Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib

The Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side-effects of ibrutinib. The second generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with Non-Hodgkin Lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide (CRP-XL) and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, while size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited SFKs and that SFKs have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of vWF and FVIII ex vivo by addition of intermediate purity FVIII (haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma vWF and FVIII

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.

BACKGROUND: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. METHODS: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils  1. Baseline HR23B expression was assessed by immunohistochemistry. RESULTS: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3-4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2-5.4) in solid-organ cancers and 2.6 months (95%CI 1.2-5.6) in lymphomas. HR23B status did not predict response. CONCLUSIONS: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013

Infection-related morbidity and mortality among older patients with DLBCL treated with full- or attenuated-dose R-CHOP

Infection-related morbidity and mortality are increased in older patients with diffuse large B-cell lymphoma (DLBCL) compared with population-matched controls. Key predictive factors for infection-related hospitalization during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and deaths as a result of infection in older patients during and after treatment with R-CHOP remain incompletely understood. For this study, 690 consecutively treated patients age 70 years or older who received full-dose or attenuated-dose R-CHOP treatment were analyzed for risk of infection-related hospitalization and infection-related death. Median age was 77 years, and 34.4% were 80 years old or older. Median follow-up was 2.8 years (range, 0.4-8.9 years). Patient and baseline disease characteristics were assessed in addition to intended dose intensity (IDI). Of all patients, 72% were not hospitalized with infection. In 331 patients receiving an IDI $80$1 infections compared with 23.3% of 355 patients receiving an IDI of,80% (odds ratio, 1.61; 95% confidence interval, 1.15-2.25; P 5 .006). An increased risk of infection-related admission was independently associated with IDI .80% across the whole cohort. Primary quinolone prophylaxis independently reduced infection-related admission. A total of 51 patients died as a result of infection. The 6-month, 12-month, 2-year, and 5-year cumulative incidences of infection-related death were 3.3%, 5.0%, 7.2%, and 11.1%, respectively. Key independent factors associated with infection-related death were an International Prognostic Index (IPI) score of 3 to 5, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score $6, and low albumin, which enabled us to generate a predictive risk score. We defined a smaller group (15%) of patients (IPI score of 0-2, albumin .36 g/L, CIRS-G score,6) in which no cases of infection-related deaths occurred at 5 years of follow-up. Whether patients at higher risk of infection-related death could be targeted with enhanced antimicrobial prophylaxis remains unknown and will require a randomized trial

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Stand-alone intrathecal central nervous system (CNS) prophylaxis provide unclear benefit in reducing CNS relapse risk in elderly DLBCL patients treated with R-CHOP and is associated increased infection-related toxicity

Central nervous system (CNS) relapse following R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) occurs in 2–5% of patents with diffuse large B-cell lymphoma (DLBCL). Many patients aged ≥70 years are unsuitable for high-dose methotrexate (HDMTX) prophylaxis and therefore often receive stand-alone intrathecal prophylaxis. The CNS international prognostic index (CNS-IPI) is a clinical CNS relapse risk score that has not specifically been validated in elderly patients. The value of CNS prophylaxis in patients aged ≥70 years remains uncertain. Data on 690 consecutively R-CHOP-treated DLBCL patients aged ≥70 years were collected across 8 UK centres (2009–2018). CNS prophylaxis was administered per physician preference. Median age was 77·2 years and median follow-up was 2·8 years. CNS-IPI was 1–3 in 60·1%, 4 in 23·8%, 5 in 13·0% and 6 in 3·3%. Renal and/or adrenal (R/A) involvement occurred in 8·8%. Two-year overall CNS relapse incidence was 2·6% and according to CNS-IPI, 1–3:0·8%, 4:3·6%, 5:3·8% and 6:21·8%. Two-year CNS relapse incidence for R/A was 10·0%. When excluding HDMTX (n=31) patients, there remained no change in unadjusted/adjusted CNS relapse for intrathecal prophylaxis effect according to CNS-IPI. CNS-IPI is valid in elderly R-CHOP-treated DLBCL patients, with the highest risk in those with CNS-IPI 6 and R/A involvement. We observed no clear benefit for stand-alone intrathecal prophylaxis but observed an independent increased risk of infection-related admission during R-CHOP when intrathecal prophylaxis was administered