High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an Intergruppo Italiano Linfomi randomized trial

Background and Objectives. Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). Design and Methods. Between 1996 and 2001, 130 DLCL patients, aged <= 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible. Results. The complete remission rate was 59% in arm A and 70% in arm B (p=0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio=1.15, 95% confidence intervals =0.72-1.84, p=0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio=1.67, 95% confidence interval=0.98-2.85, p=0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A. Interpretations and Conclusions. HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy

Prognostic factors in symptomatic Waldenstrom's macroglobulinemia

We analyze the prognostic value of the presenting features of a series of patients with symptomatic Waldenstrom's macroglobulinemia who were homogeneously treated. A total of 215 patients (119 males) with a median age of 62.6 years (range, 24.9 to 91.6) were retrospectively analyzed. The median overall follow-up was 57.6 months (range, 0.6 to 281): 58 (0.9 to 281) for living patients and 52.2 (0.6 to 261.3) for those who died. All patients were treated with alkylating agent-based chemotherapy. The overall median survival was 77.2 months, without significant differences based on the duration of the previous monoclonal gammopathy of undetermined significance (MGUS) phase. The multivariate Cox analysis performed on the whole population showed that age, hemoglobin level, and serum albumin level predicted survival. The addition of beta(2)-microglobulin, available in the subgroup of 60 patients diagnosed after 1990, in a Cox stepwise selection showed that this parameter was by far the main prognostic determinant. Application of the Dhodapkar, Morel, and Gobbi scoring systems to this population of patients showed that all three stratified the population into groups with significantly distinct prognoses. A prognostic index based on age, hemoglobin, and albumin is capable of identifying various groups of patients with different therapeutic needs

ABVD versus Stanford V versus MEC in unfavourable Hodgkin's lymphoma: results of a randomised trial

Background: Between January 1996 and April 2000, 355 patients with advanced Hodgkin's disease (HD) (stage II bulky disease, III and IV) were enrolled in a prospective, multicentre, randomised trial aimed at comparing the efficacy of two new promising regimens: Stanford V and MEC hybrid. ABVD was chosen as the control arm. Radiotherapy was planned at the end of induction therapy on residual masses or on sites of previous bulky lesions. One hundred and seventeen, 123 and 115 patients were treated with Stanford V, MEC and ABVD, respectively. The records of 275 enrolled patients (89 Stanford V, 88 MEC, 98 ABVD) have been reviewed and are the subject of this report. Results: After induction therapy a complete response (CR) was observed in 93, 89 and 74% of patients treated with MEC, ABVD and Stanford V, respectively, with a statistically significant difference (P = 0.013) between the arms. After a median follow-up of 24 months, 16 relapses have been recorded among 196 patients who achieved a CR. Relapse rates are 16, 6 and 4% for Stanford V, ABVD and MEC, respectively (P = 0.042). The 3-year survival was 93%, without any significant difference among the arms. However, a significant difference emerged in terms of failure free survival (FFS). Patients treated with Stanford V did the worst compared with those treated with ABVD or MEC (P = 0.001). Toxicity was comparable in the three treatment arms. Conclusion: For this randomised study, both ABVD and MEC gave superior results to Stanford V in term of response and FFS; MEC seems to be the best regimen in terms of relapse-free survival, even if a significant difference has not yet been achieved. Notwithstanding the short follow-up, these results seem to be very impressive in defining the best standard treatment for HD for this subset of patients

MESENCHYMAL STEM CELLS MODULATE IN VITRO FIBROBLAST ACTIVITY IN SYSTEMIC SCLEROSIS

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Essential thrombocythemia or chronic idiopathic myelofibrosis? A single-center study based on hematopoietic bone marrow histology.

Reported here is the case of a 6-week-old female infant with a severe Bordetella pertussis infection requiring supportive pressure-positive ventilation in the intensive care unit. After being discharged from the intensive care unit, she developed hemolytic anemia, thrombocytopenia and acute renal failure, which suggested a diagnosis of hemolytic uremic syndrome. The clinical outcome was favorable with no renal consequences. This case suggests there may be a direct cause-effect relationship between B. pertussis infection and hemolytic uremic syndrome

Molecular targeting of the PKC-beta inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression.

The protein kinase C (PKC) pathway has been shown to play a role in the regulation of cell proliferation in several haematological malignancies, including multiple myeloma (MM). Recent data have shown that a PKC inhibitor, enzastaurin, has antiproliferative and proapoptotic activity in a large panel of human myeloma cell lines (HMCLs). In order to further characterise the effect of enzastaurin in MM, we performed gene expression profiling of enzastaurin-treated KMS-26 cell line. We identified 62 upregulated and 32 downregulated genes that are mainly involved in cellular adhesion (CXCL12, CXCR4), apoptosis (CTSB, TRAF5, BCL2L1), cell proliferation (IGF1, GADD45A, BCMA (B-cell maturation antigen), CDC20), transcription regulation (MYC, MX11, IRF4), immune and defence responses. Subsequent validation by Western blotting of selected genes in four enzastaurin-treated HMCLs was consistent with our microarray analysis. Our data indicate that enzastaurin may affect important processes involved in the proliferation and survival of malignant plasma cells as well as in their interactions with the bone marrow microenvironment and provide a preclinical rationale for the potential role of this drug in the treatment of MM

Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia:a population-matched analysis

To elucidate whether reduced-intensity conditioning (RIC) decreases treatment-related mortality (TRM) after allogeneic stem cell transplantation (allo-SCT) for chronic lymphocytic leukemia (CLL), we retrospectively compared 73 RIC cases from a recent EBMT survey with 82 patients from the EBMT database who had undergone standard myeloablative conditioning ( MC) for CLL during the same time period. The two populations were matched by adjusting the primary risk factor, the conditioning regimen, in a series of Cox models for age, sex, donor type, remission status at transplant and analyzed for its effect on TRM, relapse incidence, event-free (EFS) and overall survival ( OS). After adjustment, a significant reduction of TRM became evident for the RIC population ( hazard ratio (HR) 0.4 (95% confidence interval 0.18-0.9); P=0.03). On the other hand, RIC was associated with an increased relapse incidence (HR 2.65 (0.98-7.12); P=0.054). There was no significant difference between RIC and MC in terms of EFS (HR 0.69 (0.38-1.25); P=0.22) and OS (HR 0.65 (0.33-1.28); P=0.21). We conclude that RIC appears to favorably influence TRM after allo-SCT for CLL. This observation, as well as possible detrimental effects of RIC on relapse risk, should be confirmed by prospective studies