimens were associated with a lower risk compared with zidovudine-containing regimens.
Infusional CDE with rituximab for the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma: preliminary results of a phase I/II study.
Tirelli U, Spina M, Jaeger U, Nigra E, Blanc PL, Liberati AM, Benci A, Sparano JA.
National Cancer Institute, Aviano, Italy.
Infusional CDE (cyclophosphamide, doxorubicin, etoposide; iCDE) is one of the most effective chemotherapeutic regimen for human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL), with a complete remission rate of 46% and a median overall survival of 8.2 months (Sparano JA, Blood 1993; 81:2810). Since the majority of HIV-associated NHL are CD20-positive we reasoned that the addition of rituximab to iCDE (R-iCDE) could also improve the poor outcome of these patients. As a first step we investigated the safety of R-iCDE in a phase I/II study. Thirty patients with aggressive HIV-associated NHL were enrolled between June 1998 and October 2000. Characteristics of 29 evaluable patients were: median age: 38 years (range 29-65 years); male sex 24/29; histology: DLCL 16 (55%), Burkitt 10 (35%), ALCL 2 (7%), unclassified 1 (3%); stage: I (35%), II (10%), III (10%), IV (45%); International Prognostic Index: 0, 1 (59%), 2 (24%), 3 (17%), 4, 5 (0); CD4 count: median 132/ mm3 (range 3-470/mm3). Patients received rituximab (375 mg/m2) in conjunction with iCDE (five or six cycles). All patients were treated with G-CSF and highly active antiretroviral therapy (HAART). Twenty-six of 29 patients received treatment as planned, while chemotherapy had to be discontinued in three patients (2 persistent thrombocytopenias, 1 cerebral hemorrhage). Grade 3 or 4 toxicity was observed as follows: neutropenia 79%, anemia 45%, thrombocytopenia 34%, bacterial infection 34%, opportunistic infection 7%, mucositis 17%. A dose reduction was necessary in 22%. Complete remission was achieved in 86% of the patients, partial remission in 4%. Ten percent had progressive disease. After a median follow-up of 9 months the median overall survival is not reached. The actuarial survival at 2 years is 80% and the actuarial progression-free survival is 79%. Four of 29 patients (14%) have died, three from NHL and one from cryptosporidiosis. These findings suggest that the combination of rituximab with iCDE in patients with HIV-associated NHL is safe and feasible and that the addition of the anti-CD20 antibody does not increase the risk for infections. The high complete remission rate also indicates a potential therapeutic benefit and warrants further randomized trials.