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Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes.We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients.Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related.Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia.Amgen.

The ability to predict cell-permeable candidate molecules has great potential to assist drug discovery projects. Large molecules that lie beyond the Rule of Five (bRo5) are increasingly important as drug candidates and tool molecules for chemical biology. However, such large molecules usually do not cross cell membranes and cannot access intracellular targets or be developed as orally bioavailable drugs. Here, we describe a random forest (RF) machine learning model for the prediction of passive membrane permeation rates developed using a set of over 1000 bRo5 macrocyclic compounds. The model is based on easily calculated chemical features/descriptors as independent variables. Our random forest (RF) model substantially outperforms a multiple linear regression model based on the same features and achieves better performance metrics than previously reported models using the same underlying data. These features include: (1) polar surface area in water, (2) the octanol-water partitioning coefficient, (3) the number of hydrogen-bond donors, (4) the sum of the topological distances between nitrogen atoms, (5) the sum of the topological distances between nitrogen and oxygen atoms, and (6) the multiple molecular path count of order 2. The last three features represent molecular flexibility, the ability of the molecule to adopt different conformations in the aqueous and membrane interior phases, and the molecular "chameleonicity." Guided by the model, we propose design guidelines for membrane-permeating macrocycles. It is anticipated that this model will be useful in guiding the design of large, bioactive molecules for medicinal chemistry and chemical biology applications.

Patients with lymphoproliferative disorders such as CLL and Mantle Cell Lymphoma (MCL) who are resistant to covalent BTK inhibitors (cBTKi), especially if also venetoclax-refractory, have an unmet therapeutic need. Pirtobrutinib, a non-covalent BTK inhibitor, achieves high response rates in cBTKi refractory patients regardless of mechanism of cBTKi resistance. This led to recent accelerated FDA approval in MCL. The toxicity profile in early studies suggests suitability for use in combination approaches. We summarize existing pre-clinical and clinical data with pirtobrutinib.

Survival outcomes for patients with del17p (n=21) treated with ibrutinibrituximab (IR) - Complex vs Non-Complex karyotype.

Changes in hematologic parameters on treatment with ibrutinib and rituximab up to 3 years.

Changes in absolute T cell numbers on treatment with ibrutinib and rituximab up to 3 years.

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Background: Ibrutinib is an active therapy with an acceptable safety profile for patients with chronic lymphocytic leukemia (CLL), including high-risk patients with del17p or with TP53 mutations. Ibrutinib is broadly indicated for the treatment of patients with CLL and specifically including those with 17p deletion. The optimal use of ibrutinib in combination with other agents remains controversial.Experimental Design: We report the long-term outcome [median follow-up of 47 months (range, 36–51 months)] of 40 patients with high-risk CLL, treated on the first ibrutinib combination trial with rituximab (IR). The majority of patients (36/40) were previously treated.Results: Median age was 65 years, and 21 patients (52%) had 17p deletion. Median duration on treatment was 41 months (range, 2–51 months), and median number of treatment cycles was 42 (range, 2–49). Overall response rate was 95%, and 9 patients (23%) attained a complete remission. Twenty-one patients discontinued treatment, 10 due to disease progression, 9 for other causes, and 2 due to stem cell transplantation; the remaining 19 patients continue on ibrutinib. Median progression-free survival for all patients was 45 months, which was significantly shorter in the subgroup of patients with del17p (n = 21, 32.3 months, P = 0.02). Fourteen patients (35%) died, five from progressive disease, five from infections, and four from other causes. Median overall survival has not been reached.Conclusions: IR combination therapy leads to durable remissions in high-risk CLL; the possible benefit from the addition of rituximab is currently explored in a randomized trial. Clin Cancer Res; 23(9); 2154–8. ©2016 AACR.

Changes in serum levels of immunoglobulins on treatment with ibrutinib and rituximab (IR) over time.

