Faculty Bibliography

Introduction: Natalizumab, approved for 300 mg intravenous every-4-weeks dosing, is associated with PML risk. Objective(s): To determine whether natalizumab EID is associated with reduced PML risk compared with SID. Patients and Methods: Average dosing intervals (ADIs) were >= 3 to < 5 weeks for SID and > 5 to <= 12 weeks for EID. The primary analysis assessed ADI in the last 18 months of infusion history. The secondary analysis identified any prolonged period of EID at any time in the infusion history. The tertiary analysis assessed ADI over the full infusion history. Result(s): In primary analyses, median exposure (months) was 44 for SID and 59 for EID. The PML HR (95% confidence interval) was 0.06 (0.01-0.22; P < 0.001) for primary and 0.12 (0.05-0.29; P < 0.001) for secondary analyses; no EID PML cases were observed in tertiary analyses (Kaplan-Meier log-rank test P = 0.02). Discussion(s): NA. Conclusion(s): In JCV Ab + patients, natalizumab EID is associated with a clinically and statistically significant reduction in PML risk as compared with SID.

We evaluated the feasibility of ruxolitinib therapy followed by a reduced intensity conditioning (RIC) regimen for myelofibrosis (MF) patients undergoing transplant in a two stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and non-relapse mortality (NRM) in comparison to previous Myeloproliferative Disorders Research consortium 101 study. The plan was to enrol 11 patients each in related donor (RD), and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) or ≥6 failures occurred in the RD and URD arm, respectively. A total of 21 patients were enrolled (RD, 7; URD, 14). The RD arm did not meet the pre-determined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated due to poor accrual and significant failures. F Of the 19 patients undergoing transplant, ruxolitinib was tapered successfully in each patient without significant side effects, and 9 patients (47%) had significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute and chronic graft-versus-host disease at 24 months were 16%, 28%, 64% and 76%, respectively. On an intention to treat basis, the 2-year overall survival (OS) for RD and URD arms was 51% and 70%, respectively. Ruxolitinib can be integrated as pre-transplant treatment for MF patients, and a tapering strategy prior to transplant is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant. The trial is registered at www.clinicaltrials.gov (NCT01790295).

Objective: We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with nephrotic syndrome compared to healthy controls. Study Design: Plasma zonulin levels were measured by ELISA in 114 children enrolled in the NEPTUNE study. Clinical and laboratory data were retrieved from the NEPTUNE database. Results: The median age of the patients was 10 (IQR = 5 to 14) years, 59 were male, 64 had minimal change disease, 47 focal segmental glomerulosclerosis, median eGFR was 96 (IQR = 80 to 114) ml/min/1.73 m², and median urine protein:creatinine ratio was 0.5 (IQR = 0.1 to 3.4) (g:g). The plasma zonulin level was 14.2 ± 5.0 vs. 10.2 ± 2.5 ng/ml in healthy adults in a report using the same assay kit, P = 0.0025. These findings were confirmed in an independent cohort of children with nephrotic syndrome compared to healthy age-matched controls, P = 0.01. Zonulin concentrations did not differ in children with minimal change disease vs. focal segmental glomerulosclerosis, frequently relapsing vs. steroid-dependent vs. steroid-resistant clinical course, and were not influenced by the immunosuppressive treatment regimen. There was no relationship between plasma zonulin levels and the absolute or percentage change in proteinuria from enrollment until the time of the zonulin assay. Conclusion: Plasma zonulin levels are elevated in childhood nephrotic syndrome regardless of level of proteinuria or specific treatment. The cause of the high plasma zonulin levels and whether zonulin contributes to glomerular injury requires further study.

Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m² per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.

PURPOSE/OBJECTIVE:Hypofractionated whole-breast radiation therapy (RT) has proved to be equivalent to conventionally fractionated RT in multiple randomized trials. There is controversy regarding its use in younger women because of their underrepresentation in trials and the concern for late toxicity. We evaluated disease control and cosmetic outcomes in patients aged <50 years treated with hypofractionated RT in 4 prospective single-institutional trials. METHODS AND MATERIALS/METHODS:From 2003 to 2015, 1313 patients were enrolled in 4 prospective protocols investigating the use of adjuvant hypofractionated RT after breast-conserving surgery with a daily or weekly concomitant boost. We identified the records of 348 patients aged <50 years at consultation for this analysis. Overall survival, disease-free survival, and local recurrence-free survival were estimated using the Kaplan-Meier method by study and across studies using meta-analytic methods. The late effects of RT, clinician-rated cosmesis, and patient-rated cosmesis were also evaluated. RESULTS:With a median follow-up period of 66.9 months, the overall survival rate was 99.6%, the disease-free survival rate was 96.3%, and the local recurrence-free survival rate was 97.7% at 3 years. Clinician-rated cosmesis (n = 242) was excellent or good in 93.4% of cases and fair or poor in 6.6%. Patient-rated cosmesis (n = 259) was excellent or good in 86.1% and fair or poor in 13.9%. When patients rated themselves differently than their physicians, patients more often rated themselves poorly compared with their physicians (P = .0044, Cochran-Mantel-Haenszel test). CONCLUSIONS:At a median follow-up of 5 years, an analysis of patients aged <50 years demonstrated that hypofractionated RT was safe and effective, with good to excellent cosmesis as assessed by both clinicians and patients.

