Can a modified ketogenic diet be a nutritional strategy for patients with McArdle disease? Results from a randomized, single-blind, placebo-controlled, cross-over study.

BACKGROUND: McArdle disease is caused by myophosphorylase deficiency leading to blocked glycogenolysis in skeletal muscle. Consequently, individuals with McArdle disease have intolerance to physical activity, muscle fatigue, and pain. These symptoms vary according to the availability of alternative fuels for muscle contraction. In theory, a modified ketogenic diet (mKD) can provide alternative fuels in the form of ketone bodies and potentially boost fat oxidation. METHODS: This randomized, single-blind, placebo-controlled, cross-over study aimed to investigate if a mKD improves exercise capacity in individuals with McArdle disease. Participants were randomized to follow a mKD (75-80% fat, 15% protein, 5-10% carbohydrates) or placebo diet (PD) first for three weeks, followed by a wash-out period, and then the opposite diet. The primary outcome was change in heart rate during constant-load cycling. Secondary outcomes included change in plasma metabolites, perceived exertion, indirect calorimetry measures, maximal exercise capacity, and patient-reported outcomes. RESULTS: Fifteen out of 20 patients with genetically verified McArdle disease completed all study visits, and 14 were included in the data analyses. We found that the mKD induced a metabolic shift towards increased fat oxidation (∼60% increase), and a 19-fold increase in plasma ß-hydroxybutyrate (p < 0.05). The mKD did not improve heart rate responses during constant-load cycling but did improve patient-reported outcomes and maximal exercise capacity (∼20% increase) compared to the PD. CONCLUSION: The mKD did not alleviate all McArdle disease-related symptoms but did induce some positive changes. To date, no satisfactory treatment options exist other than exercise training. To that end, a mKD can be a possible nutritional strategy for some individuals with McArdle disease who are motivated to undertake a restrictive diet. CLINICAL TRIAL REGISTRATION: clinical trials.gov: NCT04044508.

Results of a Phase II trial of gemcitabine, mitoxantrone, and rituximab in relapsed or refractory mantle cell lymphoma.

BACKGROUND: Gemcitabine (G) has shown activity in mantle cell lymphoma (MCL) as a single agent. The combination of mitoxantrone (M) and rituximab (R) is also active in MCL. The primary objective of this study was to determine the efficacy of G+M+R in relapsed or refractory MCL. PATIENTS AND METHODS: Sixteen patients were enrolled between April 2005 and January 2007, 88% had Stage IV MCL, Median patient age was 74 years. Patients received gemcitabine 900 mg/m(2) IV (30-60 min infusion) on Days 1 and 8, mitoxantrone 10 mg/m(2) IV (5-10 min infusion) on day 1, and rituximab 375 mg/m(2) IV on Day 1 (max 400 mg/hour) of the 21-day cycle. Patients received a median of 6 cycles (range, 1-8). RESULTS: Best responses were CR 20% (95%CI, 0, 40.2), PR 27% (95%CI, 4.3, 49.1), SD 40% (95%CI, 15.2, 64.8), and PD 13% (95%CI, 0, 30.5). Median survival and PFS have not been reached with a median follow-up of 10.7 months. The most common Grade 3-4 toxicities were neutropenia (100%), thrombocytopenia (67%), leukopenia (53%), and anemia (33%). The study was closed early due to slow accrual owing to an alternative treatment which became available at the time. CONCLUSION: The combination of G+M+R in MCL was well-tolerated with manageable toxicity using growth factors to minimize neutropenia; further studies are warranted.