Acute myeloid leukemia (AML) can be treated with either high or low-intensity regimens. Highly sensitive assays for measurable residual disease (MRD) now allow for a more precise assessment of response quality. We hypothesized that treatment intensity may not be a key predictor of outcomes assuming an optimal response to therapy is achieved. We performed a single-center retrospective study including 635 patients with newly diagnosed AML responding to either intensive cytarabine/anthracycline-based chemotherapy (IA, n=385) or low-intensity venetoclax-based regimens (LOW + VEN, n=250) and who had adequate flow cytometry-based MRD testing performed at the time of best response. The median overall survival (OS) was 50.2, 18.2, 13.6, and 8.1 months for the IA MRD(-), LOW + VEN MRD(-), IA MRD(+), and LOW + VEN MRD(+) cohorts, respectively. The 2-year cumulative incidence of relapse (CIR) was 41.1%, 33.5%, 64.2%, and 59.9% for the IA MRD(-), LOW + VEN MRD(-), IA MRD(+), and LOW + VEN MRD(+) cohorts, respectively. The CIR was similar between patients within MRD categories irrespective of the treatment regimen received. The IA cohort was enriched for younger patients and more favorable AML cytogenetic/molecular categories. By multivariate analysis (MVA), age, best response (CR/CRi/MLFS), MRD status, and ELN 2017 risk remained significantly associated with OS, whereas best response, MRD status, and ELN 2017 risk were significantly associated with CIR. Treatment intensity was not significantly associated with either OS or CIR. Achievement of MRD-negative complete remission should be the key objective of AML therapy in both high- and low-intensity treatment regimens.

Polymyxins are last-line antibiotics for the treatment of Gram-negative ‘superbugs’. However, nephrotoxicity can occur in up to 60% of patients administered intravenous polymyxins. The mechanisms underpinning nephrotoxicity remain unclear. To understand polymyxin-induced nephrotoxicity, human renal proximal tubule cells were treated for 24 h with 0.1 mM polymyxin B or two new analogues, FADDI-251 or FADDI-287. Transcriptomic analysis was performed, and differentially expressed genes (DEGs) were identified using ANOVA (FDR < 0.2). Cell viability following treatment with polymyxin B, FADDI-251 or FADDI-287 was 66.0 ± 5.33%, 89.3 ± 3.96% and 90.4 ± 1.18%, respectively. Transcriptomics identified 430, 193 and 150 DEGs with polymyxin B, FADDI-251 and FADDI-287, respectively. Genes involved with metallothioneins and Toll-like receptor pathways were significantly perturbed by all polymyxins. Only polymyxin B induced perturbations in signal transduction, including FGFR2 and MAPK signaling. SIGNOR network analysis showed all treatments affected essential regulators in the immune system, autophagy, cell cycle, oxidative stress and apoptosis. All polymyxins caused significant perturbations of metal homeostasis and TLR signaling, while polymyxin B caused the most dramatic perturbations of the transcriptome. This study reveals the impact of polymyxin structure modifications on transcriptomic responses in human renal tubular cells and provides important information for designing safer new-generation polymyxins.

New antifungals with unique modes of action are urgently needed to treat the increasing global burden of invasive fungal infections. The fungal inositol polyphosphate kinase (IPK) pathway, comprised of IPKs that convert IP

Coastal locations around the United States, particularly along the Atlantic coast, are experiencing recurrent flooding at high tide. Continued sea-level rise (SLR) will exacerbate the issue where present, and many more locations will begin to experience recurrent high-tide flooding (HTF) in the coming decades. Here we use established SLR scenarios and flooding thresholds to demonstrate how the combined effects of SLR and nodal cycle modulations of tidal amplitude lead to acute inflections in projections of future HTF. The mid-2030s, in particular, may see the onset of rapid increases in the frequency of HTF in multiple US coastal regions. We also show how annual cycles and sea-level anomalies lead to extreme seasons or months during which many days of HTF cluster together. Clustering can lead to critical frequencies of HTF occurring during monthly or seasonal periods one to two decades prior to being expected on an annual basis. High-tide flooding (HTF) is more likely with sea-level rise. Projections along the United States coastline, considering likely sea-level rise and tidal amplitude cycles, suggest increased HTF event clustering in time and rapid increases in annual HTF frequency as early as the mid-2030s.

Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Kerry L Hancock,1 Sinthia Bosnic-Anticevich,2– 4 John D Blakey,5,6 Mark Hew,7,8 Li Ping Chung,9 Biljana Cvetkovski,3 Scott Claxton,10 Peter Del Fante,11 Eve Denton,7,8 Joe Doan,12 Kanchanamala Ranasinghe,13,14 Lucy Morgan,15– 17 Anita Sharma,18 Peter K Smith,19 Deb Stewart,20 Philip J Thompson,21– 23 Russell Wiseman,24 John W Upham,25 Kwok Y Yan,26 Victoria Carter,27 Kiranjeet Dhillon,28 Florian Heraud,28 Thao Le,27 Rebecca Vella,28 David Price27– 30 On behalf of the OPCA Improving Asthma outcomes in Australia Research Group1Chandlers Hill Surgery, Happy Valley, SA, 5159, Australia; 2Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; 3Woolcock Institute of Medical Research, Glebe, MSW, 2037, Australia; 4Sydney Local Health District, Camperdown, NSW, 2050, Australia; 5Respiratory Medicine, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, WA, 6009, Australia; 6Curtin University Medical School, Bentley, Western Australia, 6102, Australia; 7Allergy, Asthma & Clinical Immunology, Alfred Health, Melbourne, VIC, 3004, Australia; 8Public Health and Preventive Medicine, Monash University, Victoria, 3800, Australia; 9Fiona Stanley Hospital, 11 Robin Warren Dr, Murdoch, WA, 6150, Australia; 10Genesis Care Sleep and Respiratory, Joondalup, WA, 6027, Australia; 11Hutt Street General Practice, Adelaide, SA, 5000, Australia; 12HealthPlus Medical Centre, Kogarah, NSW, 2217, Australia; 13School of Medicine, Griffith University, Nathan, QLD, Australia; 14Cannon Hill Family Doctors, Cannon Hill, QLD, 4170, Australia; 15Sydney Medical School, University of Sydney, Sydney, NSW, Australia; 16Department of Thoracic Medicine, Concord Hospital, Sydney, NSW, Australia; 17Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia; 18Platinum Medical Centre, Chermside, QLD, 4032, Australia; 19Griffith University, Southport, QLD, Australia; 20Adjunct Lecturer, School of Medicine, University of Tasmania, Churchill Ave, Hobart, TAS, 7005, Australia; 21The Lung Health Clinic, Hollywood Medical Centre, Nedlands, 6009, Australia; 22The University of Western Australia, Perth, Western Australia, 6009, Australia; 23Curtin University, Bentley, Western Australia, 6102, Australia; 24Suncoast Medical Centre, Coolum Beach, QLD, 4573, Australia; 25Diamantina Institute & PA-Southside Clinical Unit, the University of Queensland, Woolloongabba, QLD, 4102, Australia; 26Department of Respiratory Medicine, W, Camperdown, NSW, 2050, Australia; 27Optimum Patient Care, Cambridgeshire, CB24 3BA, UK; 28Optimum Patient Care Australia, Brisbane, QLD, 4000, Australia; 29Observational and Pragmatic Research Institute, Midview City, 573969, Singapore; 30Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UKCorrespondence: David Price, Optimum Patient Care Australia, 320 Adelaide St, Brisbane, QLD, 4000, Australia, Tel +4 05 764 842, Email dprice@opri.sgIntroduction: Asthma poses a significant burden for the Australian population. Understanding severe exacerbation rates, and steroid-related burden for adults diagnosed with asthma stands to offer insights into how this could be reduced.Methods: Electronic medical records (EMR) and questionnaires from the Optimum Patient Care Research Database Australia (OPCRDA) were utilised retrospectively. OPCRDA is a real-world database with > 800,000 medical records from Australian primary care practices. Outcomes were severe asthma exacerbations in Australian adults, over a 12-month period, stratified by Global Initiative for Asthma (GINA) treatment intensity steps, and steroid associated comorbidities.Results: Of the 7868 adults treated for asthma, 19% experienced at least one severe exacerbation in the last 12-months. Severe exacerbation frequency increased with treatment intensity (≥ 1 severe exacerbation GINA 1 13%; GINA 4 23%; GINA 5a 33% and GINA 5b 28%). Questionnaire participants reported higher rates of severe exacerbations than suggested from their EMR (32% vs 23%) especially in steps 1, 4 and 5. Patients repeatedly exposed to steroids had an increased risk of osteoporosis (OR 1.95, 95% CI 1.43– 2.66) and sleep apnoea (OR 1.78, 95% CI 1.30– 2.46).Conclusion: The Australian population living with GINA 1, 4, 5a and 5b asthma have high severe exacerbation rates and steroid-related burden, especially when compared to other first world countries, with these patients needing alternative strategies or possibly specialist assessment to better manage their condition.Keywords: asthma, exacerbations, oral corticosteroids, adults, Australia