PURPOSE/OBJECTIVE:This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients. EXPERIMENTAL DESIGN/METHODS:Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, with focal radiotherapy to a metastatic site at week 1, (3 doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5 and 15 to isolate PBMCs, plasma and serum. RESULTS:Twenty-three patients were randomized, median age 57 (range 35 to 77). Seven grade 3/4 adverse events occurred in 5/11 patients in the 1mg/kg arm and in 2/12 patients in the 10mg/kg arm, respectively. Response was limited to 3 stable disease. At a median follow up of 12 months, 20/23 patients are deceased. Patients receiving the 10mg/kg had a significantly higher median overall survival than those receiving 1mg/kg fresolimumab dose (hazard ratio: 2.73 with 95% CI: 1.02, 7.30; p=0.039). The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. CONCLUSIONS:TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.

Background and aims: Natalizumab, approved for intravenous 300mg every 4 weeks dosing, is associated with a risk of PML. Previous analyses of US TOUCH registry data found that, in anti-JC virus antibody positive (JCV Ab+) patients, natalizumab EID was associated with significantly lower PML risk compared with standard interval dosing (SID; Table). Those analyses were limited to patients with known JCV Ab seropositive status and excluded patients with infusions at >12-week intervals (ie, dosing gaps). Sensitivity and post-hoc analyses were conducted to explore the robustness of these results. Methods: In the previous primary analysis, SID was based on average dosing intervals (ADIs) of >=3 to <5 weeks; EID was based on ADIs of >5 to <=12 weeks. In prespecified sensitivity analyses, alternative EID definitions and inclusion of PML cases occurring pre-2012, prior to JCV Ab testing, was evaluated. A post hoc analysis included patients with dosing gaps. EID and SID PML hazard ratios (HRs) were compared with covariate (age, sex, prior immunosuppressant use, initiation calendar year, and infusion number)-adjusted Cox regression models and Kaplan-Meier estimates. Results: Across all sensitivity and post-hoc analyses, HRs and 95% CIs were similar to those in the primary analysis. Conclusion: In the US, natalizumab EID is associated with a statistically significant, clinically meaningful lower PML risk in JCV Ab+ patients compared with SID; changes in EID definition and inclusion/exclusion criteria did not reveal differences from the primary analysis. As TOUCH does not collect effectiveness data, EID's benefit-risk could not be evaluated

BACKGROUND: The King-Devick (K-D) test of rapid number naming is a reliable visual performance measure that is a sensitive sideline indicator of concussion when time scores worsen (lengthen) from preseason baseline. Within cohorts of youth athletes <18 years old, baseline K-D times become faster with increasing age. We determined the relation of rapid number-naming time scores on the K-D test to electronic measurements of saccade performance during preseason baseline assessments in a collegiate ice hockey team cohort. Within this group of young adult athletes, we also sought to examine the potential role for player age in determining baseline scores. METHODS: Athletes from a collegiate ice hockey team received preseason baseline testing as part of an ongoing study of rapid rink-side performance measures for concussion. These included the K-D test (spiral-bound cards and tablet computer versions). Participants also performed a laboratory-based version of the K-D test with simultaneous infrared-based video-oculographic recordings using an EyeLink 1000+. This allowed measurement of the temporal and spatial characteristics of eye movements, including saccadic velocity, duration, and intersaccadic interval (ISI). RESULTS: Among 13 male athletes, aged 18-23 years (mean 20.5 +/- 1.6 years), prolongation of the ISI (a combined measure of saccade latency and fixation duration) was the measure most associated with slower baseline time scores for the EyeLink-paired K-D (mean 38.2 +/- 6.2 seconds, r = 0.88 [95% CI 0.63-0.96], P = 0.0001), the K-D spiral-bound cards (36.6 +/- 5.9 seconds, r = 0.60 [95% CI 0.08-0.87], P = 0.03), and K-D computerized tablet version (39.1 +/- 5.4 seconds, r = 0.79 [95% CI 0.42-0.93], P = 0.001). In this cohort, older age was a predictor of longer (worse) K-D baseline time performance (age vs EyeLink-paired K-D: r = 0.70 [95% CI 0.24-0.90], P = 0.008; age vs K-D spiral-bound cards: r = 0.57 [95% CI 0.03-0.85], P = 0.04; age vs K-D tablet version: r = 0.59 [95% CI 0.06-0.86], P = 0.03) as well as prolonged ISI (r = 0.62 [95% CI 0.11-0.87], P = 0.02). Slower baseline K-D times were not associated with greater numbers of reported prior concussions. CONCLUSIONS: Rapid number-naming performance using the K-D at preseason baseline in this small cohort of collegiate ice hockey players is best correlated with ISI among eye movement-recording measures. Baseline K-D scores notably worsened with increasing age, but not with numbers of prior concussions in this small cohort. While these findings require further investigation by larger studies of contact and noncontact sports athletes, they suggest that duration of contact sports exposure may influence preseason test performance.