BACKGROUND Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was −348 μg per liter (95% confidence interval, −517 to −179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)

Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods Males aged 12-50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible.

Introduction: Nuwiq â (human-cl rhFVIII) is a 4 th generation recombinant human FVIII, without chemical modification or protein fusion, produced in a human cell-line. Aims/Methods: This study (NuPreviq) was a prospective, open-label, multicentre, phase IIIb study of the efficacy and safety of personalized prophylaxis with Nuwiq â in 66 previously treated adults with severe haemophilia A. NuPreviq had three phases: (i) a 72-h pharmacokinetic (PK) phase; (ii) a 1-3 month standard prophylaxis phase; and (iii) a 6-month personalized prophylaxis phase. The personalized prophylaxis regimen was based on individual PK modelling for each patient according to whether their PK profile most closely fitted a two-or one-compartment model (NuPreviq approach). In cases of uncertainty, a noncompartment model was applied. Results: The median dosing interval during personalized prophylaxis was 3.5 days, with 57% of patients on ≤2 weekly dosing. Mean annualized bleeding rates during personalized prophylaxis were 1. .1% of patients were spontaneous bleed-free. Compared with standard prophylaxis, median weekly prophylaxis dose was reduced by 7.2% from 100.0 to 92.8 IU kg À1 during the last 2 months of personalized prophylaxis. There were no FVIII inhibitors or treatment-related serious or severe adverse events. Conclusion: PK-guided personalized prophylaxis with Nuwiq â provided bleeding protection and enabled the dosing interval to be extended to twice weekly or less in many patients and an overall dose reduction.

Introduction: Chemoimmunotherapy has become a standard approach in previously untreated and also in pretreated CLL. Addition of Rituximab to FC in fit patients has proven superior to chemotherapy alone and more recently aCD20 treatment was shown to improve outcomes in patients treated with Chlorambucil, suggesting that immunotherapy may be of benefit, independent of the chosen chemotherapy backbone. In follicular and mantle cell lymphoma rituximab maintenance treatment has become a clinical standard. While we and others have presented Phase II data on the feasibility of Rituximab maintenance after chemoimmunotherapy induction, there are currently no available randomized data on the efficacy of such an approach. Study design: Patients were recruited after informed consent at the end of any Rituximab-containing induction treatment in 1st or 2nd line that achieved at least a PR. Excluded were patients with uncontrolled bacterial or viral infections and conditions that might severely affect life-expectancy (such as other malignancy, heart disease etc). The trial was registered at clinicaltrials.gov with the identifier NCT01118234. Randomization was stratified by country, line of treatment, induction response and type of induction regimen. Primary endpoint was PFS and a planned sample-size of 256 patients was calculated. All patients were recruited in participating centers between September 2009 and December 2013. An interim analysis was planned to be conducted after half of the planned events (i.e. 46) were observed and is presented here. Results: The current analysis includes 263 patients enrolled into the trial. Patients had a median age of 63 years, 28.9% were female and 80.6% were enrolled after 1st induction treatment. Hierarchical FISH cytogenetic risk was available in 221 patients: del17p 3.1%, del11q 27.6%, tris 12 10.8%, del13q 36.2%, and normal FISH karyotype 21.2%. IgVH Mutation state was available in 161 patients at time of interim analysis and 67% were unmutated. The induction regimen was FCR in 73.5% and BR in 20.2%, the response to induction treatment was CR/CRi in 58% and PR in 41.8% of patients and 57% scored negative in an 8-colour MRD flowcytometric analysis after induction. Rituximab treatment was allocated to 134 patients and 129 were in the observation arm. No significant imbalances in randomization were found in the above-mentioned parameters. Median observation time is currently 17.3 months. Regarding toxicities the current state of monitoring allows an analysis on the level of SAEs only. SAE causes were well balanced between arms with the exception of infectious SAEs - 32 in the rituximab and 22 in the observation arm, 3 deaths were attributed to infections (1 in the rituximab arm and 2 in the observation arm) - and secondary malignancies (8 in the rituximab arm vs. 1 in the observation arm). Four of the neoplasms in the rituximab arm were localized non-melanoma skin cancers and the 2 deaths from malignomas occurred one in each arm. Regarding efficacy, currently 27.9% have progressed in the observation arm and 14.9% in the rituximab arm. Ten patients died in the observation arm and 7 in the rituximab arm. The primary endpoint (PFS) is significantly in favour of rituximab maintenance (see Fig) with a p-value of 0.007 and a PFS at 17.3 months of 85.1% vs.75.5% in rituximab vs. observation arms, respectively. To account for toxicities and secondary neoplasms an EFS was calculated counting secondary malignancies, termination of treatment due to toxicities, progression or death as events. In this analysis the benefit was preserved, albeit with a lower p-value of 0.03. The observed benefit seemed independent from response after induction (CR vs. PR), but associated with positive MRD state after induction. Further factors that influenced the benefit in exploratory subgroup analyses were sex, cytogenetics, IgVH and B-symptoms at diagnosis. Conclusions: Rituximab maintenance after chemoimmunotherapy induction in CLL seems feasible, although with an increase in infectious complications, and shows signs of efficacy in this interim analysis. The presented interim analysis refutes the alternative hypothesis and allows the trial to continue. Exploratory analyses suggest that with longer follow-up it may be possible to define subpopulations with larger benefit from extended immunotherapy. Figure: PFS by treatment arm (Observation arm: …; Rituximab arm: __) Figure:. PFS by treatment arm (Observation arm: …; Rituximab arm: __) Disclosures Greil: Roche: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Off Label Use: Rituximab in Maintenace Treatment of CLL. Kozak:Roche: Honoraria, Travel grants Other. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharm: Consultancy, Honoraria. Petzer:Celgene: Honoraria, unrestricted grant Other. Egle:Roche: Honoraria, Research Funding, Travel Grants Other.

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