Self-reported adherence to oral cancer therapy: relationships with symptom distress, depression, and personal characteristics

Background: Therapeutic cancer chemotherapy is most successful when complete dosing is achieved. Because many newer therapeutic agents are oral and self-administered by the patient, adherence is a concern. The purpose of our analysis was to explore relationships between adherence, patient characteristics, and barriers to adherence. Methods: This secondary analysis utilized self-reported data from a randomized trial of self-care management conducted at two cancer centers in the US. Symptom distress was measured using the 15-item Symptom Distress Scale (SDS-15) and depression with the Patient Health Questionnaire-9 (PHQ-9). Adherence to oral medication was self-reported using the 8-item Morisky Medication Adherence Scale (MMAS-8). Measures were collected via Web-based, study-specific software ~8 weeks after treatment start date. Odds of low/medium adherence (score <8) were explored using univariate logistic regression. Given the number of factors and possible relationships among factors, a classification tree was built in lieu of a multivariable logistic regression model. Results: Of the eligible participants enrolled, 77 were on oral therapy and 70 had an MMAS score. Forty-nine (70%) reported a high adherence score (=8). Higher odds of low/medium adherence were associated with greater symptom distress (P=0.09), more depression (P=0.05), chemotherapy vs hormonal oral medication (P=0.03), being female (P=0.02), and being randomized to the control group in the parent trial (P=0.09). Conversely, high adherence was associated with working (P=0.08), being married/partnered (P=0.004), and being older (P=0.02). Factors identified as significantly related to low/medium adherence from the univariate logistic regression analyses were supported by the classification tree results. Conclusion: Nonadherence to therapeutic oral medications in patients with cancer was associated with being unmarried/unpartnered, symptom distress, younger age, not working, and female sex. These findings may help to identify patients at risk for nonadherence and for whom supportive interventions to enhance adherence may be needed

A state-wide initiative to promote genetic testing in an underserved population

Genetic testing for cancer susceptibility has been widely studied and utilized clinically. Access to genetic services in research and practice is largely limited to well-insured, Caucasian individuals. In 2009, the Cancer Resource Foundation (CRF) implemented the Genetic Information for Treatment Surveillance and Support (GIFTSS) program to cover the out-of-pocket expenses associated with cancer genetic testing, targeting high-risk individuals with limited financial means and limited health insurance coverage. Here, we (i) describe the characteristics of participants in the Massachusetts (MA) GIFTSS program and (ii) evaluate mutations found in this diverse sample. A secondary retrospective data analysis was performed using de-identified demographic data obtained from laboratory requisition forms and cancer genetic testing result information from the laboratory source. Eligible participants were those who utilized the MA GIFFTS program from 2009 through December of 2014. Data were summarized using descriptive measures of central tendency. Participants were residents of Massachusetts who had health insurance and had a reported income within 250-400% of the federal poverty level. Genetic testing results were categorized following clinical guidelines. Overall, 123 (13%) of participants tested positive for a mutation in a cancer susceptibility gene. For those with a cancer diagnosis, 65 (12%) were found to have a positive result and 20 (7%) had a variant of uncertain significance (VUS). For those unaffected patients, 58 (15%) had a positive result and 10 (3%) were found to have a VUS. The results from this study are useful in describing genetic testing outcomes in this high-risk underserved community. Repeatedly, the literature reports that individuals from diverse or limited resource settings are less likely to access genetic testing. Continued research efforts should be devoted to promoting the access of genetic testing in the high-risk, underserved community

Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities

Despite improvements in our understanding of the molecular basis of acute myeloid leukemia (AML), the association between genetic mutations with morphological dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow (BM) specimens from 168 patients with de novo AML; none of these patients had cytogenetic abnormalities according to the 2016 World Health Organization Classification. We then performed targeted sequencing of diagnostic BM aspirates for recurrent mutations associated with myeloid malignancies. We found that cohesin pathway mutations [q (FDR-adjusted P)=0.046] were associated with a higher degree of megakaryocytic dysplasia and STAG2 mutations were marginally associated with greater myeloid lineage dysplasia (q=0.052). Frequent megakaryocytes with separated nuclear lobes were more commonly seen among cases with cohesin pathway mutations (q=0.010) and specifically in those with STAG2 mutations (q=0.010), as well as NPM1 mutations (q=0.022 when considering the presence of any vs. no megakaryocytes with separated nuclear lobes). RAS pathway mutations (q=0.006) and FLT3-ITD (q=0.006) were significantly more frequent in cases without evaluable erythroid cells. In univariate analysis of the 153 patients treated with induction chemotherapy, NPM1 mutations were associated with longer event-free survival (EFS) (P=0.042), while RUNX1 (P=0.042), NF1 (P=0.040), frequent micromegakaryocytes (P=0.018) and presence of a subclone (P=0.002) were associated with shorter EFS. In multivariable modeling, NPM1 was associated with longer EFS, while presence of a subclone and frequent micromegakaryocytes remained significantly associated with shorter EFS

