Part 1 results of the open-label, randomized, global phase 3 SPARKLE trial supported continued assessment of ibrutinib with either modified rituximab, ifosfamide, carboplatin, and etoposide (RICE) or rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) in pediatric patients with relapsed/refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL). We report final results of Part 2 evaluating the efficacy of ibrutinib plus RICE or RVICI vs RICE/RVICI alone. Patients aged 1 to 30 years (initial diagnosis <18 years) were randomized 2:1 to receive ibrutinib with or without RICE/RVICI. Primary endpoint was event-free survival (EFS) based on independent committee-confirmed events. Fifty-one patients were enrolled. Median age was 15 years; Burkitt lymphoma, Burkitt leukemia, and Burkitt-like lymphoma (total: 45%) and diffuse large B-cell lymphoma/primary mediastinal B-cell lymphoma (51%) were the most common subtypes. At the preplanned interim analysis, median EFS was 6.1 vs 7.0 months with ibrutinib plus RICE/RVICI vs RICE/RVICI, respectively (hazard ratio, 0.9; 90% confidence interval, 0.5-1.6; P = .387); further enrollment was ceased. With ibrutinib plus RICE/RVICI vs RICE/RVICI, median overall survival was 14.1 vs 11.1 months, overall response rate was 69% vs 81%, and 46% vs 44% proceeded to stem cell transplantation. In both treatment arms, 100% of patients experienced grade ≥3 treatment-emergent adverse events. No EFS benefit was seen with ibrutinib. Salvage was generally poor in patients who received prior rituximab, regardless of treatment arm. No new safety signals were observed. Ibrutinib exposure in pediatric patients fell within the target range of exposure in adults. Trial is registered on www.clinicaltrials.gov (NCT02703272).

• MeSH
• Lymphoma, Large B-Cell, Diffuse * MeSH
• Child MeSH
• Etoposide MeSH
• Ifosfamide * MeSH
• Carboplatin MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Rituximab MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Etoposide MeSH
• ibrutinib MeSH Browser
• Ifosfamide * MeSH
• Carboplatin MeSH
• Rituximab MeSH

BACKGROUND: We provide an overview of Bayesian estimation, hypothesis testing, and model-averaging and illustrate how they benefit parametric survival analysis. We contrast the Bayesian framework to the currently dominant frequentist approach and highlight advantages, such as seamless incorporation of historical data, continuous monitoring of evidence, and incorporating uncertainty about the true data generating process. METHODS: We illustrate the application of the outlined Bayesian approaches on an example data set, retrospective re-analyzing a colon cancer trial. We assess the performance of Bayesian parametric survival analysis and maximum likelihood survival models with AIC/BIC model selection in fixed-n and sequential designs with a simulation study. RESULTS: In the retrospective re-analysis of the example data set, the Bayesian framework provided evidence for the absence of a positive treatment effect of adding Cetuximab to FOLFOX6 regimen on disease-free survival in patients with resected stage III colon cancer. Furthermore, the Bayesian sequential analysis would have terminated the trial 10.3 months earlier than the standard frequentist analysis. In a simulation study with sequential designs, the Bayesian framework on average reached a decision in almost half the time required by the frequentist counterparts, while maintaining the same power, and an appropriate false-positive rate. Under model misspecification, the Bayesian framework resulted in higher false-negative rate compared to the frequentist counterparts, which resulted in a higher proportion of undecided trials. In fixed-n designs, the Bayesian framework showed slightly higher power, slightly elevated error rates, and lower bias and RMSE when estimating treatment effects in small samples. We found no noticeable differences for survival predictions. We have made the analytic approach readily available to other researchers in the RoBSA R package. CONCLUSIONS: The outlined Bayesian framework provides several benefits when applied to parametric survival analyses. It uses data more efficiently, is capable of considerably shortening the length of clinical trials, and provides a richer set of inferences.

• Keywords
• Bayes factor, Bayesian, Historical data, Model-averaging, Survival analysis,
• MeSH
• Bayes Theorem MeSH
• Humans MeSH
• Colonic Neoplasms * drug therapy   MeSH
• Disease-Free Survival MeSH
• Retrospective Studies MeSH
• Research Design * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

IMPORTANCE: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). OBJECTIVE: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. DESIGN, SETTING, AND PARTICIPANTS: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization. INTERVENTION: Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events. RESULTS: A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group. CONCLUSIONS AND RELEVANCE: Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02393859.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy   mortality   therapy   MeSH
• Child MeSH
• Immunotherapy * MeSH
• Kaplan-Meier Estimate MeSH
• Infant MeSH
• Combined Modality Therapy MeSH
• Consolidation Chemotherapy adverse effects   MeSH
• Leukemia, B-Cell drug therapy   mortality   MeSH
• Humans MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Follow-Up Studies MeSH
• Child, Preschool MeSH
• Disease-Free Survival MeSH
• Antibodies, Bispecific adverse effects   therapeutic use   MeSH
• Antineoplastic Agents adverse effects   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Recurrence MeSH
• Risk Factors MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH
• Names of Substances
• blinatumomab MeSH Browser
• Antibodies, Bispecific MeSH
• Antineoplastic Agents MeSH

