Tandem autologous stem cell transplantation in high-risk de novo multiple myeloma: final results of the prospective and randomized IFM 99-04 protocol

The combination of high levels of beta2-microglobulin (beta2-m) and chromosome 13 deletion allows identification of a high-risk subgroup of patients with de novo multiple myeloma (MM). In this population of patients, we have evaluated the impact of a murine anti-interleukin 6 (anti-IL-6) monoclonal antibody (BE-8) as part of the second conditioning regimen in a multicenter prospective randomized trial of tandem autologous stem cell transplantation (ASCT). Conditioning for the first ASCT was accomplished with melphalan 200 mg/m2 and for the second one with melphalan 220 mg/m2 plus dexamethasone with or without BE-8 infusion. This trial included 219 patients, of whom 166 were randomized, 85 without BE-8 (arm A) and 81 with BE-8 (arm B). The median overall survival (OS) and event-free survival (EFS) times of the whole group of patients were 41 and 30 months, respectively. Response rates, OS, and EFS were not different between the 2 arms of the trial. OS at 54 months was 46% in arm A and 51% in arm B (P = .90); median EFS was 35 months in arm A and 31 in arm B (P = .39). In high-risk patients the dose intensity of melphalan at 420 mg/m2 led to encouraging results, but the addition of anti-IL-6 monoclonal antibody to the second conditioning regimen did not improve either OS nor EFS.     

Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.

High-dose therapy has become a common treatment for myeloma. The objective of this study (Intergroupe Francophone du Myélome [IFM] 9502 trial) was to compare in a prospective and randomized trial the 2 most widely used conditioning regimens before autologous stem cell transplantation in newly diagnosed symptomatic patients younger than 65 years old: 8 Gy total body irradiation plus 140 mg/m(2) melphalan (arm A) versus 200 mg/m(2) melphalan (arm B). A total of 282 evaluable patients were compared--140 in arm A and 142 in arm B. Baseline characteristics and disease response to 4 cycles of the VAD regimen performed before randomization and autologous stem cell transplantation were identical in the 2 treatment arms. In arm B, hematologic recovery was significantly faster for both the duration of neutropenia and thrombocytopenia, transfusion requirements were also significantly lower, and the median duration of hospitalization was significantly shorter. In arm A, the incidence of severe mucositis was significantly increased. The median duration of event-free survival was similar in both arms (21 vs 20.5 months, P =.6), but the 45-month survival was 65.8% in arm B versus 45.5% in arm A (P =.05). This difference might be attributed in part to better salvage regimens after relapse in arm B compared with arm A. We conclude that 200 mg/m(2) melphalan is a less toxic and at least as effective conditioning regimen when compared with 8 Gy total body irradiation with 140 mg/m(2) melphalan. This regimen should be considered as the standard of care before autologous stem cell transplantation in multiple myeloma.     

Impact of HAART-related side effects on unsafe sexual behaviours in HIV-infected injecting drug users: 7-year follow up

OBJECTIVE: To investigate the impact of non-lipodystrophy HAART-related side effects on unprotected sexual behaviours among HIV-infected drug users. DESIGNAND PARTICIPANTS: HAART-treated patients who reported having occasional partners during the follow-up period after HAART initiation were selected among patients of the MANIF 2000 cohort of HIV-infected drug users. METHODS: Visits where patients reported unsafe sexual behaviours with occasional partners were compared to visits where they reported safe sexual behaviours using a logistic model based on Generalized Estimating Equations. RESULTS: One-hundred and ninety-two HAART-treated patients reported occasional sexual partners at least once during follow-up, accounting for a total of 464 visits. Among these 192 patients, 134 (70%) declared at least once unsafe sexual behaviours with occasional partners. During follow-up, three or more HAART-related side effects were reported in 273 of the 464 visits. When comparing visits where patients reported unsafe sexual behaviours with occasional partners (n = 249) with those where they reported safe sexual behaviours (n = 215), experiencing three or more HAART-related side effects was significantly associated with unsafe sex after adjustment for cofactors such as injecting drug status, reporting more than two sexual partners and having sex more than once a week. CONCLUSIONS: Perceived side effects play a role in determining unsafe sexual behaviours. HIV prevention interventions must consider the negative impact of HAART-related side effects on sexual risk-taking behaviours. Drug maintenance programs contribute to sexual risk reduction among drug injecting patients.     

