Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial.

BACKGROUND: Rivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain. METHODS: This randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2·5. Patients were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily. Randomisation was done centrally, stratified by centre and patient type (with vs without systemic lupus erythematosus). The primary outcome was percentage change in endogenous thrombin potential (ETP) from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change. Analysis was by modified intention to treat. Other thrombin generation parameters, thrombosis, and bleeding were also assessed. Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation. This trial is registered with the ISRCTN registry, number ISRCTN68222801. FINDINGS: Of 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who received warfarin were assessed. At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric mean 1086 nmol/L per min, 95% CI 957-1233 vs 548, 484-621, treatment effect 2·0, 95% CI 1·7-2·4, p<0·0001). Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 47-66 vs 86 nmol/L, 72-102, treatment effect 0·6, 95% CI 0·5-0·8, p=0·0006). No thrombosis or major bleeding were seen. Serious adverse events occurred in four patients in each group. INTERPRETATION: ETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in thrombotic risk compared with standard-intensity warfarin, this drug could be an effective and safe alternative in patients with antiphospholipid syndrome and previous venous thromboembolism. FUNDING: Arthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre.

A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial).

This prospective study aimed to develop reproducible diagnostic criteria for sporadic Burkitt lymphoma (BL), applicable to routine practice, and to evaluate the efficacy of dose-modified (dm) CODOX-M/IVAC in patients diagnosed using these criteria. The study was open to patients with an aggressive B-cell lymphoma with an MKI67 fraction approaching 100%. Immunophenotype and fluorescent in situ hybridization (FISH) were used to separate BL from other aggressive B-cell lymphomas. BL was characterized by the presence of a cMYC rearrangement as a sole cytogenetic abnormality occurring in patients with a germinal center phenotype with absence of BCL-2 expression and abnormal TP53 expression. A total of 128 patients were eligible for the study, of whom 58 were considered to have BL and 70 to have diffuse large B-cell lymphoma (DLBCL). There were 110 clinically fit patients who received dmCODOX-M (methotrexate, dose 3 g/m(2)) with or without IVAC according to risk group. The 2-year progression-free survival was 64% (95% confidence interval [CI] 51%-77%) for BL, 55% (95% CI 42%-66%) for DLBCL, 85% (95% CI 73%-97%) for low risk, and 49% (95% CI 38%-60%) for high-risk patients. The observed differences in outcome and other clinical features validate the proposed diagnostic criteria. Compared with the previous trial LY06 with full-dose methotrexate (6.7 g/m(2)), there was a reduction in toxicity with comparable outcomes. This study was registered at www.clinicaltrials.gov as NCT00040690.

Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin's lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519).

PURPOSE: To perform an open-label, randomized, controlled trial comparing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with two multidrug regimens (MDRs) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Eight hundred seven patients with advanced HL (stage III to IV, or earlier stage with systemic symptoms or bulky disease) were randomly assigned between ABVD and MDR specified before randomization as alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) with prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABIOE), or hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was planned for incomplete response or initial bulk disease. RESULTS: At 52 months median follow-up, 212 event-free survival (EFS) events (disease progression or any death) were reported. In the primary comparison, at 3 years EFS was 75% (95% CI, 71% to 79%) for ABVD and 75% (95% CI, 70% to 79%) for MDRs (hazard ratio [HR] = 1.05; 95% CI, 0.8 to 1.37; HR more than 1.0 favors ABVD). The 3-year overall survival (OS) rates were 90% (95% CI, 87% to 93%) in patients allocated ABVD and 88% (95% CI, 84% to 91%) in patients allocated MDRs (HR = 1.22; 95% CI, 0.84 to 1.77). Patients receiving MDRs experienced more grade 3/4 infection, mucositis, and neuropathy. One occurrence of myelodysplastic syndrome was reported, but no acute leukemia was reported. When the two MDRs are compared separately with ABVD, neither the alternating nor the hybrid regimen showed a statistically significant difference from ABVD for EFS or OS. Subgroup analysis suggested that MDRs may be associated with poorer outcomes in older patients (heterogeneity test of OS older or younger than 45 years, P = .020). CONCLUSION: There was no evidence of significant difference in EFS or OS between ABVD and MDRs in the trial overall or if the two MDR versus ABVD comparisons are considered separately. ABVD remains the standard for treatment of advanced HL.