PURPOSE: Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed. PATIENTS AND METHODS: The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization. RESULTS: Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 v 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; P < .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 v 12.9 months; HR, 0.586; P < .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% v 8.0%), vomiting (24.2% v 4.3%), and diarrhea (23.2% v 12.3%). There was no increase in new primary malignancies (5.2% v 6.2%); rates of on-study deaths were 2.6% versus 2.2%. CONCLUSION: Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.

• MeSH
• Progression-Free Survival MeSH
• Double-Blind Method MeSH
• Glycine adverse effects   analogs & derivatives   therapeutic use   MeSH
• Proteasome Inhibitors adverse effects   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Multiple Myeloma drug therapy   MeSH
• Placebos MeSH
• Antineoplastic Agents adverse effects   therapeutic use   MeSH
• Aged MeSH
• Boron Compounds adverse effects   therapeutic use   MeSH
• Stem Cell Transplantation MeSH
• Maintenance Chemotherapy MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Glycine MeSH
• Proteasome Inhibitors MeSH
• ixazomib MeSH Browser
• Placebos MeSH
• Antineoplastic Agents MeSH
• Boron Compounds MeSH

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

• MeSH
• Radiotherapy, Adjuvant MeSH
• Transplantation, Autologous MeSH
• Time Factors MeSH
• Child MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Sarcoma, Ewing mortality   secondary   therapy   MeSH
• Risk Assessment MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local MeSH
• Adolescent MeSH
• Young Adult MeSH
• Bone Neoplasms mortality   pathology   therapy   MeSH
• Lung Neoplasms mortality   secondary   therapy   MeSH
• Neoadjuvant Therapy * adverse effects   mortality   MeSH
• Pneumonectomy MeSH
• Child, Preschool MeSH
• Disease Progression MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   adverse effects   MeSH
• Risk Factors MeSH
• Hematopoietic Stem Cell Transplantation * adverse effects   mortality   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Research Support, N.I.H., Extramural MeSH
• Comparative Study MeSH
• Geographicals
• Europe MeSH

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.

• Publication type
• Journal Article MeSH

PURPOSE: Patients with ischemic cardiomyopathy (ICM) are prone to scar-related ventricular tachycardia (VT). The success of VT ablation depends on accurate arrhythmogenic substrate localization, followed by optimal delivery of energy provided by constant electrode-tissue contact. Current manual and remote magnetic navigation (RMN)-guided ablation strategies aim to identify a reentry circuit and to target a critical isthmus through activation and entrainment mapping during ongoing tachycardia. The MAGNETIC VT trial will assess if VT ablation using the Niobe™ ES magnetic navigation system results in superior outcomes compared to a manual approach in subjects with ischemic scar VT and low ejection fraction. METHODS AND RESULTS: This is a randomized, single-blind, prospective, multicenter post-market study. A total of 386 subjects (193 per group) will be enrolled and randomized 1:1 between treatment with the Niobe ES system and treatment via a manual procedure at up to 20 sites. The study population will consist of patients with ischemic cardiomyopathy with left ventricular ejection fraction (LVEF) of ≤35% and implantable cardioverter defibrillator (ICD) who have sustained monomorphic VT. The primary study endpoint is freedom from any recurrence of VT through 12 months. The secondary endpoints are acute success; freedom from any VT at 1 year in a large-scar subpopulation; procedure-related major adverse events; and mortality rate through 12-month follow-up. Follow-up will consist of visits at 3, 6, 9, and 12 months, all of which will include ICD interrogation. CONCLUSIONS: The MAGNETIC VT trial will help determine whether substrate-based ablation of VT with RMN has clinical advantages over manual catheter manipulation. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02637947.

• Keywords
• Atrial fibrillation, Catheter ablation, Heart failure, Ischemic cardiomyopathy, Robotic magnetic navigation, Ventricular tachycardia,
• MeSH
• Adult MeSH
• Ventricular Dysfunction, Left diagnostic imaging   etiology   prevention & control   MeSH
• Single-Blind Method MeSH
• Catheter Ablation methods   MeSH
• Tachycardia, Ventricular complications   diagnostic imaging   surgery   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetics MeSH
• Body Surface Potential Mapping methods   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Stroke Volume MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Geographicals
• United States MeSH