Chemoimmunotherapy with combined fludarabine, cyclophosphamide and rituximab (FCR) has been an effective treatment for patients with chronic lymphocytic leukemia (CLL). We initiated a phase II trial for previously untreated patients with CLL with mutated IGHV and absence of del(17p)/TP53 mutation. Patients received ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for three cycles. Patients who achieved complete remission (CR)/CR with incomplete count recvoery (CRi) with marrow undetectable measurable residual disease (U-MRD) received additional nine cycles of ibrutinib with three cycles of obinutuzumab; all others received nine additional cycles of ibrutinib and obinutuzumab. Patients in marrow U-MRD remission after cycle 12 discontinued all treatment, including ibrutinib. Forty-five patients were treated. The median follow-up is 41.3 months. Among the total 45 treated patients, after three cycles, 38% achieved CR/CRi and 87% achieved marrow U-MRD. After cycle 12, the corresponding numbers were 67% and 91%, respectively. Overall, 44/45 (98%) patients achieved marrow U-MRD as best response. No patient had CLL progression. The 3-year progression-free survival (PFS) and overall survival (OS) were 98% and 98%, respectively. Per trial design, all patients who completed cycle 12 discontinued ibrutinib, providing for a time-limited therapy. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% patients, respectively. The iFCG regimen with only 3 cycles of chemotherapy is an effective, time-limited regimen for patients with CLL with mutated IGHV and without del(17p)/TP53 mutation.

Chronic lymphocytic leukaemia (CLL) rarely presents in adolescent and young adult (AYA) patients (patients aged 15-39 years). Disease characteristics and outcomes of AYA patients with CLL are not well understood, particularly in the era of novel oral targeted therapies. We analysed outcomes of 227 AYA patients with CLL diagnosed in the last two decades and evaluated at our institution. Median time to first treatment (TTFT) was 2·2 years, and five- and 10-year overall survival (OS) were 90% and 78%, respectively. Pre-treatment elevated beta 2-microglobulin, advanced Rai stage, del(11q) or del(17p) by FISH, unmutated IGHV and CD38 positivity were associated with both shorter TTFT and OS. Within the subgroup of patients who received oral targeted therapy at any time, del(11q) or del(17p) and complex karyotype were associated with shorter OS. First-line treatment choice was significantly associated with time to second treatment (P < 0·001). Patients harbouring del(11q) or del(17p) experienced shorter time to Richter transformation and were more likely to undergo an allogeneic stem cell transplant. There was a significant association between age and both OS and time to Richter transformation. Our study is the first analysis of AYA patients with CLL with a large number of patients treated with oral targeted therapies.