Low-Dose Weekly Decitabine and Venetoclax in TP53-Mutated Myeloid Malignancies

Decitabine (Dec) and Azacitidine (Aza) that target DNA methyltransferase 1 (DNMT1) are hypomethylating agents (HMAs) approved to treat acute myeloid leukemia (AML) in combination with Venetoclax (Ven). The combination is also used to treat high-risk myelodysplastic syndromes, especially TP53-mutated (TP53mut) cases in which responses to HMA alone are short-lived. In most patients (pts), however, myelosuppression from treatment leads to frequent Ven duration and/or dose-reductions, and/or cycle delays. An approach to decrease HMA-mediated myelosuppression but maintain S-phase dependent DNMT1-targeting, evaluated in a previous clinical trial (https://doi.org/10.1111/bjh.16281), is to administer noncytotoxic doses/concentrations of Dec (0.2 mg/kg; ~5 mg/m 2) by a frequent-distributed schedule of 1X/week. An approach to decrease Ven mediated myelosuppression but maintain cooperation with HMA, shown in pre-clinical studies, is to administer a single-dose prior to HMA. Ven can depolarize mitochondrial membranes; mitochondrial membrane-potential is essential to function of the mitochondrial enzyme DHODH that produces cytidine/deoxycytidine that competes with HMA in cells. Thus, Ven prior to HMA dosing temporarily inhibits de novo pyrimidine synthesis, to counter a major mechanism of resistance to HMA in MDS/AML, without suppressing normal myelopoiesis (https://doi.org/10.1182/blood-2020-143200). We conducted a retrospective analysis of all pts with TP53mut MDS or AML treated with weekly Ven and low-dose subcutaneous Dec at our institution. We analyzed the characteristics of these pts, response to therapy, and outcomes using standard descriptive statistics. Mutational testing was performed using a commercial next-generation sequencing (NGS) panel. Five pts, 3 male and 2 female, with TP53mut MDS or AML were treated with weekly Ven 400 mg on D1 and subcutaneous Dec 0.2 mg/kg on D2, administered weekly in 28 day cycles. Two pts had MDS (1 de novo, 1 treatment related) and 3 pts had AML (1 de novo, 2 secondary from prior MDS). Four pts (80%) received the treatment in frontline, all with poor performance status (PS), and 1 pt (20%) had R/R disease. Median age at diagnosis was 79 years [41-82]. The only young pt had prolonged severe cytopenias after 1 cycle Dec standard dosing during the peak of COVID-19 pandemic so was switched to this regimen. Of the 4 frontline treated pts, 2 pts had high-risk MDS, and 2 pts had adverse risk AML. The R/R pt had high-risk MDS transformed to AML that was refractory to 2 prior lines of therapy: standard Aza/Ven x5 cycles, then standard Vyxeos. Disease cytogenetics were complex in all pts. 60% (3/5) pts had sole TP53mut on NGS, with median variant allelic frequency (VAF) 48% [28-79]. 80% (4/5) pts were transfusion dependent prior to treatment. Median time to initiating therapy was 7 days from initial or refractory diagnosis [3-59] and median follow-up was 7.8 months (mo) [2.9-11.4]. The overall response rate (ORR) was 100%: 4/4 frontline pts had complete remissions (CR), and the 1 R/R pt achieved morphologic leukemia-free state (MLFS). Median time to best response was 2.9 mo. 50% (2/4) pts became transfusion independent. 40% (2/5) pts lost their TP53mut at best response, and another 40% (2/5) pts had significant reductions (83% and 38%) in TP53 mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects (AE) . AE included G3/G4 neutropenia (80%), G1 thrombocytopenia (40%), nausea (20%), fatigue (20%), lower extremity edema (20%), pneumonia (60%), and neutropenic fever (20%) with a median of 1 unplanned hospitalization per pt during follow-up. 60% (3/5) pts remain in CR on continued therapy for a median of 7.8 mo [7.2-9.4] thus far. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. No pt had measurable relapse during follow-up. Combination weekly Ven with subcutaneous low-dose Dec is well tolerated yielding high rates of clinical and molecular response in pts with TP53mut MDS/AML. Although small, this case-series extends previous clinical trial proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population. The regimen allowed frequent, sustained exposure to therapy often not possible with standard HMA/Ven regimens. Figure 1 Figure 1. Disclosures Shastri: Kymera Therapeutics: Research Funding; Guidepoint: Consultancy; GLC: Consultancy; Onclive: Honoraria. Gritsman: iOnctura: Research Funding. Feldman: Glycomimetics: Current Employment, Current holder of stock options in a privately-held company. Verma: Celgene: Consultancy; Acceleron: Consultancy; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Novel insights into irritability: the relationship between subjective experience, age and mood

