Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Incorporation of asparaginase (ASNase) and pegylated asparaginase (PEG-ASP) into pediatric-inspired regimens for adults with acute lymphoblastic leukemia (ALL) has led to improved treatment outcomes albeit with increased toxicities. This study compared the efficacy and safety of the Children's Oncology Group standard PEG-ASP (SD) dosing (>1000, median 2500 IU/m2/dose) in adult Philadelphia chromosome-negative ALL patients receiving multiagent chemotherapy vs reduced dose PEG-ASP (RED) (≤1000, median 500 IU/m2/dose) during induction. 51 patients were included, 26 in RED and 25 in SD (median age 49 vs 37 years, p = .027). Median day 7 ASNase activity level for RED was 0.16 IU/mL. All 11 patients who received PEG-ASP 1000 IU/m2 and 9/11 patients who received 500 IU/m2 achieved an ASNase level ≥0.1 IU/mL. Patients receiving RED experienced fewer total grade 3/4 toxicities during induction compared to SD (p = .02) while still attaining therapeutic ASNase levels. RED permits safer ASNase use in adults with ALL and should be tested in a larger cohort prospectively.

Comparison of the incidence of febrile neutropenia in obese and normal weight breast cancer patients receiving myelosuppressive chemotherapy and prophylactic pegfilgrastim.

PURPOSE: Common breast cancer chemotherapy regimens are associated with a risk of febrile neutropenia, so prophylactic colony-stimulating factors are incorporated for high-risk patients. Filgrastim utilizes weight-based dosing; however, its sustained-release formulation utilizes fixed dosing. The purpose of this study is to determine whether obese breast cancer patients who receive pegfilgrastim are at increased risk of developing febrile neutropenia. METHODS: This study is a single-center, retrospective chart review. Breast cancer patients were categorized as normal weight (body mass index < 30), overweight (body mass index 30-39), or obese (body mass index ≥ 40). RESULTS: A total of 442 eligible patients were identified between 1 July 2012 and 19 May 2016. Twenty-eight were included in the obese group. Twenty-eight patients from each non-obese group were randomly selected to make up the overweight and normal weight groups. Incidence of febrile neutropenia was 1, 2, and 2 of 28 in the normal weight, overweight, and obese research groups, respectively. Increased use of antibiotics was observed in the obese group as compared to the normal and overweight groups (2, 1, 1, respectively; p = 0.0005). Median number of days on antibiotics was statistically significantly higher in the obese group at 10 days compared to the normal and overweight groups at seven days ( p = 0.03). CONCLUSION: Obese patients are not at increased risk of febrile neutropenia. However, they may have a lower threshold for febrile neutropenia and require more antibiotics after chemotherapy. Clinical significance of these results cannot be determined given the small sample size, so further multicenter studies are required.

Olaparib: A tale of two dosage forms.

Olaparib is the first poly(ADP-ribose) polymerase (PARP) inhibitor approved by the Food and Drug Administration (FSA), with three approvals in two different cancer types. The original dosage form of olaparib was a 50 mg capsule, requiring 16 capsules per day for patients at full dose therapy which prompted development of a tablet dosage form with improved bioavailability. Herein, major trials for olaparib are reviewed and the two dosage forms are compared from a pharmacokinetic and clinical perspective.

Treatment of Acute Promyelocytic Leukemia in Adults.

The treatment of acute promyelocytic leukemia (APL) has evolved rapidly in the past two decades after the introduction of highly active drugs, including tretinoin (all- trans-retinoic acid) and arsenic trioxide. It is now possible to treat this disease without the use of traditional cytotoxic chemotherapy. Today's clinical guidelines include multiple regimens, some of which continue to use cytotoxic chemotherapy. This leaves the practicing oncologist with multiple treatment options when faced with a new case of APL. In an effort to standardize our approach to the treatment of newly diagnosed APL, we sought to develop a set of treatment recommendations at our institution. We identified eight major controversial issues in the treatment of APL. These controversial issues include the optimal dose and schedule of both all- trans-retinoic acid and arsenic trioxide, the optimal regimen for high-risk APL, the need for intrathecal prophylaxis, the use of prophylactic corticosteroids, and the need for maintenance therapy after consolidation. We reviewed the relevant literature and used the Delphi method among the coauthors to reach consensus for recommendations on the basis of the best available data and our own clinical experience. In this clinical review, we present our consensus recommendations, the reasoning behind them, and the grading of the evidence that supports them.

Impact of a Clinical Decision Support Tool on Cancer Pain Management in Opioid-Tolerant Inpatients.

