Converging or Crossing Curves: Untie the Gordian Knot or Cut it? Appropriate Statistics for Non-Proportional Hazards in Decitabine DACO-016 Study (AML)

Introduction: Among patients with acute myeloid leukemia (AML), the DACO-016 randomized study showed reduction in mortality for decitabine [Dacogen® (DAC), Eisai Inc., Woodcliff Lake, NJ, USA] compared with treatment choice (TC): at primary analysis the hazard ratio (HR) was 0.85 (95% confidence interval 0.69-1.04; stratified log-rank P=0.108). With two interim analyses, two-sided alpha was adjusted to 0.0462. With 1-year additional follow-up the HR reached 0.82 (nominal P=0.0373). These data resulted in approval of DAC in the European Union, though not in the United States. Though pre-specified, the log-rank test could be considered not optimal to assess the observed survival difference because of the non-proportional hazard nature of the survival curves. Methods: We applied the Wilcoxon test as a sensitivity analysis. Patients were randomized to DAC (N=242) or TC (N=243). One-hundred and eight (44.4%) patients in the TC arm and 91 (37.6%) patients in the DAC arm selectively crossed over to subsequent disease modifying therapies at progression, which might impact the survival beyond the median with resultant converging curves (and disproportional hazards). Results: The stratified Wilcoxon test showed a significant improvement in median (CI 95%) overall survival with DAC [7.7 (6.2; 9.2) months] versus TC [5.0 (4.3; 6.3) months; P=0.0458]. Conclusion: Wilcoxon test indicated significant increase in survival for DAC versus TC compared to log-rank test. Funding: Janssen-Cilag GmbH

Chemotherapy Exposure and outcomes of Chronic Lymphoid Leukemia Patients

This study describes chemotherapy exposure, healthcare utilization, overall survival (OS) and progression-free survival (PFS) among patients diagnosed with chronic lymphoid leukemia (CLL). Newly diagnosed CLL patients who received chemotherapy were selected from the Eindhoven Cancer Registry between 1998-2011, linked on a patient-level to the PHARMO Database Network including data on in- and out-patient drug dispensings, hospitalizations and clinical laboratory measurements. Chemotherapy was classified in regimens of use based on chemotherapy combinations. OS and PFS were determined after diagnosis and after chemotherapy. Healthcare utilization was assessed in the year before diagnosis and in the year after chemotherapy. In total, 125 CLL patients received chemotherapy: 52 patients (42%) started chemotherapy within 6 months and 73 patients (58%) started chemotherapy ≥6 months after diagnosis. Mean (±SD) age was 67(±10) years and 68% was male. About 50% had one treatment line and about 25% two lines of treatment. Chlorambucil was the most common type of first line chemotherapy. Prior diagnosis, 44% were hospitalized for any cause and 94% had at least one drug dispensing. After chemotherapy, this was 43% and 98%, respectively. One-year survival rate after diagnosis was 94%. Median PFS after first treatment line was 17 months for patients starting within 6 months and 27 months for patients starting ≥6 months after diagnosis. In conclusion, most CLL patients receiving chemotherapy were treated with chlorambucil. One-year after initial diagnosis, 94% were still alive. Median PFS after first line chemotherapy ranged from 17 to 27 months, depending on the timing of chemotherapy

Burden of illness of follicular lymphoma and marginal zone lymphoma

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs.$8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area

Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial

We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade >= 3 adverse events were leucopenia (31.4%) and thrombocytopenia (6.8%). The overall response rate (ORR) by investigator-based assessment was 85.4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86.2% vs. 84.3%). Further follow-up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow-up, 55.5 months); median progression-free survival (PFS) was 35.3 months and median overall survival (OS) was not reached. In patients with high-risk versus standard-risk cytogenetics, median PFS was 19.9 vs. 43.6 months (P<0.0001), and median OS was 54.7 months versus not reached (P=0.0022). VCD is an effective and tolerable induction regimen; results suggest that VCD induces high response rates independently of cytogenetic risk status, but after long-term follow-up, cytogenetic high risk is associated with markedly reduced PFS and OS post-ASCT