Robbin Christensen

Smaller white-matter volumes are associated with larger deficits in attention and learning among long-term survivors of acute lymphoblastic leukemia†

The primary objective of this study was to test the hypothesis that survivors of childhood acute lymphoblastic leukemia (ALL) have deficits in neurocognitive performance, and smaller white‐matter volumes are associated with these deficits.

Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/Refractory Leukemia

PURPOSE To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia. PATIENTS AND METHODS Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m(2)) and clofarabine (stratum one: 40 mg/m(2), n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m(2), n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m(2) and 150 mg/m(2) twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8. RESULTS At sorafenib 200 mg/m(2), two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2). Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3-internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission. CONCLUSION Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.

Efficacy of Glucarpidase (Carboxypeptidase G2) in Patients with Acute Kidney Injury After High-Dose Methotrexate Therapy

Because the incidence rate of renal impairment is 2–10% for patients treated with high‐dose methotrexate and renal impairment develops in 0–12.4% of patients treated for osteosarcoma, we sought to evaluate the efficacy of glucarpidase, a recently approved drug that rapidly hydrolyzes methotrexate to inactive metabolites, which allows for nonrenal clearance in patients with delayed renal methotrexate elimination.

Stability of Cyclophosphamide in Extemporaneous Oral Suspensions

Background: Cyclophosphamide, an alkylating agent, is widely used for the treatment of many adult and pediatric malignancies. The stability of cyclophosphamide in aqueous- and methylcellulose-based oral suspending vehicles is currently unknown. Objective: To develop and validate a stability-indicating high-performance liquid chromatography (HPLC) method to measure cyclophosphamide concentrations in simple syrup and Ora-Plus, and assess the 56-day chemical stability and physical appearance of cyclophosphamide in these suspensions at both room temperature (22 °C) and 4 °C. Methods: The intravenous formulation of cyclophosphamide was diluted to 20 mg/mL in NaCI 0.9%, compounded 1:1 with either suspending vehicle, and stored in the dark in 3-mL amber polypropylene oral syringes at 4 °C and 22 °C. Aliquots from each syringe were obtained on days 0.3, 7, 14, 21, 28, 35, 42, 49, and 56 and assayed using the validated stability-indicating HPLC-UV method. A C18 analytical column was used to separate cyclophosphamide from the internal standard, ifosfamide, with a mobile phase of 21% acetonitrile in 79% sodium phosphate buffer. The suspension was examined for odor change, visually examined under normal fluorescent light for color change, and examined under a light microscope for evidence of microbial growth. Results: Samples of cyclophosphamide in both simple syrup and Ora-Plus were stable when kept at 4 °C for at least 56 days. At room temperature, cyclophosphamide in simple syrup and Ora-Plus had a shell life of 8 and 3 days, respectively. No changes in color or odor or evidence of microbial growth were observed. Conclusions: Cyclophosphamide can be extemporaneously prepared in simple syrup or Ora-Plus and stored for at least 2 months under refrigeration without significant degradation.

Stability of Sunitinib in Oral Suspension

Background: Sunitinib Is a novel, oral, multitargeted tyrosine kinase Inhibitor with antiangiogenic and antitumor activity. No liquid formulation of sunitinib malate is commercially available for pediatric administration. Objective: To prepare extemporaneously an oral liquid formulation of sunitinib malate from commercially available capsules and study its chemical and physical stability in suspension at room temperature and under refrigeration at 4 °C. Methods: Six Independent samples were prepared by mixing the contents of 3 sunitinib malate capsules (each equivalent to 50 mg of sunitinib) with 15 mL of a 1:1 mixture of Ora-Plus; Ora-Sweet solution to yield a final concentration of 10 mg/mL Suspensions were stored in amber plastic bottles with child-resistant caps. Three samples were refrigerated at 4 °C and 3 were stored at room temperature. Aliquots from each bottle were obtained on days 1, 2, 3, 5, 7, 14, 21, 30, and 60 and diluted to a final concentration of 300 ng/mL with 500 ng/mL of clozapine in 50% acetonttrile. Sunitinib concentrations were then measured by a liquid chromatography–tandem mass spectrometry assay validated in our laboratory. Results: At room temperature and under refrigeration at 4 °C, sunitinib in a 10-mg/mL suspension of sunitinib malate with Ora-Plus:Ora-Sweet 1:1 maintained greater than 96% of its initial concentration for 60 days, Visual appearance (color and consistency) and odor of drug suspension remained unchanged during the study. Conclusions: Sunitinib is stable in an oral suspension prepared from commercially available capsules for at least 60 days al room temperature and refrigeration at 4 °C. This liquid formulation is better suited for administration to children and adults with cancer who cannot swallow sunitinib capsules.

