Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

BACKGROUND: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. METHODS: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m2 on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m2 on day 1; intravenous doxorubicin 50 mg/m2, vincristine 1·4 mg/m2, and cyclophosphamide 750 mg/m2 on day 2; oral prednisone 100 mg/m2 on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m2 on day 1, intravenous rituximab 375 mg/m2 on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m2 every 12 h on days 1-3, intravenous rituximab 375 mg/m2 on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 109 cells per L or 10 mg per day for platelets 60-100 × 109 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313). FINDINGS: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events. INTERPRETATION: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. FUNDING: Fondazione Italiana Linfomi and Celgene.

Deep brain stimulation in early-stage Parkinson disease: Five-year outcomes.

OBJECTIVE: To report 5-year outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early-stage Parkinson disease (PD) pilot clinical trial. METHODS: The pilot was a prospective, single-blind clinical trial that randomized patients with early-stage PD (Hoehn & Yahr II off medications) to receive bilateral STN DBS plus optimal drug therapy (ODT) vs ODT alone (IDEG050016, NCT0282152, IRB040797). Participants who completed the 2-year trial participated in this observational follow-up study, which included annual outpatient visits through 5 years. This analysis includes 28 patients who were taking PD medications for 6 months to 4 years at enrollment. Outcomes were analyzed using both proportional odds logistic regression and linear mixed effects models. RESULTS: Early STN DBS + ODT participants required lower levodopa equivalent daily doses (p = 0.04, ß = -240 mg, 95% confidence interval [CI] -471 to -8) and had 0.06 times the odds of requiring polypharmacy at 5 years compared to early ODT participants (p = 0.01, odds ratio [OR] 0.06, 95% CI 0.00 to 0.65). The odds of having worse rest tremor for early STN DBS + ODT participants were 0.21 times those of early ODT participants (p < 0.001, OR 0.21, 95% CI 0.09 to 0.45). The safety profile was similar between groups. CONCLUSIONS: These results suggest that early DBS reduces the need for and complexity of PD medications while providing long-term motor benefit over standard medical therapy. Further investigation is warranted, and the Food and Drug Administration has approved the conduct of a prospective, multicenter, pivotal clinical trial of DBS in early-stage PD (IDEG050016). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DBS implanted in early-stage PD decreases the risk of disease progression and polypharmacy compared to optimal medical therapy alone.

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.

OBJECTIVE: To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset. METHODS: The prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further. RESULTS: UPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT (p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy (p < 0.001, p = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT (p = 0.001). CONCLUSIONS: These results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor.

Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson's Disease Is Not Associated with Increased Body Mass Index.

Previous studies suggest that deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson's disease (PD) leads to weight gain. This study analyzes changes in body mass index (BMI) in 29 subjects from a prospective, single-blind trial of DBS in early stage PD (age 50-75, Hoehn & Yahr stage II off medication, treated with antiparkinsonian medications for ≥6 months but <4 years, and without a history of motor fluctuations, dyskinesias, or dementia). Subjects were randomized to DBS plus optimal drug therapy (DBS+ODT; n = 15) or ODT (n = 14) and followed for 24 months. Weight and height were recorded at baseline and each follow-up visit and used to calculate BMI. BMIs were compared within and between groups using nonparametric t-tests. Mean BMI at baseline was 29.7 in the ODT group and 32.3 in the DBS+ODT group (p > 0.05). BMI change over two years was not different between the groups (p = 0.62, ODT = -0.89; DBS+ODT = -0.17). This study suggests that STN-DBS is not associated with weight gain in subjects with early stage PD. This finding will be tested in an upcoming FDA-approved phase III multicenter, randomized, double-blind, placebo-controlled, pivotal clinical trial evaluating DBS in early stage PD (ClinicalTrials.gov identifier NCT00282152).

Subthalamic Nucleus Deep Brain Stimulation May Reduce Medication Costs in Early Stage Parkinson's Disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson's disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT). OBJECTIVE: The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs. METHODS: Medication data collected at each visit were used to calculate medication costs. Medications were converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS. RESULTS: Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of $7,150 over the study period. Projected medication cost savings over 10 years reach $64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months (p <  0.05; OR = 0.2; 95% CI: 0.04-0.97). CONCLUSIONS: STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD.