Background The relationship between irritability as a subjective experience and the behavioural indicators typically used to measure the construct are not known. Its links to mood, and contextual relationships, vary with age and are yet to be thoroughly examined. Aims First, to interrogate the relationship between the subjective experience of irritability and mood, and that with its behavioural indicators. Second, to determine how these relationships vary with age and over time. Method This study examined data from a previous clinical trial of adolescents and young adults (N = 82) with bipolar disorder, who received a psychological intervention over 18 months. Participants completed a battery of questionnaires, which included assessments of irritability. Analyses of covariance were conducted to examine the interaction between mood symptoms, subjective measures of irritability, behavioural measures of irritability and age over time. Results Subjective irritability scores differed significantly over time when controlling for manic, but not depressive, symptom scores. Further, subjective irritability significantly differed when controlling for behavioural measures of irritability (temper outbursts and argumentativeness). There were significant interactions between scores of depressive symptoms, temper outbursts and subjective irritability with age, wherein younger participants showed no correlation between depressive symptoms and temper outbursts. In addition, younger participants showed lower correlations between subjective irritability and both depressive and temper outburst scores, than older participants. Conclusions Subjective irritability is linked to mood morbidity and behavioural outbursts, and these relationships are contingent on age. Our novel findings suggest that subjective irritability should be assessed in greater detail in patients with mood disorders.

Investigation of Therapeutic Response Markers for Acupuncture in Parkinson’s Disease: An Exploratory Pilot Study

In this preliminary pilot study, we investigated the specific genes implicated in the therapeutic response to acupuncture in patients with Parkinson’s disease (PD). Transcriptome alterations following acupuncture in blood samples collected during our previous clinical trial were analyzed along with the clinical data of six patients with PD, of which a representative patient was selected for transcriptomic analysis following acupuncture. We also examined the changes in the expression of PD biomarker genes known to be dysregulated in both the brain and blood of patients with PD. We validated these gene expression changes using quantitative real-time polymerase chain reaction (qPCR) in the blood of the remaining five patients with PD who received acupuncture treatment. Following acupuncture treatment, the transcriptomic alterations in the representative patient were similar to those induced by dopaminergic therapy. Among the PD biomarkers, ankyrin repeat domain 22 (ANKRD22), upregulated following dopaminergic therapy, and synapsin 1 (SYN1), a common gene marker for synaptic dysfunction in PD, were upregulated following acupuncture. These alterations correlated with changes in gait parameters in patients with PD. Our data suggest ANKRD22 and SYN1 as potential biomarkers to predict/monitor therapeutic responses to acupuncture in patients with PD, especially in those with gait disturbance. Further research is needed to confirm these findings in a large sample of patients with PD.

Recirculatory Fibrinolytic-Assisted External Ventricular Drainage (EVD) for Intraventricular Hemorrhage

Background Elevated intracranial pressure and acute obstructive hydrocephalus secondary to intraventricular hemorrhage (IVH) can be treated by external ventricular drainage (EVD). The treatment time and the risk of EVD-related complications can be reduced with fibrinolytic agents’ instillation via an EVD catheter, but previous clinical trial results did not reveal a significant improvement in terms of long-term functional outcomes. A recirculatory fibrinolytic-assisted EVD system was designed. The clot dissolution effectiveness of the system under different drug dosages and fluid flow rates was tested in an ex vivo model. Results The results showed that the mean clot mass was quickly reduced in an initial fibrinolytic agent dose-independent stage, followed by a dose-dependent stage. Elevating fibrinolytic agent dosages beyond a certain threshold did not contribute to shorter dissolution times. Optimal treatment parameters for such a system were determined. A recirculatory flow rate of 10–18 ml/min with a low-dose of 30 000–60 000 IU of uPA resulted in an 80% clot mass reduction within four hours. Conclusions This recirculating fibrinolytic system is a promising novel modification of conventional IVH treatment that could reduce clot dissolution times and procedure-related complications.