Alternative formulations of sorafenib for use in children

Sorafenib is an oral multikinase inhibitor with antiangiogenic and antitumor activity. In most cases, the commercially available 200 mg tablet is not suitable for administration to children. We studied the chemical and physical stability of extemporaneously prepared formulations and evaluated the pharmacokinetic profile of cut tablets and smaller‐dosage capsules of sorafenib in children.

A randomized, double-blind, placebo-controlled trial of methylphenidate for attentional problems in survivors of childhood cancer

8510 Background: Children surviving acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT) have a higher incidence of attention and learning problems in school than their healthy peers. Our preliminary data suggested that attention deficits among survivors may acutely respond to methylphenidate (MPH; J Clin Oncol 19:1802-8, 2001) but no similar data are available from the school. METHODS We screened 343 long-term survivors of ALL and BT to identify those with attentional deficits on a computer-administered continuous performance test, attentional symptoms endorsed on parent or teacher report, and academic achievement deficits. Of 74 with the identified phenotype, 54 (30 ALL, 24 BT) completed a randomized, double-blind, three-week home cross-over trial of Placebo (P; b.i.d.), low dose MPH (LD; 0.3 mg/kg; maximum dose 10 mg b.i.d.), and moderate dose MPH (MD; 0.6 mg/kg; maximum dose 20 mg b.i.d.). The primary endpoints were weekly teacher reports. RESULTS The 30 male and 24 female patients ranged from 0.54 to 12.57 (M=5.25) years of age at diagnosis and 6.83 to 17.49 (M=11.63) years of age at participation. Comparisons of teacher reports on the Cognitive/Inattention, Hyperactive, and ADHD Index scales are shown below. Significant improvement (*P<0.01) with LD was seen on all 3 outcomes and with MD on the ADHD Index. No significant advantage of MD over LD was observed. CONCLUSIONS Short-term treatment with low-dose MPH can reduce attentional problems among survivors of childhood ALL and BT. Forty-five of the 54 (83%) patients showed a positive response to MPH and continue on medication. Long-term follow-up planned at 12 months will reveal which subsets of patients are more likely to benefit from MPH. [Figure: see text] No significant financial relationships to disclose.

Addressing challenges of clinical trials in acute pain: The Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study:

Background/aims: Neuropathic pain is a known component of vaso-occlusive pain in sickle cell disease; however, drugs targeting neuropathic pain have not been studied in this population. Trials of acute pain are complicated by the need to obtain consent, to randomize participants expeditiously while optimally treating pain. We describe the challenges in designing and implementing the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study (NCT01954927), a phase II, randomized, double-blind, placebo-controlled trial to determine the effect of gabapentin for vaso-occlusive crisis. Methods: In the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study, we aim to assess the analgesic effect of gabapentin during vaso-occlusive crisis. Difficulties we identified included avoiding delay of notification of study staff of potential participants which we resolved by automated notification. Concern for rapid randomization and drug dispensation was addressed through careful planning with an investigational pharmacy and a single liquid formulation. We considered obtaining consent during well-visits to avoid the time constraints with acute presentations, but the large number of patients and limited duration that consent is valid made this impractical. Results: In all, 79% of caregivers/children approached have agreed to participate. The trial is currently active, and enrollment is at 45.8% of that targeted (76 of 166) and expected to continue for two more years. Maintaining staff availability after-hours remains problematic, with 8% of screened patients missed for lack of available staff. Lessons learned: Lessons learned in designing a trial to expedite procedures in the acute pain setting include (1) building study evaluations upon a standard-of-care backbone; (2) implementing a simple study design to facilitate consent and data capture; (3) assuring ample, well-trained study staff; and (4) utilizing technology to automate procedures whenever possible. Conclusion: This study design has circumvented many of the logistical barriers usually associated with acute pain trials and may serve as a prototype for future studies.