Neuropsychological effects of deep brain stimulation in subjects with early stage Parkinson's disease in a randomized clinical trial.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for patients with advanced Parkinson's disease (PD) and motor symptom complications. Recently, attention has been focused on whether offering DBS earlier in the course of PD is beneficial. OBJECTIVE: The purpose of this study was to determine the effects of DBS on neuropsychological functioning in subjects with early stage PD. METHODS: Thirty subjects with early PD (Hoehn & Yahr Stage II off medication) were randomized to optimal drug therapy (ODT) (n = 15) or bilateral subthalamic nucleus (STN) DBS+ODT (n = 15) after completing an expanded informed consent process specially designed for the study and administered by a medical ethicist and the study team. Comprehensive neuropsychological testing was completed in the treatment-withdrawn state at baseline and at 12 month and 24 month follow-ups. RESULTS: Two serious adverse events occurred in the DBS+ODT group. One subject experienced a stroke and another developed infected hardware that contributed to specific declines in cognitive functioning. However, compared to the ODT group, the remaining subjects in the DBS+ODT group exhibited modest reductions on a few measures of attention, executive function, and word fluency at 12 months. These differences were largely diminished at 24 months, especially when those with the adverse events were excluded. CONCLUSIONS: The results of this trial provide novel data regarding the effects of DBS on cognitive function in early PD. We believe that the findings and insights from this trial can help guide the safety analysis and risk-benefit evaluations in future discussions of DBS in early stage PD.

Methods for Surgical Targeting of the STN in Early-Stage Parkinson's Disease.

Patients with Parkinson's disease (PD) experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn-Yahr Stage III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery, the ability to identify this nucleus in early-stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN in 15 patients with early PD (Hoehn-Yahr Stage II), using a combination of image guided surgery, microelectrode recordings, and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates and root mean squared activity) have previously been found to be lower than in later-stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson's patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early-stage PD using traditional methods.

Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson's disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. METHODS: Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50-75, on medication ≥6 months but ≤4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n = 15) or DBS + ODT (n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. RESULTS: As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. CONCLUSIONS: This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD.

Continuation of long-term care for cervical dystonia at an academic movement disorders clinic.

Patients with cervical dystonia (CD) receive much of their care at university based hospital outpatient clinics. This study aimed to describe the clinical characteristics and treatment experiences of patients who continued care at our university based movement disorders clinic, and to document the reasons for which a subset discontinued care. Seventy patients (77% female) were recruited from all patients at the clinic (n = 323). Most (93%) were treated with botulinum neurotoxin (BoNT) injection, and onabotulinumtoxinA was initially used in 97%. The average dose of onabotulinumtoxinA was 270.4 U (range 50-500) and the median number of injections was 14 (range: 1-39). Twenty one patients later received at least one cycle of rimabotulinumtoxinB (33%); of those, 10 switched back to onabotulinumtoxinA (48%). The initial rimabotulinumtoxinB dose averaged 11,996 units (range: 3000-25,000 over 1-18 injections). Twenty one patients (30%) discontinued care. Reasons cited included suboptimal response to BoNT therapy (62%), excessive cost (24%), excessive travel burden (10%), and side effects of BoNT therapy (10%). Most patients (76%) did not seek further care after leaving the clinic. Patients who terminated care received fewer treatment cycles (5.5 vs. 13.0, p = 0.020). There were no other identifiable differences between groups in gender, age, disease characteristics, toxin dose, or toxin formulation. These results indicate that a significant number of CD patients discontinue care due to addressable barriers to access, including cost and travel burden, and that when leaving specialty care, patients often discontinue treatment altogether. These data highlight the need for new initiatives to reduce out-of-pocket costs, as well as training for community physicians on neurotoxin injection in order to lessen the travel burden patients must accept in order to receive standard-of-care treatments.

Pilot study assessing the feasibility of applying bilateral subthalamic nucleus deep brain stimulation in very early stage Parkinson's disease: study design and rationale.

BACKGROUND: Deep brain stimulation provides significant symptomatic benefit for people with advanced Parkinson's disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinson's disease, and results of animal studies suggest that it may spare dopaminergic neurons in the substantia nigra. OBJECTIVE: We report the methodology and design of a novel Phase I clinical trial testing the safety and tolerability of deep brain stimulation in early Parkinson's disease and discuss previous failed attempts at neuroprotection. METHODS: We recently conducted a prospective, randomized, parallel-group, single-blind pilot clinical trial of deep brain stimulation in early Parkinson's disease. Subjects were randomized to receive either optimal drug therapy or deep brain stimulation plus optimal drug therapy. Follow-up visits occurred every six months for a period of two years and included week-long therapy washouts. RESULTS: Thirty subjects with Hoehn & Yahr Stage II idiopathic Parkinson's disease were enrolled over a period of 32 months. Twenty-nine subjects completed all follow-up visits; one patient in the optimal drug therapy group withdrew from the study after baseline. Baseline characteristics for all thirty patients were not significantly different. CONCLUSIONS: This study demonstrates that it is possible to recruit and retain subjects in a clinical trial testing deep brain stimulation in early Parkinson's disease. The results of this trial will be used to support the design of a Phase III, multicenter trial investigating the efficacy of deep brain stimulation in early Parkinson's disease.