A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma.

A systematic review and meta-analysis was performed to determine the efficacy and toxicity of thalidomide in previously untreated patients with myeloma. Medline, Embase, Cochrane Controlled Trials Register, and abstracts from the American Society of Hematology and the American Society of Clinical Oncology were searched for randomized controlled trials (RCTs) of either induction or maintenance thalidomide in adults with previously untreated myeloma. Nine RCTs of induction thalidomide, three RCTs of maintenance thalidomide, and one RCT of induction and maintenance thalidomide were identified, involving a total of 4144 subjects. When thalidomide was added to standard, non-transplantation myeloma therapy, overall survival (OS) improved (HR 0.67; 95% CI 0.56-0.81). When thalidomide was given as maintenance following autologous transplantation (ASCT), there was a trend to improved OS (HR 0.61, 95% CI 0.37-1.01); when the only trial which combined induction and maintenance thalidomide was excluded from this analysis, a significant survival advantage emerged (HR 0.49, 95% CI 0.32-0.74). The relative risk of venous thromboembolism (VTE) with induction thalidomide was 2.56 (95% CI 1.88-3.49). A meta-analysis of trials/sub-groups administering low molecular weight heparin (LMWH) as VTE prophylaxis, suggested a persistently increased relative risk of VTE with induction thalidomide (RR 1.54, 95% CI 1.07-2.22). The relative risk of VTE was substantially lower, but still elevated, when thalidomide was given as maintenance therapy following ASCT (RR 1.95, 95% CI 1.15-3.30). In summary, thalidomide appears to improve the overall survival of patients with newly diagnosed myeloma both when it is added to standard, non-transplantation therapy, and when it is given as maintenance therapy following ASCT. However, thalidomide is associated with toxicity, particularly a significantly increased risk of VTE.

A prospective, non-randomised phase 1-2 trial of VACOP-B with filgrastim support for HIV-related non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) remains an important complication of associated HIV infection despite advances in antiretroviral therapy (ART), and the optimum chemotherapy regimen for this disease remains to be defined. A dose-escalation trial was performed to determine the maximum tolerated doses of etoposide and doxorubicin as part of the 12-week VACOP-B regimen, supported by filgrastim (r-metHuG-CSF). Patients with aggressive histology HIV-related NHL who were previously untreated with chemotherapy, and who had no active opportunistic infection were eligible for the study. Chemotherapy consisted of cyclophosphamide 350 mg/m2, vincristine 2 mg, bleomycin 10 U/m2; and prednisone 100 mg q2 days x 12 weeks, with increasing doses of doxorubicin 25-50 mg/m2 and etoposide 25-50 mg/m2 intravenously and 50-100 mg/m2 orally. Central nervous system prophylaxis (intrathecal cytarabine 50 mg x 4 doses), antifungal, and Pneumocystis carinii prophylaxis were used, and filgrastim was administered to prevent neutropenic complications. One dose level was expanded to permit the concomitant use of ART. Endpoints were determination of maximum tolerated dose of doxorubicin and etoposide, treatment tolerability, and survival. Forty-seven patients were enrolled, most with diffuse large-cell or immunoblastic NHL. Protocol-defined maximum tolerated dose was not reached and the limits of dose-limiting toxicity were not exceeded, even in patients receiving ART. Thirty-two cycles (4.9%) were delayed >6 days because of toxicity; 30 patients (64%) completed all 12 weeks of treatment. After completion of therapy, 14 patients had a complete response (30%), and 4 had a partial response (8%). Median time to progression was 9 months. At 42 months, progression-free survival was 25% and overall survival was 28%.

Very severe thrombocytopenia and fragmentation hemolysis mimicking thrombotic thrombocytopenic purpura associated with a giant intracardiac vegetation infected with Staphylococcus epidermidis: role of monocyte procoagulant activity induced by bacterial supernatant.

