Citations

PURPOSEThere remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa.METHODSMEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS).RESULTSThe median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups.CONCLUSIONThe sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Objective To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment. Methods A daily headache diary was completed during the 12-week, double-blind treatment phase of a placebo-controlled trial comparing erenumab 70 mg, 140 mg, and placebo, and weeks 1–12, 21–24, 37–40, and 49–52 of the open-label treatment phase. Chronic migraine to episodic migraine reversion rates were assessed over the double-blind treatment phase; persistent reversion to episodic migraine over 24 weeks (double-blind treatment phase through the first 12 weeks in the open-label treatment phase), long-term persistent reversion to episodic migraine over 64 weeks (double-blind treatment phase plus open-label treatment phase); delayed reversion to episodic migraine through the first 12 weeks of the open-label treatment phase among patients remaining in chronic migraine during the double-blind treatment phase. Results In the double-blind treatment phase, 53.1% (95% confidence interval: 47.8–58.3) of 358 erenumab-treated completers had reversion to episodic migraine; monthly reversion rates to episodic migraine were typically higher among patients receiving 140 mg versus 70 mg. Among 181 completers (receiving erenumab for 64 weeks), 98 (54.1% [95% confidence interval: 46.6–61.6]) had reversion to episodic migraine during the double-blind treatment phase; of those, 96.9% (95% confidence interval: 91.3–99.4) had persistent reversion to episodic migraine, 96.8% (95% confidence interval: 91.1–99.3) of whom had long-term persistent reversion to episodic migraine. Delayed reversion to episodic migraine occurred in 36/83 (43.4% [95% confidence interval: 32.5–54.7]) patients; of these, 77.8% (95% confidence interval: 60.9–89.9) persisted in reversion through week 64. Conclusions Patients with reversion to episodic migraine at week 12 will likely persist as episodic migraine with longer-term erenumab; others may achieve delayed reversion to episodic migraine. Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02066415

The microbiome plays an important role in human health by mediating the path from environmental exposures to health outcomes. The relative abundances of the high‐dimensional microbiome data have an unit‐sum restriction, rendering standard statistical methods in the Euclidean space invalid. To address this problem, we use the isometric log‐ratio transformations of the relative abundances as the mediator variables. To select significant mediators, we consider a closed testing‐based selection procedure with desirable confidence. Simulations are provided to verify the effectiveness of our method. As an illustrative example, we apply the proposed method to study the mediation effects of murine gut microbiome between subtherapeutic antibiotic treatment and body weight gain, and identify Coprobacillus and Adlercreutzia as two significant mediators.

Abstract Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2–targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.

