Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B

The Aethera Trial: An Ongoing Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at High Risk of Residual Hodgkin Lymphoma Following Autologous Stem Cell Transplant

n/

Updated Efficacy and Safety Data from the AETHERA Trial of Consolidation with Brentuximab Vedotin after Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse

Abstract Introduction The AETHERA trial is a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov #NCT01100502), which evaluated whether post-ASCT consolidation treatment with brentuximab vedotin (BV) could prevent disease progression in Hodgkin lymphoma (HL) patients at high risk for relapse. The study met its primary endpoint: significant improvement in progression-free survival (PFS) per independent review with BV versus placebo (hazard ratio [HR]=0.57, P=0.001) (Moskowitz, 2015). The 2 most common adverse events (AEs) in the BV- treatment group were peripheral sensory neuropathy (56%) and neutropenia (35%). We are presenting updated efficacy and safety data after approximately 1 additional year of follow-up after the primary analysis. Methods Patients were randomized to receive BV 1.8 mg/kg q3wk or placebo for 16 cycles (approximately 12 months), 30-45 days after transplantation. Randomization was stratified by response to frontline therapy and by best clinical response to pre-ASCT salvage therapy. Patients whose disease had progressed after salvage treatment were not eligible. Patients received CT scans quarterly for the first year and then at 18 and 24 months during long-term follow-up (LTFU). Clinical lymphoma assessments were performed at each cycle of treatment, quarterly during the first year of LTFU, and every 6 months thereafter. AEs were collected for 30 days after the end of treatment, except for peripheral neuropathies and secondary malignancies, which were followed throughout LTFU. Clinical responses to subsequent BV treatment received after progression were also recorded. Results A total of 329 patients were randomized to the BV- (n=165) or placebo- (n=164) treatment arms. Median PFS per investigator assessment was not reached (95% CI not estimable [NE]-NE) in the BV arm and was 15.8 months (95% CI 8.5-44.0) in the placebo arm (HR=0.52, 95% CI 0.37-0.71). A sustained plateau with substantial separation is evident between both treatment groups, with improved PFS at 3-years post-randomization with BV consolidation versus placebo (Figure). The 3-year PFS rate was 61% (95% CI 52-68) for the BV arm and 43% (95% CI 36-51) for the placebo arm. Six PFS events (2 progressions and 4 deaths) were recorded after the 24-month evaluation period in the BV arm and 3 in the placebo arm (2 progressions and 1 death). The HR for PFS per independent review was 0.58 (95% CI 0.41-0.82). No new secondary malignancies have been observed since the primary analysis. The number of cases were comparable between the 2 treatment arms (n=4 BV, n=2 placebo). Malignancies on the BV arm included bladder cancer, lung cancer, pancreatic cancer, and myelodysplastic syndrome (n=1 each). In the placebo arm, secondary malignancies included mantle cell lymphoma and myelodysplastic syndrome (n=1 each). Among the 112 patients on the BV arm who experienced treatment-emergent peripheral neuropathy based on a Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) analysis, 99 patients (88%) experienced some improvement (23%) or complete resolution (65%) of neuropathy symptoms at the time of analysis. Discontinuation of treatment due to an AE occurred in 54 patients (33%) on the BV arm, most commonly due to peripheral sensory and motor neuropathies (14% and 7%, respectively). Patients who discontinued treatment as a result of an AE received a median of 9.5 cycles (range, 1 to 15) on the BV arm. The 2-year PFS rate in these patients was 69% (95% CI 54-79) versus 82% (95% CI 71-89) for patients who completed all 16 treatment cycles. Conclusions Consolidation treatment with BV in HL patients at high risk of relapse after ASCT showed an improvement in PFS versus placebo, approximately 3 years since the last patient was randomized. Kaplan-Meier analysis of PFS per investigator assessment showed a continued benefit of BV consolidation. No additional secondary malignancies have been observed in either treatment arm and most patients experienced resolution of peripheral neuropathy symptoms. We are currently analyzing clinical responses to BV treatment after disease progression. Figure 1. Progression-Free Survival per Investigator Assessment Figure 1. Progression-Free Survival per Investigator Assessment Disclosures Sweetenham: Seattle Genetics Inc.: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. This study investigates the use of brentuximab vedotin for consolidation therapy soon after ASCT. . Walewski:Mundipharma; Roche; Takeda: Honoraria, Other: Travel expenses; Amgen; Boehringer Ingelheim; Celgene; Janssen-Cilag; Mundipharma; Roche; Takeda; Teva: Consultancy; Bayer (Inst); Bayer/Onyx (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celltrion (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); GlaxoSmithKline (Inst); Mundipharma (Inst); Pfizer (Inst); Roche (Inst); Roche/Genentech (Inst); Seattle Geneti: Research Funding. Nademanee:Celgene: Consultancy; Seattle Genetics Inc.: Research Funding; Spectrum: Research Funding; Gilead: Consultancy. Masszi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Agura:Seattle Genetics Inc.: Research Funding. Holowiecki:Seattle Genetics Inc.: Research Funding; Takeda: Other: Travel expenses. Abidi:Seattle Genetics Inc.: Research Funding. Chen:Gilead: Consultancy, Other: Advisory Board; Janssen: Consultancy, Other: Advisory Board; Seattle Genetics: Consultancy, Other: Advisory Board; Genentech, Inc.: Consultancy, Other: Advisory Board. Stiff:Seattle Genetics Inc.: Consultancy, Honoraria, Research Funding. Viviani:Italfarmaco SpA: Consultancy; Teva Italia SpA: Consultancy; Takeda Italia SpA: Consultancy; Takeda International: Consultancy. Carella:Seattle Genetics Inc.: Research Funding. Osmanov:Seattle Genetics Inc.: Research Funding. Bachanova:Seattle Genetics Inc.: Consultancy, Research Funding. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Hunder:Seattle Genetics Inc.: Employment, Equity Ownership

