Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia.

We observed that high-dose methylprednisolone (HDMP) and rituximab was well tolerated and had promising activity when used in combination to treat patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). This prompted us to evaluate the use of these agents in frontline therapy. A total of 28 patients with a median age of 65 years enrolled in this study. Patients received HDMP at 1 g/m(2) each day for 3 days during each of the three 4-week cycles together with rituximab and prophylactic antimicrobial therapy. The treatment was well tolerated with few adverse events of grade III or higher. The overall response rate was 96% (N=27). Nine patients (32%) achieved a complete remission (CR), two of which were without detectable minimal residual disease (MRD). Six patients with MRD received consolidation with alemtuzumab; five of these patients achieved an MRD-negative CR. With over 3 years of follow-up median progression-free survival was 30.3 months with only 39% of patients requiring additional therapy, and an overall survival was 96%. This study demonstrates that HDMP and rituximab is an effective nonmyelosuppressive treatment combination for patients with CLL that warrants consideration particularly for patients with limited myeloid reserve that might not tolerate standard treatment regimens

Serum sodium changes in marathon participants who use NSAIDs

Introduction: The primary mechanism through which the development of exercise-associated hyponatraemia (EAH) occurs is excessive fluid intake. However, many internal and external factors have a role in the maintenance of total body water and non-steroidal anti-inflammatory medications (NSAIDs) have been implicated as a risk factor for the development of EAH. This study aimed to compare serum sodium concentrations ([Na]) in participants taking an NSAID before or during a marathon (NSAID group) and those not taking an NSAID (control group). Methods: Participants in a large city marathon were recruited during race registration to participate in this study. Blood samples and body mass measurements took place on the morning of the marathon and immediately post marathon. Blood was analysed for [Na]. Data collected via questionnaires included athlete demographics, NSAID use and estimated fluid intake. Results: We obtained a full data set for 28 participants. Of these 28 participants, 16 took an NSAID on the day of the marathon. The average serum [Na] decreased by 2.1 mmol/L in the NSAID group, while it increased by 2.3 mmol/L in the control group NSAID group (p=0.0039). Estimated fluid intake was inversely correlated with both post-marathon serum [Na] and ∆ serum [Na] (r=-0.532, p=0.004 and r=-0.405 p=0.032, respectively). Conclusion: Serum [Na] levels in participants who used an NSAID decreased over the course of the marathon while it increased in those who did not use an NSAID. Excessive fluid intake during a marathon was associated with a lower post-marathon serum [Na]

Case Series of Triathletes with Takotsubo Cardiomyopathy Presenting with Swimming-Induced Pulmonary Edema

OBJECTIVES: To report three cases of triathletes who presented with swimming-induced pulmonary edema (SIPE) following water immersion. They were subsequently diagnosed with Takotsubo cardiomyopathy (TCM). DESIGN: Retrospective case series. METHOD: All cases were recreational athletes competing in mass participation triathlons between June 2018 and 2019. They were initially managed by the event medical team and subsequently at the local tertiary level hospital. Written consent was gained from all the subjects. RESULTS: The three triathletes were aged between 50 and 60 years, two were females, and all presented with acute dyspnoea on exiting the water. Two also presented with chest pain and haemoptysis. A diagnosis of SIPE was suspected by the medical event team on initial presentation of low oxygen saturations and clinical signs of pulmonary oedema. All were transferred to the local emergency department and had signs of pulmonary oedema on chest radiographs. Further investigations led to a diagnosis of TCM with findings of T wave inversion in anterolateral electrocardiogram leads and apical hypokinesia on transthoracic echocardiogram and unobstructed coronary arteries. CONCLUSIONS: This case series presents triathletes diagnosed with SIPE and TCM following the open water swim phase. It is unclear whether the myocardial dysfunction contributed to causation of SIPE or was the result of SIPE. Mass participation race organizers must be prepared that both SIPE and TCM can present in this population. Those presenting with an episode of SIPE require prompt evaluation of their cardiac and pulmonary physiology. Further research is required to ascertain the exact nature of the relationship between TCM and SIPE

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia.

The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage

Real-world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

© 2019 by The American Society of Hematology Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n 5 195) and PCYC-1115/1116 (RESONATE-2, n 5 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n 5 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n 5 173, 52% any-grade; n 5 15, 5% grade 3) and fatigue (n 5 119, 36% any-grade; n 5 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n 5 60, 18%) and pneumonia (n 5 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade $3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n 5 4), anemia (n 5 3), and atrial fibrillation (n 5 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069

Wnt5a induces ROR1 to associate with 14-3-3ζ for enhanced chemotaxis and proliferation of chronic lymphocytic leukemia cells.

Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia (CLL) cells by inducing the recruitment of ARHGEF2 to ROR1. Mass spectrometry on immune precipitates of Wnt5a-activated ROR1 identified 14-3-3ζ, which was confirmed by co-immunoprecipitation. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells by treatment with cirmtuzumab, a humanized mAb targeting ROR1. Silencing 14-3-3ζ via small interfering RNA impaired the capacity of Wnt5a to: (1) induce recruitment of ARHGEF2 to ROR1, (2) enhance in vitro exchange activity of ARHGEF2 and (3) induce activation of RhoA and Rac1 in CLL cells. Furthermore, CRISPR/Cas9 deletion of 14-3-3ζ in ROR1-negative CLL cell-line MEC1, and in MEC1 cells transfected to express ROR1 (MEC1-ROR1), demonstrated that 14-3-3ζ was necessary for the growth/engraftment advantage of MEC1-ROR1 over MEC1 cells. We identified a binding motif (RSPS857SAS) in ROR1 for 14-3-3ζ. Site-directed mutagenesis of ROR1 demonstrated that serine-857 was required for the recruitment of 14-3-3ζ and ARHGEF2 to ROR1, and activation of RhoA and Rac1. Collectively, this study reveals that 14-3-3ζ plays a critical role in Wnt5a/ROR1 signaling, leading to enhanced CLL migration and proliferation

Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia

© 2020 The Authors Ibrutinib positively modulates many T-cell subsets in chronic lymphocytic leukemia (CLL). To understand ibrutinib\u27s effects on the broader landscape of immune cell populations, we comprehensively characterized changes in circulating counts of 21 immune blood cell subsets throughout the first year of treatment in patients with relapsed/refractory (R/R) CLL (n = 55, RESONATE) and previously untreated CLL (n = 50, RESONATE-2) compared with untreated age-matched healthy donors (n = 20). Ibrutinib normalized abnormal immune cell counts to levels similar to those of age-matched healthy donors. Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes. T-cell function was assessed in response to T-cell receptor stimulation in patients with R/R CLL (n = 21) compared with age-matched healthy donors (n = 18). Ibrutinib significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets. These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function

Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

BackgroundPatients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. MethodsIn this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. ResultsThe median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15;