Prognosis in relapsed and refractory acute myeloid leukemia (R/R AML) patients is dismal, with no satisfactory and standard salvage chemotherapy regimen. We performed a systematic review in order to analyze the clinical outcomes reported with conventional chemotherapy schemes in adult patients with R/R AML. To have a better understanding of the R/R ground, we included studies in R/R AML adult population at any disease stage (i.e., primary refractory as well as first relapse or beyond). Study selection included a total number of 157 out of 850 records, with a wide variety of schedules. Furthermore, only 24 studies were randomized clinical trials (RCTs), being the majority of the studies retrospective analyses in small cohorts. This review reveals that several intensive regimens (cytarabine + mitoxantrone + etoposide or gemtuzumab, and cytarabine + purine analogue ± antracycline) achieve relatively high complete remission (CR) rates (44 to 59.4%). However, most of these schemes did not obtain substantial CR duration (4.9 to 9.8 months) or overall survival (6.2 to 8.7 months). In unfit/vulnerable patients non-intensive approaches are recommended to control disease progression and minimize treatment-related mortality. A better knowledge of the prognostic factors, more effective and less toxic combinations using conventional and new therapies, as well as improvements in allo-HSCT procedure and timing, could play a role to improve the clinical outcomes in the future. Clinical trials should be the first treatment option in R/R AML, both in fit and unfit patients.

Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous malignancy that is primarily treated with combinations of cytarabine and anthracyclines. Although this scheme remains effective in most of the patients, variability of outcomes in patients has been partly related with their genetic variability. Several pharmacogenetic studies have analyzed the impact of polymorphisms in genes encoding transporters, metabolizers or molecular targets of chemotherapy agents. A systematic review on all eligible studies was carried out in order to estimate the effect of polymorphisms of anthracyclines and cytarabine pathways on efficacy and toxicity of AML treatment. Other emerging genes recently studied in AML, such as DNA repair genes, genes potentially related to chemotherapy response or AML prognosis, have also been included.

Objective Strength training is recommended for people with hemophilia; however, published data are anecdotal and have methodological limitations. The purpose of this study was to evaluate the safety and effectiveness of progressive moderate-to-vigorous intensity elastic resistance training on physical function and pain in this patient population. Methods A randomized controlled trial was conducted in a university laboratory setting where 20 patients (17 with severe, 1 with moderate, and 2 with mild hemophilia) aged 21 to 53 years received evaluations at baseline and 8-week follow-up. Participants were allocated to intervention (progressive strength training) or control (usual daily activities) groups. The intervention group trained 2 days per week during 8 weeks with elastic resistance. Intensity during the first 2 weeks was a 20-repetition maximum and increased progressively toward 15, 12, and finally 10 repetition maximum. The primary outcome was muscle strength. Secondary outcomes were the Timed “Up and Go” Test score, sit-to-stand, range of motion, Haemophilia Joint Health Score, kinesiophobia score, global impression of pain change, general self-rated health status, and desire to exercise. Results The intervention group showed greater strength improvements than the control group in almost all of the joints, with moderate to high effect sizes. The intervention group also showed better Timed “Up and Go” and sit-to-stand scores than the control group (moderate effect size), greater range of motion at the knee flexion with the right leg (trivial effect size), and better Haemophilia Joint Health Score at the left knee (small effect size). The intervention group showed greater overall pain reduction, self-rated overall status, and desire to exercise than the control group. Conclusions Progressive strength training with elastic resistance performed twice a week during 8 weeks is safe and effective in people with hemophilia to improve muscle strength and functional capacity, reduce general pain, and improve self-rated health status and desire to exercise. Impact This study provides evidence for the use of a specific strength training regimen for people with hemophilia. Lay Summary People with hemophilia of differing levels of severity, with adequate coverage with clotting factor, can safely engage in progressive strength training and can improve their functioning.

The pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

Niemann-Pick type C (NP-C) is a rare neurodegenerative disorder. Management is mainly supportive and symptomatic. The investigational use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) showed a promising role in treating NP-C, although efficacy and safety have not been established. We conducted searches of MEDLINE, Cochrane, EMBASE, and other databases of reported cases of HP-β-CD compassionate use in NP-C disease. Sixteen reported cases were eligible, including evaluable information of 17 patients. The median onset age of HP-β-CD was 14 years (range 2-49 years). Intrathecal route was employed in 16 patients, in 3 patients simultaneously to IV infusions. Intracerebroventricular route was used in two patients. An objective improvement of clinical outcomes was measured in 14 patients, mainly by the NIH NP-C Clinical Severity Score and brainstem auditory evoked potential. Besides, an increase in metabolism and activities of the brain were observed in image tests and cholesterol biomarkers. Most patients showed some clinical benefit or a stabilization of NP-C progression. There were 17 adverse events (AEs) reported in 11 patients, 11 of them related to the drug and 6 to the route of administration. Loss of hearing was reported in four patients. The most severe AE were fever and chemical meningitis. Results suggest that efficacy may be partial and dependent on the early administration of the drug, the severity of the disease, and interpersonal variability. HP-β-CD could help stabilize NP-C with low toxicity potential, although some AEs have been reported. Moreover, controlled clinical trials would be necessary to evaluate the role of HP-β-CD in NP-C.

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The knowledge of the role of pharmacogenetics in anthracyclines metabolism could explain the differences observed in their disposition in leukemic cells. These genetic variants are proposed biomarkers in clinical practice in order to individualize chemotherapy schemes, potentially increasing the effectiveness and reducing the toxicities.