The pathogenesis of very severe thrombocytopenia in bacterial endocarditis is uncertain. We report a 50-year-old male with platelet counts < 10 x 10(9)/l and fragmentation hemolysis complicating Staphylococcus epidermidis pacemaker endocarditis with a giant vegetation. Antibiotics, corticosteroids, high-dose intravenous gammaglobulin, and plasmapheresis (for initially-suspected thrombotic thrombocytopenic purpura) failed to produce significant platelet count increase. However, therapeutic-dose heparin anticoagulation was associated with a platelet count increase from <10 to approximately 40 x 10(9)/l, with parallel reduction in thrombin-antithrombin complexes (from 8.9 to 3.5 microg/l), facilitating surgical intervention. The thrombocytopenia promptly resolved following surgical removal of the vegetation. Culture supernatant from S. epidermidis isolated from the patient's blood induced monocytes to express procoagulant activity (assessed by factor Xa generation) equivalent to lipopolysaccharide (1 microg/ml), with half-maximal activation seen with culture supernatant diluted to 1:12,800. These data are consistent with previous animal models of endocarditis demonstrating staphylococci-induced procoagulant changes in monocytes. This case demonstrates that heparin anticoagulation can be therapeutic in infective endocarditis-associated severe thrombocytopenia in a non-bleeding patient, and that such therapy may ameliorate the platelet count enough to permit surgical intervention.

Mortality rates and causes of death among all HIV-positive individuals with hemophilia in Canada over 21 years of follow-up.

Many individuals with hemophilia were infected with human immunodeficiency virus (HIV) in the early 1980s through contaminated blood products. Most also were co-infected with hepatitis C virus (HCV). Deaths among the entire cohort of HIV-positive hemophiliacs in Canada up to 2003 are described. Using registry data, we analyzed Kaplan-Meier survival curves, determined the effect of age at HIV seroconversion on mortality, and described cause-specific proportional mortality patterns over time. Of 2427 Canadians with hemophilia, 660 (27.2%) were HIV-positive, of whom 406 (61.5%) died. In contrast, 114 (6.5%) deaths occurred in HIV-negative controls. Median age at HIV seroconversion was 20 (range, < 1-67 years), and median survival was 15.0 years (95% confidence interval, 13.6-16.4 years). Younger age at HIV seroconversion was associated with improved survival; however, this finding was not explained by differences in causes of death across age groups. Following the introduction of highly active antiretroviral therapy, the proportion of deaths due to acquired immune deficiency syndrome has decreased, while the proportion of deaths due to liver disease has increased. There were 1134 HCV-positive individuals, of whom only 444 (39.2%) were also HIV-positive. Liver disease is a growing health concern among many hemophiliacs, not only those who are HIV-positive.

Developing a tracking system for coagulation factor concentrates in southern Ontario.

BACKGROUND: In response to the transfusion- transmitted AIDS epidemic, Canadian authorities recommended the development of tracking systems and improved reporting of adverse events. This study describes the development of a verifiable and comprehensive regional tracking system for coagulation factor concentrates. STUDY DESIGN AND METHODS: The Hamilton- Niagara Regional Hemophilia Program received distribution and utilization data from Canadian Blood Services, 26 regional hospitals, and 70 individuals with bleeding disorders on home-based therapy. Purpose-specific software, the Canadian Hemophilia Assessment and Resource Management System (CHARMS), was used to store, monitor, analyze, and validate data. RESULTS: During a 1-year period (2001), all factor concentrates distributed in this region were accounted for. A higher proportion of FVIII and FIX concentrates (88 vs. 12%) was infused at home than in hospitals, and a higher proportion (63 vs. 28%) was used to prevent than to treat bleeds. During a period of shortage, a 5-percent reduction in utilization of both FVIII and FIX concentrates was documented. One recall was managed swiftly and efficiently. Two patients reported allergic skin reactions. CONCLUSION: A verifiable tracking system has been developed that can provide ongoing data for both clinical and administrative purposes. Data collection from patients needs to be made more efficient and real-time recording is an important future objective. Such a system can be instituted locally for less than 1.5 percent of the cost of the factor concentrate used.

