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

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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

Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma

Hodgkin, 9p24Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2. Pembrolizumab, a programmed death 1-blocking antibody, demonstrated a high overall response rate (ORR) in patients with relapsed or refractory classic Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 ( ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of pembrolizumab in three cohorts of patients with rrHL, defined on the basis of lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without BV after transplantation. Patients received pembrolizumab 200 mg once every 3 weeks. Response was assessed every 12 weeks. The primary end points were ORR by central review and safety. Results A total of 210 patients were enrolled and treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). At the time of analysis, patients received a median of 13 treatment cycles. Per central review, the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was 22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2% for cohort 2, and 70.0% for cohort 3. Thirty-one patients had a response 65 6 months. The safety profile was largely consistent with previous pembrolizumab studies. Conclusion Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease

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

Perception of Thermal Pain and the Thermal Grill Illusion Is Associated with Polymorphisms in the Serotonin Transporter Gene

AIM: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI. RESULTS: Thresholds to heat- and cold-pain correlated strongly (rho  = -0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p = 0.02) and cold-pain (p = 0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p = 0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men. CONCLUSION/SIGNIFICANCE: We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms