John Hayslip

Cost-Effectiveness of Extended Adjuvant Rituximab for US Patients Aged 65-70 Years with Follicular Lymphoma in Second Remission

PURPOSE A recent Intergroup trial showed that receiving adjuvant rituximab after having a second remission from follicular lymphoma (FL) improved progression-free and overall survival (OS). The current study was conducted to determine the incremental cost-effectiveness ratio of this strategy in the United States. PATIENTS AND METHODS We constructed a transition state model to estimate the incremental cost-effectiveness ratio of extended adjuvant rituximab for 2 years for patients having a second FL remission. Event-free and OS rates were estimated from the recently published Intergroup trial. These were adjusted to reflect the contribution of non-cancer-specific mortality for patients aged 65-70 years, a more commonly affected age group than in the Intergroup trial, which had a median age of 54 years. Previously reported quality of life and cost estimates were obtained from peer-reviewed sources. RESULTS Five years after a second induction with R-CHOP (rituximab with cyclophosphamide/doxorubicin/vincristine/ prednisone), disease-free survival is expected to be 47% and 22%, and the OS rates are estimated to be 73% and 61% for extended adjuvant rituximab and observation, respectively, during the second remission. The discounted incremental cost-effectiveness ratio for the addition of adjuvant rituximab is estimated to be

Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co- Administration of Mesna—A Randomized, Cross-Over Clinical Study

19,522 per quality-adjusted life-years gained. CONCLUSION Extended adjuvant rituximab offers a clinical benefit to patients aged 65-70 years who have a second remission from FL at a cost generally acceptable to the US healthcare system.

A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia

Purpose Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines. Methods Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy. Results Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration. Conclusions The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI. Trial Registration clinicaltrials.gov NCT01205503.

Validated LC-MS/MS method for simultaneous determination of SIM and its acid form in human plasma and cell lysate： Pharmacokinetic application

We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ≥60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2 mg/m(2) with once weekly idarubicin 10 mg/m(2) for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61-83) and 7 relapsed (median age 58, range 40-77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8 mg/m(2) and idarubicin 10 mg/m(2)); idarubicin was reduced to 8 mg/m(2) without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2 mg/m(2) and idarubicin 8 mg/m(2). Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954.

Simvastatin interacts synergistically with tipifarnib to induce apoptosis in leukemia cells through the disruption of RAS membrane localization and ERK pathway inhibition

Simvastatin (SIM) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC–MS/MS method was developed to measure SIM and its acid form (SIMA) in plasma and peripheral blood mononuclear cells (PBMCs) obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75:25 (% v/v) acetonitrile:ammonium acetate (0.1 M, pH 5.0) mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5–500 ng/mL for SIM and 5–500 ng/mL for SIMA in plasma and 2.5–250 ng/mL for SIM and 5–250 ng/mL for SIMA in cell lysate. Recovery was >58% for SIM and >75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients.

Decision making and distress among individuals diagnosed with follicular lymphoma.

Tipifarnib, a farnesyltransferase inhibitor (FTI), was initially designed to disrupt RAS farnesylation and membrane localization necessary for RAS function. However, alternative geranylgeranylation has been postulated as an escape mechanism by which RAS bypasses the effect of FTI treatment. In this study, we demonstrate that simvastatin, an HMG-CoA reductase inhibitor, augments the cytotoxic effect of tipifarnib by blocking the alternative geranylgeranylation of RAS. Notably, this effect was accompanied by disruption of RAS membrane localization and ERK downregulation. In addition, the apoptotic effect of this combination was associated with downregulation of the antiapoptotic Mcl-1 protein and activation of the caspase cascade. These findings demonstrate that combining tipifarnib and simvastatin was successful in targeting RAS/ERK signaling and inducing apoptosis in leukemia cells. Both simvastatin and tipifarnib were used at clinically achievable doses, which make the combination promising for future clinical studies.

Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial

Follicular lymphoma (FL) is an indolent lymphoma that generally responds well to treatment. However, individuals with FL commonly face multiple complex treatment decision-making (TDM) experiences because it frequently follows a relapsing and remitting course. This study explored TDM and distress among individuals with FL (N = 32). Results indicated that most participants reported little decisional conflict or regret and wanted to be actively involved in TDM. However, more than 25% of participants reported clinically-relevant cancer-specific distress, and 60% indicated moderate or higher anxiety symptoms. Research is needed to clarify the cause and course of the psychological distress revealed in this study.

Differences in Vitamin D Nutritional Status Between Newly Diagnosed Cancer Patients from Rural or Urban Settings in Kentucky

BACKGROUND Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. METHODS We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed. FINDINGS Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients. INTERPRETATION Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. FUNDING Sanofi.

Immunonutrition: does it have a role in improving recovery in patients receiving a stem cell transplant?

Although poor nutritional status and weight loss in cancer patients is known to affect outcomes, little is known about malnutrition differences based on geographic location. We investigated nutritional and inflammatory status of 220 newly diagnosed adults with solid tumors at the University of Kentuckys Markey Cancer Center during December 2008 through October 2011. Chi-square tests were used to determine any associations between suboptimal nutritional levels and rural–urban areas of residence. Out of the 13 lab values collected, the only significant difference between rural and urban participants was found for vitamin D resulting in more rural subjects (67.4%) having a suboptimal vitamin D status as compared to those residing in urban areas (53.3%, P = 0.04). Controlling for baseline demographics including age, race, sex, body mass index, nutritional status, and type of cancer, logistic regression analyses concluded those in rural areas had nearly a twofold increase in the odds of having a suboptimal vitamin D level compared to those in urban areas (odds ratio = 1.97; 95% confidence interval = 1.04, 3.74). Further investigation into the rural–urban differences in vitamin D needs to be investigated in order to improve outcomes during cancer treatment.

Abstract 3778: Pharmacokinetic, safety and efficacy of high dose simvastatin in refractory and relapsed chronic lymphocytic leukemia (CLL) patients

Numerous clinical trials have demonstrated that immunomodulating diets (IMDs) reduce treatment complications such as the risk of acquired infections, length of hospital stay, and wound complications in patients receiving planned surgery. These complications are possibly exacerbated by malnutrition at the time of surgery, resulting in decreased cell-mediated and humoral immune responses, which can be improved with the utilization of IMDs both prior to and following surgery. Although numerous randomized studies have investigated IMDs in the surgical setting, IMDs have not been well studied to evaluate whether their use improves outcomes for other patient groups with high incidence of malnutrition and acquired infections. Patients receiving stem cell transplantation following preparative myeloablative chemotherapy for treatment of a hematologic malignancy would be a prime example of another patient group who would share these characteristics. Given the proposed mechanism of action by which IMDs have aided recovery after surgery, it is reasonable to expect that IMDs may aid recovery after stem cell transplantation, and current preclinical and clinical data support the need for further clinical studies.