Urinary Metabolomic Profile of Preterm Infants Receiving Human Milk with Either Bovine or Donkey Milk-Based Fortifiers

Fortification of human milk (HM) for preterm and very low-birth weight (VLBW) infants is a standard practice in most neonatal intensive care units. The optimal fortification strategy and the most suitable protein source for achieving better tolerance and growth rates for fortified infants are still being investigated. In a previous clinical trial, preterm and VLBW infants receiving supplementation of HM with experimental donkey milk-based fortifiers (D-HMF) showed decreased signs of feeding intolerance, including feeding interruptions, bilious gastric residuals and vomiting, with respect to infants receiving bovine milk-based fortifiers (B-HMF). In the present ancillary study, the urinary metabolome of infants fed B-HMF (n = 27) and D-HMF (n = 27) for 21 days was analyzed by 1H NMR spectroscopy at the beginning (T0) and at the end (T1) of the observation period. Results showed that most temporal changes in the metabolic responses were common in the two groups, providing indications of postnatal adaptation. The significantly higher excretion of galactose in D-HMF and of carnitine, choline, lysine and leucine in B-HMF at T1 were likely due to different formulations. In conclusion, isocaloric and isoproteic HM fortification may result in different metabolic patterns, as a consequence of the different quality of the nutrients provided by the fortifiers.

Evaluating biomarkers for treatment selection from reproducibility studies

Summary We consider evaluating new or more accurately measured predictive biomarkers for treatment selection based on a previous clinical trial involving standard biomarkers. Instead of rerunning the clinical trial with the new biomarkers, we propose a more efficient approach which requires only either conducting a reproducibility study in which the new biomarkers and standard biomarkers are both measured on a set of patient samples, or adopting replicated measures of the error-contaminated standard biomarkers in the original study. This approach is easier to conduct and much less expensive than studies that require new samples from patients randomized to the intervention. In addition, it makes it possible to perform the estimation of the clinical performance quickly, since there will be no requirement to wait for events to occur as would be the case with prospective validation. The treatment selection is assessed via a working model, but the proposed estimator of the mean restricted lifetime is valid even if the working model is misspecified. The proposed approach is assessed through simulation studies and applied to a cancer study.

The Knowledge and Opinions of Indian Researchers Regarding India’s New Drugs and Clinical Trial Regulations:An Online Survey (Preprint)

BACKGROUND Although a few studies examined possible problems regarding the previous clinical trial regulatory guideline issued in 2016, no study investigated the awareness and opinions of researchers about the new regulatory guidelines issued in 2019. OBJECTIVE This study aimed to describe the Indian researchers’ knowledge and views regarding India’s new drug and clinical trial rules of 2019. METHODS A cross-sectional online questionnaire study was carried out by randomly selecting various Indian researchers (men and women) from multiple sources between July 2019 and September 2019. The survey questionnaires, which had already been validated, were developed using Google Forms. A web link was generated for participants to take the survey. Descriptive statistics, such as counts and percentages or means and standard deviations, were computed to describe the demographic characteristics, knowledge, and views of Indian researchers. RESULTS Out of 106 researchers, 75 researchers (70.8%), and 65 their managers, and clinical staff (61.3%) knew the new regulations. Further, 36 (63.2%), 32 (53.1%), and 31 (54.5%) researchers were agreed with the reduction in the timeline, free post-trial drug access, and welcoming equality, respectively. Further, 37 researchers (64.9%) agreed with the new changes on how to deal with severe adverse effects and compensation. Overall, 34 researchers (59.6%) accepted the new rules. Additionally, 71 researchers (67%) said that the new regulations would mostly impact on profit clinical trial studies. Generally, 91 researchers (87.5%) deemed that the new rules are highly favorable to the promotion of clinical research in India. CONCLUSIONS The majority of researchers have the knowledge, agreed with the changes and deemed that the new regulations of 2019 are highly favorable to the promotion of clinical research in India.

Determining clinically meaningful decline in preclinical Alzheimer disease

ObjectiveTo determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)–related decline.MethodsIn 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect.ResultsCognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures.ConclusionsA preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%–50% delays clinically relevant impairment by 3 years—a potentially meaningful treatment effect. However, assuming a 40%–50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.

Patients’ understanding of clinical research: An Italian cancer patient survey

Introduction: Patients’ awareness of clinical research and their involvement in clinical trials is of great importance, but it is difficult to estimate the extent of knowledge on the research being undertaken. Methods: We evaluated the level of knowledge about clinical research using a self-reporting survey distributed to 967 adult patients with cancer attending the Departments of Medical Oncology and Onco-Haematology Units of IRST IRCCS and 4 hospitals in the region of Emilia-Romagna, Italy. The questionnaire was composed of 10 specific items on research knowledge. Patients responding correctly to at least 8 of the 10 items were considered to have a good understanding of clinical research. Results: The questionnaire was completed by 769 patients (response rate 79.5%). Only 19% of patients were found to have a good understanding of clinical research. Patients with higher education and those who had previous clinical trial experience showed a significantly better understanding. Fifty-three percent of patients said that they would be willing to participate in a trial studying a new drug and 75% expressed an interest in taking part in informative meetings/events about clinical studies. Conclusions: Our results show that patients’ understanding of clinical research is limited and highlight an interest in learning more.