A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets.

BACKGROUND: Removal of the plasma supernatant from platelets before transfusion is effective in preventing acute reactions to platelets caused by cytokines. Prestorage WBC reduction of platelets may be even more effective at preventing reactions as the WBCs are removed and WBC-derived cytokines do not accumulate in this component. This study evaluates the effectiveness of plasma removal and two methods of prestorage WBC reduction for preventing acute reactions to platelets. STUDY DESIGN AND METHODS: Platelets given to adults with hematologic malignancies were randomly allocated to one of three types: plasma supernatant removed and a platelet storage solution added, whole blood-derived platelets that are prestorage WBC reduced by filtration before storage, and prestorage WBC-reduced apheresis platelets. Patients were monitored before, during, and after transfusion, and the severity of reactions was graded on a Likert scale. RESULTS: A total of 129 patients from four centers were given 1190 platelet transfusions. The overall frequency of reactions was 13.6 percent (162 of 1190), 21.3 percent (36 of 169) for the plasma-removed platelets, 11.4 percent (59 of 517) for random donor WBC-reduced platelets, and 13.3 percent (67 of 504) for apheresis WBC-reduced platelets (p=0.384). The overall frequency of severe reactions was 4.1 percent with plasma-removed platelets, 1.7 percent for whole blood-derived, prestorage WBC-reduced platelets, and 1.4 percent for prestorage WBC-reduced apheresis platelets. CONCLUSION: The frequency of reactions to plasma-removed platelets and prestorage WBC-reduced platelets was not significantly different; however, the power of the study for this comparison was low. There was no difference in the frequency of reactions to the two types of prestorage WBC-reduced platelets. The frequency of severe reactions to prestorage WBC-reduced platelets is low, occurring in only 1 to 2 percent of transfusions.

A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies.

Cytokine-mobilized peripheral blood is increasingly used instead of bone marrow as the source of cells for allogeneic transplantation. Although cells lead to faster hematologic recovery, their effects on graft-versus-host disease, relapse, and survival are less certain. Between January 1996 and February 2000, 228 patients with chronic myeloid leukemia, acute myeloid leukemia, or myelodysplasia were randomized to receive either bone marrow or peripheral blood allografts from HLA-matched siblings. All patients received busulfan and cyclophosphamide as conditioning chemotherapy and cyclosporine and methotrexate as graft-versus-host disease prophylaxis. We compared the times to neutrophil and platelet recovery, acute and chronic graft-versus-host disease, relapse, and overall survival between the groups. The median times to neutrophil recovery were 19 days and 23 days and the times to platelet recovery were 16 days and 22 days in the peripheral blood and bone marrow groups, respectively (P <.0001 for both comparisons). The cumulative incidence of grades II to IV acute graft-versus-host disease 100 days after transplantation was 44% in both groups (hazard ratio, 0.99; 95% confidence interval, 0.66-1.49; P >.9), and the incidence of extensive chronic graft-versus-host disease at 30 months after transplantation was 40% with peripheral blood and 30% with bone marrow (hazard ratio, 1.23; 95% confidence interval, 0.78-1.96; P =.37). There was no statistically significant difference in the probability of relapse of the underlying disease between the groups. The probabilities of survival at 30 months after transplantation were 68% and 60% in the peripheral blood and bone marrow groups, respectively (hazard ratio, 0.62; 95% confidence interval, 0.39-0.97; P =.04). In patients with chronic myeloid leukemia, acute myeloid leukemia, and myelodysplasia undergoing allogeneic transplantation from matched siblings, the use of peripheral blood instead of bone marrow leads to faster hematologic recovery, similar risk of graft-versus-host disease, and improved survival.