Background: Pain is both common and undertreated in the hematology/oncology population despite national guidelines and a focus from The Joint Commission. Objective: Herein, we describe the features of a pain clinical decision support tool (PCDST) embedded into the electronic medical record (EMR) and report its impact on oncology inpatients at risk for uncontrolled pain. Methods: The PCDST was developed to identify patients with potentially uncontrolled pain, defined as a pain score ≥4. Clinical pharmacists were encouraged to use the tool to determine whether interventions were needed to better control pain. Pain and safety outcomes between 2 cohorts of opioid-tolerant adult inpatients presenting with severe pain were compared prior to and following the implementation of the PCDST. Results: The primary endpoint, attainment of analgesia at 24 hours from admission, was met in 10 of 30 (33.3%) patients in the preimplementation group and in 14 of 32 (43.8%) of patients in the postimplementation group (P = .78). Secondary endpoints including time to analgesia, mean pain score, frequency of pharmacy intervention, and National Comprehensive Cancer Network (NCCN) guideline-adherent pain regimens were not found to be statistically significantly different between the 2 groups. The number of mean nursing pain assessments in the first 24 hours from admission was found to be significantly higher in the postimplementation group compared with the preimplementation group (12 vs 7.4, P < .001). Safety events were rare and not statistically different between groups. Conclusion: Overall, a modest, but statistically nonsignificant, improvement in pain outcomes was associated with patients admitted after the implementation of a pharmacist-managed electronic pain scoring tool.

Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen.

Asparaginase is a critical component of acute lymphoblastic leukemia (ALL) treatment in children; however, its use in adults is often avoided as a result of toxicities including hepatotoxicity, thrombosis, and pancreatitis which have been reported more commonly in adults than in children. In this retrospective analysis, short-acting L-asparaginase (L-ASP) and long-acting polyethylene glycol (PEG)-asparaginase (PEG-ASP) were compared for grade 3-4 toxicities and characterized by patient and drug-related factors to identify strategies for toxicity avoidance in adults with ALL. Asparaginase was administered during sequential courses of chemotherapy using a pediatric-inspired treatment regimen. Forty-eight patients who received PEG-ASP and nine patients who received L-ASP were identified. The rates of toxicity were as follows for the PEG-ASP and L-ASP groups, respectively: hepatotoxicity (60% vs. 33%, P = 0.275), pancreatitis (17% vs. 22%, P = 0.650), thrombosis (19.0% vs. 0%, P = 0.328), or any grade 3-4 toxicity (71% vs. 44%, P = 0.143). Toxicity did not correlate with dose, either by individual dose based on flat or BSA-based measures. Logistic regression identified obesity as a risk factor for heptatotoxicity (OR = 8.44, 95% CI: 1.395-51.117). Hypofibrinogenemia was identified as a pharmacodynamic marker for predicting hepatotoxicity. In conclusion, grade 3-4 toxicity was not statistically different between adult ALL patients receiving PEG-ASP and L-ASP, but toxicity was strongly associated with obesity and hypofibrinogenemia, not dose.

Directed evolution toward improved production of L-ribose from ribitol.

Improvement of the one-step production of L-ribose from ribitol using a recombinant Escherichia coli is described. The gene encoding the enzyme mannitol-1-dehydrogenase (MDH) from Apium graveolens has previously been codon-optimized, cloned into the constitutive pZuc10 vector, and expressed in E. coli. This MDH catalyzes the NAD-dependent conversion of mannitol to D-mannose and has the ability to convert several polyols to their L-sugar counterparts, including ribitol to L-ribose. Here, three rounds of directed evolution using libraries generated through error-prone PCR and screened using a dinitrosalicylate reagent were prepared. Mutants were selected for improved conversion of L-ribose, and the best mutant was isolated by combining two round 2 mutations. Libraries were also selected for thermal stability and screened at increasingly higher temperatures with each round of mutagenesis. An overall 19.2-fold improvement was observed with a final conversion of 46.6 +/- 1.7% and a productivity of 3.88 +/- 0.14 gL(-1)d(-1) in 50 mL shaken flasks at 34 degrees C. Further characterization of the mutants suggests that increased enzyme thermal stability and expression are responsible for the increase in L-ribose production. The mutant E. coli production strain isolated represents an improved system for large-scale production of L-ribose.

Single-step bioconversion for the preparation of L-gulose and L-galactose.

Both carbohydrate monomers L-gulose and L-galactose are rarely found in nature, but are of great importance in pharmacy R&D and manufacturing. A method for the production of L-gulose and L-galactose is described that utilizes recombinant Escherichia coli harboring a unique mannitol dehydrogenase. The recombinant E. coli system was optimized by genetic manipulation and directed evolution of the recombinant protein to improve conversion. The resulting production process requires a single step, represents the first readily scalable system for the production of these sugars, is environmentally friendly, and utilizes inexpensive reagents, while producing L-galactose at 4.6 g L(-1)d(-1) and L-gulose at 0.90 g L(-1)d(-1).