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring “5+2” reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68–96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33–81%) and 42% (90% CI 17–65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843)

Patient-reported symptom distress, and most bothersome issues, before and during cancer treatment

Introduction: Frequently reported symptoms and treatment side effects may not be the most bothersome issues to patients with cancer. The purpose of this study was to investigate patient-reported symptom distress and bothersome issues among participants with cancer. Methods: Participants completed the Symptom Distress Scale-15 before treatment (T1) and during cancer treatment (T2) and reported up to two most bothersome issues among symptoms rated with moderate-to-severe distress. We compared symptom ratings and perceived bother and explored two approaches predicting patients’ most bothersome issues: worst absolute symptom score or worst change from pretreatment. Results: Significantly, (P≤0.0002) more patients reported moderate-to-severe distress at T2 for eight of 13 symptoms. At T1, 81% of patients reported one and 56% reported multiple symptoms with moderate-to-severe distress, while at T2, 89% reported one and 69% reported multiple symptoms with moderate-to-severe distress. Impact on sexual activity/interest, pain, fatigue, and insomnia were the most prevalent symptoms with moderate-to-severe distress. Fatigue, pain, and insomnia were perceived most often as bothersome. When one symptom was rated moderate-to-severe, predictive accuracy of the absolute score was 46% and 48% (T1 & T2) and 38% with the change score (T2–T1). When two or more symptoms were rated moderate-to-severe, predictive accuracy of the absolute score was 76% and 79% (T1 & T2) and 70% with the change score (T2–T1). Conclusion: More patients experienced moderate-to-severe symptom distress after treatment initiation. Patient identification of bothersome issues could not be assumed based on prevalence of symptoms reported with moderate-to-severe distress. The absolute symptom distress scores identified patients’ most bothersome issues with good accuracy, outperforming change scores

A randomized, open-label, cross-over pilot study investigating metabolic product kinetics of the palatable novel ketone ester, bis-octanoyl (R)-1,3-butanediol, and bis-hexanoyl (R)-1,3-butanediol ingestion in healthy adults

Introduction Bis-octanoyl (R)-1,3-butanediol (BO-BD) is a novel, palatable ketone ester that, when consumed, is hydrolyzed in the gastrointestinal tract into octanoic acid (OCT) and (R)-1,3-butanediol (BDO) which are subsequently metabolized into beta-hydroxybutyrate (BHB). Metabolism of BO-BD is hypothesized to be similar to bis-hexanoyl (R)-1,3-butanediol (BH-BD), apart from release of octanoic acid instead of hexanoic acid (HEX). Methods As part of the safety assessment for BO-BD a randomized, cross-over, open-label study in middle-aged, healthy adults ( n = 12) was undertaken to provide a qualitative comparison of plasma BHB, OCT, HEX and BDO concentrations for 8 h following consumption of 12.5 or 25  g of BO-BD and 12.5  g of BH-BD. Results All study products increased plasma BHB and BDO up to 4 h post-consumption. BH-BD increased HEX, whereas BO-BD increased OCT. All kinetic parameters for BHB and BDO were similar between 12.5  g servings of BH-BD and BO-BD while C max and AUC for OCT were higher following 12. 5  g servings of BO-BD as compared to HEX with 12.5  g of BH-BD. All metabolites returned to baseline by 8 h post-consumption. BHB, BDO and OCT C max and AUC were increased with serving size of BO-BD from 12.5 to 25  g . Sensory acceptability scores of BO-BD were significantly higher than for BH-BD. An in vitro hydrolysis experiment using human blood plasma further confirmed that plasma esterases possess the ability to break down the novel ketone esters into BDO, and OCT or HEX. Discussion The two novel ketone ester molecules exhibit similar metabolic breakdown to BHB and BDO and result in transiently higher concentrations of the plasma fatty acids, OCT and HEX, in vivo. Conclusions Given the similar ketone delivery with greater acceptability, BO-BD may offer a more broadly translatable tool to induce physiologic ketosis than BH-BD