Thrombopenia due to pefloxacin (Peflacine): dose-dependent toxicity?]

Pefloxacin (Peflacine) can give rise to thrombocytopenia, although the responsibility of the drug can be difficult to demonstrate in infectious patients and those receiving other drugs simultaneously. We have collated 18 cases in which the responsibility of pefloxacin was suspected. In 13 cases, the patients were also taking other drugs which may have been contributory (heparin, Bactrim, Augmentin, ranitidine,...). The remaining five cases were of particular interest as pefloxacin was the only drug administered. The mean age of the patients was 75 years, and the mean bodyweight 56 kg (range, 47-65 kg). The pefloxacin dosage was 800 to 1,600 mg/day i.v. or p.o., i.e. 13-18 mg/kg/day. Thrombocytopenia occurred from five to 19 days after beginning treatment and resolved between 7 and 12 days after drug withdrawal. A number of factors argue in favor of dose dependency: 1 patient had high plasma concentrations (peak and residual); thrombocytopenia occurred in one patient when the previous, well-tolerated dosage of 800 mg/day (for 15 days) was increased to 1,600 mg/day; thrombocytopenia resolved in one patient when the dosage was reduced to 400 mg/day (1 tablet) and continued for a further 10 days. This toxic reaction may be avoided by reducing the drug dosage to 400 mg/day in elderly patients with a low bodyweight. Differential blood counts appear to be warranted for patients at risk.     

The context of HLA-DR/CD18 complex in the plasma membrane governs HLA-DR-derived signals in activated monocytes

HLA-DR-derived signals in activated monocytes mediate both pro-inflammatory cytokine production and caspase-independent death, and have been postulated to play a role in inflammation and in its resolution, respectively. Herein, using the monocytic/macrophagic human cell line THP-1 primed with IFNgamma (IFNgamma-primed THP-1), we investigated how HLA-DR may integrate both signals. Our inhibition studies demonstrated that if cell death is dependent on PKCbeta activation, the induction of TNFalpha gene expression relies on PTK activation, in particular the Src family of kinases, but both cell responses implicate the beta2-integrin CD18. Accordingly, sequential immunoprecipitation experiments demonstrated that following engagement of HLA-DR on IFNgamma-primed THP-1 cells, the HLA-DR/CD18 complex physically associates with PKCbeta and with PTK. Pharmacological disruption of lipid rafts microdomains abolished the assembly of HLA-DR/CD18/PTK signaling complex, HLA-DR-mediated tyrosine activation, and the PTK-dependent TNFalpha expression in IFNgamma-primed THP-1 cells. In contrast, HLA-DR/CD18/PKCbeta complex was still formed and able to mediate cell death after cholesterol depletion of these cells. These results indicate that while the integrity of lipid rafts is necessary for the transduction of cytokine gene expression through the HLA-DR/CD18 complex, it is not necessary for the induction of the HLA-DR/CD18-dependent cell death. Thus, our study provides experimental evidence indicating the compartmentalization of HLA-DR/CD18 complex within or outside lipid rafts as a mechanism through which HLA-DR can integrate both PTK and PKCbeta signals leading to activation and death, respectively, of activated monocytes. This might provide new insights into how MHC class II signaling may regulate inflammatory response.     

Signaling through HLA-DR induces PKC beta-dependent B cell death outside rafts

Signals through HLA-DR molecules contribute to optimal activation of antigen-presenting cells (APC) during T cell/APC interactions participating in the generation of productive interactions, and to the induction of APC death, which has been postulated to play a role in the termination of the immune response. To understand how these molecules accommodate both cellular responses, we studied the not yet well-defined signaling events and the biochemical requirements for HLA-DR-mediated death. We demonstrate that in B cells the HLA-DR-activated protein kinase C (PKC) beta is required for HLA-DR-mediated death whereas the HLA-DR-activated Src family of PTK is redundant. In contrast to HLA-DR-mediated activation of Src kinase Lyn, the aggregation of HLA-DR molecules in lipid rafts is not required for HLA-DR-mediated PKC beta activation nor for the induction of cell death. Indeed, the bulk of HLA-DR-activated PKC beta reside outside rafts. This is the first report showing that HLA-DR-induced PKC beta activation is essential for the induction of B cell death via HLA-DR, and that these HLA-DR-mediated events do not require the integrity of rafts.