Background: The rapid reduction in tumor burden by the oral B-cell lymphoma-2 inhibitor venetoclax (Ven) poses a risk of tumor lysis syndrome (TLS) for patients (pts) with chronic lymphocytic leukemia (CLL). The approved 5-week Ven dose ramp-up, along with prophylaxis and monitoring, effectively mitigate this risk of TLS but also introduce some logistical challenges to starting the drug. Moreover, the long ramp-up period may lead to clinical deterioration while pts are receiving lower doses, particularly for those with rapid disease progression after B-cell receptor pathway inhibitor (BCRi) therapy. Accelerated Ven dose ramp-up has been explored in a limited number of prior studies, including the prospective M14-032 trial (Jones et al. Lancet Oncol 2018) and a single-center retrospective study (Koenig et al. ASH 2019); these studies had conflicting results with regard to the risk of TLS. We conducted a multicenter study to systematically characterize the safety profile and feasibility of an accelerated Ven ramp-up schedule in pts with previously treated CLL. Methods: This is a retrospective chart review from 4 large academic US medical centers of 36 pts with relapsed/refractory CLL and a documented ramp-up period of <5 weeks (duration at treating physician's discretion). The study period was defined from 1 month before to 1 month after ramp-up. TLS risk before Ven initiation was assessed per the label. Safety endpoints included the proportion of pts who experienced Grade ≥3 adverse events (AEs), TLS per Howard criteria (laboratory, clinical, or any reported TLS), and/or metabolic abnormalities observed during ramp-up. Feasibility of accelerated ramp-up was measured by assessing the proportion of pts who reached the target 400-mg dose or an alternative stable dose, defined as continuous/stable Ven dosing for ≥1 month after ramp-up. Descriptive statistics were calculated. Results: The median age at Ven initiation was 67.5 years (range 53-84) and 58.3% of pts had deletion 17p or TP53 mutation (Table 1). Pts were heavily pretreated (median of 3 lines of prior therapy [range 1-7]) and 88.9% had prior BCRi therapy; 27 pts (75.0%) had BCRi as immediate prior line of therapy before Ven. Before Ven initiation, 7 pts (19.4%) were at high risk of TLS, 13 (36.1%) at medium risk of TLS, and 15 (41.7%) at low risk of TLS; 1 unknown. Last line of therapy was discontinued in 30 pts (83.3%). Twenty-one pts (58.3%) received Ven monotherapy, 11 (30.6%) received Ven plus rituximab, 1 (2.8%) received Ven plus obinutuzumab, and 3 (8.3%) received Ven plus other (including ibrutinib, duvelisib, or idelalisib). Thirty-three pts (91.7%) underwent accelerated ramp-up as an inpatient, with a median hospital stay of 11 days (range 3-28). A stable dose of Ven was reached by 34 pts (94.4%), with median time of 15 days (range 3-66) to stable dose. Twenty-eight of these 34 pts (82.4%) reached the full 400 mg as their stable dose, with median time of 19.5 days (range 11-66). Overall, 15 pts (41.7%) experienced Grade ≥3 AEs and 4 (11.1%) discontinued Ven during ramp-up (2 pts due to clinical TLS, and 1 patient each due to persistent cytopenias and enrollment in hospice care). Seven pts (19.4%) had TLS (5 [13.9%] laboratory, 2 [5.6%] clinical), and 9 pts (25.0%) developed a metabolic abnormality only that did not meet Howard criteria for TLS (Table 2). Both pts with clinical TLS received Ven ramp-up while hospitalized; 1 high risk and 1 medium risk at baseline. Life-threatening (Grade 4) acute kidney injury and hypovolemic shock were reported for both. Of those pts with TLS, 4 (57.1%) required supportive medications. All AEs of TLS (including clinical events) resolved. Conclusion: In this multicenter study exploring accelerated Ven ramp-up, 82% of pts reached a stable dose of Ven 400 mg. TLS was observed in 19% of pts, including 2 pts with clinical TLS, which in both cases was reversible. Our data suggest that although the risk of TLS with an accelerated ramp-up appears to be greater than with 5-week Ven ramp-up per label, an accelerated Ven ramp-up schedule appears feasible at experienced academic centers with close inpatient monitoring. This dosing regimen may be beneficial for relapsed CLL pts with aggressive disease, particularly those progressing immediately after BCRi therapy. While promising, the approach cannot be routinely recommended until results are validated in a prospective clinical trial. Disclosures Davids: BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; AbbVie: Consultancy; Eli Lilly: Consultancy; MEI Pharma: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy; Gilead Sciences: Consultancy; Zentalis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Surface Oncology: Research Funding. Shadman:TG therapeutics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Gilead: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Ended employment in the past 24 months. Parikh:GlaxoSmithKline: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Chen:AbbVie: Other: Institutional research grants, Research Funding. Johnson:AbbVie: Other: Institutional research grants, Research Funding. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Llamas:AbbVie: Current Employment, Other: may hold stock or options. Feng:AbbVie: Current Employment, Other: may hold stock or options. Khan:ICON plc: Current Employment, Other: a company contracted by AbbVie for this study. Lamanna:MingSight: Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Columbia University Medical Center: Current Employment; Juno: Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Research Funding. OffLabel Disclosure: "Venetoclax is a BCL-2 inhibitor indicated: for treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. CLL/SLL: Dosing with venetoclax begins with a 5-week ramp-up."

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.

Abstract Rationale Obesity is associated with pulmonary arterial hypertension (PAH), but its impact on outcomes such as health-related quality of life (HRQoL), hospitalizations, and survival is not well understood. Objectives To assess the effect of obesity on HRQoL, hospitalizations, and survival in patients with PAH. Methods We performed a cohort study of adults with PAH from the Pulmonary Hypertension Association Registry, a prospective multicenter registry. Multivariate linear mixed-effects regression was used to examine the relationship between weight categories and HRQoL using the Short Form-12 and emPHasis-10. We used multivariable negative binomial regression to estimate hospitalization incidence rate ratios (IRRs) and Cox regression to estimate hazard ratios (HRs) for transplant-free survival by weight status. Results A total of 767 subjects were included (mean age of 57 years, 74% female, 33% overweight, and 40% with obesity), with median follow-up duration of 527 days. Overweight patients and patients with obesity had higher baseline emPHasis-10 scores (worse HRQoL), which persisted over time (P < 0.001). Patients who are overweight and obese have a trend toward increased incidence of hospitalizations compared with normal-weight patients (IRR, 1.34; 95% confidence interval [95% CI], 0.94–1.92 and IRR, 1.33; 95% CI 0.93–1.89, respectively). Overweight patients and patients with obesity had lower risk of transplant or death compared with normal-weight patients (HR, 0.45; 95% CI, 0.25–0.80 and HR, 0.39; 95% CI, 0.22–0.70, respectively). Conclusions In a large multicenter, prospective cohort of PAH, patients who were overweight or obese had worse disease-specific HRQoL despite better transplant-free survival compared with normal-weight patients. Future interventions should address the specific needs of these patients.