Positron-emission tomography–based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma

Background: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods: In this retrospective study, we identified 1088 patients with grade I–IIIA FL; of whom, 238 patients with stage II–IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Results: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. Conclusion: In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy

Effectiveness of partner social support predicts enduring psychological distress after hematopoietic stem cell transplantation

Objective: Hematopoietic stem cell transplant (HSCT) survivors who are 1 to 3 years posttransplant are challenged by the need to resume valued social roles and activities—a task that may be complicated by enduring transplant-related psychological distress common in this patient population. The present study investigated whether transplant survivors who receive adequate social support from their spouse or intimate partner experience lower distress. Method: Effects of receiving a greater quantity of partner support (a common approach to studying enacted support) were compared with effects of receiving more effective partner support (i.e., support that more closely matches their needs in terms of its quantity and quality). Men and women (N = 230) who were 1 to 3 years posttransplant completed measures of partner support quantity (Manne & Schnoll, 2001), partner social support effectiveness (Rini & Dunkel Schetter, 2010), and psychological distress (Brief Symptom Inventory; Derogatis & Spencer, 1982). Potential medical and sociodemographic confounds were controlled in analyses. Results: As hypothesized, survivors reported less distress when they received more effective partner support (p < .001). Quantity of partner support was not associated with distress (p = .23). An interaction revealed that when partner support was effective, the quantity of support survivors received was not associated with their distress (p = .90); however, when partner support was ineffective, receiving a greater quantity of partner support was associated with substantially elevated distress (p = .002). Conclusions: Findings suggest that clinical approaches to addressing or preventing enduring distress after HSCT should target features of partner support related to its appraised effectiveness

Antidromic vasodilatation and the migraine mechanism

Despite the fact that an unprecedented series of new discoveries in neurochemistry, neuroimaging, genetics and clinical pharmacology accumulated over the last 20 years has significantly increased our current knowledge, the underlying mechanism of the migraine headache remains elusive. The present review article addresses, from early evidence that emerged at the end of the nineteenth century, the role of ‘antidromic vasodilatation’ as part of the more general phenomenon, currently defined as neurogenic inflammation, in the unique type of pain reported by patients suffering from migraine headaches. The present paper describes distinctive orthodromic and antidromic properties of a subset of somatosensory neurons, the vascular- and neurobiology of peptides contained in these neurons, and the clinical–pharmacological data obtained in recent investigations using provocation tests in experimental animals and human beings. Altogether, previous and recent data underscore that antidromic vasodilatation, originating from the activation of peptidergic somatosensory neurons, cannot yet be discarded as a major contributing mechanism of the throbbing head pain and hyperalgesia of migraine

The App-Runx1 Region Is Critical for Birth Defects and Electrocardiographic Dysfunctions Observed in a Down Syndrome Mouse Model

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people