Forecasted infliximab concentrations during induction predict time to remission and sustained disease control of inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) exposure is established as a predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease (IBD), and expert consensus is to achieve adequate exposure during induction to achieve and sustain remission. METHODS: We retrospectively evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Trough IFX serum levels collected immediately before the third (at week 6) and fourth (at week 14) infusions were evaluated from 307 IBD patients (median age=17 years, 50 % females, 83 % with Crohn's disease). Forecasted IFX concentration at the fourth infusion were estimated using serum IFX, antibodies to IFX, albumin and weight determined immediately before the third infusion using population PK calculator with Bayesian prior. The outcome variable was a clinical & biochemical remission status achieved (CRP levels below 3 mg/L in presence of clinical remission). Statistics consisted of Kaplan Meier analysis with calculation of Hazard ratio (HR), and logistic regression. RESULTS: IFX concentration above 15 µg/mL immediately before the third infusion associated with shorter time to clinical & biochemical remission than concentration below 15 µg/mL without reaching significance (163±14 days vs 200±16 days, respectively; p=0.052). However, using PK parameters at the third infusion, forecasted IFX concentrations above 10 µg/mL immediately before the fourth infusion were significantly associated with a higher rate (HR=1.6 95 %CI: 1.1 to 2.1 p<0.01) and shorter time to remission (148±18 days vs 200±13 days p<0.01). In the presence of IFX concentration above 15 µg/mL at the third infusion, there was a significant 2.5-fold higher likelihood of sustained clinical & biochemical remission status during maintenance as compared to IFX concentrations below 15 µg/mL (p<0.01). Forecasted IFX level above 10 µg/mL at fourth infusion associated with significantly 3.9-fold higher likelihood of clinical & biochemical remission as compared to forecasted IFX concentrations below 10 µg/mL (p<0.01). CONCLUSIONS: These data further support that optimized IFX concentrations during induction are associated with enhanced disease control in IBD.

Ommaya reservoir use in pediatric ALL and NHL: a review at St. Jude Children's Research Hospital.

PURPOSE: The intraventricular route of chemotherapy administration, via an Ommaya Reservoir (OmR) improves drug distribution in the central nervous system (CNS) compared to the more commonly used intrathecal administration. We retrospectively reviewed our experience with intraventricular chemotherapy, focused on methotrexate, in patients with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL). METHODS: Twenty-four patients (aged 7 days - 22.2 years) with 26 OmR placements were identified for a total of 25,009 OmR days between 1990 and 2019. Methotrexate cerebrospinal fluid (CSF) concentrations (n = 124) were analyzed from 59 courses of OmR therapy in 15 patients. Twenty-one courses involved methotrexate dosing on day 0 only, whereas 38 courses involved booster dosing on days 1, 2, or both. We simulated the time CSF methotrexate concentrations remained > 1 µM for 3 days given various dosing regimens. RESULTS: CSF methotrexate exposure was higher in those who concurrently received systemic methotrexate than via OmR alone (p < 10- 7). Our simulations showed that current intraventricular methotrexate boosting strategy for patients ≥ 3 years of age maintained CSF methotrexate concentrations ≥ 1 µM for 72 h 40% of the time. Alternatively, other boosting strategies were predicted to achieve CSF methotrexate concentrations ≥ 1 µM for 72 h between 46 and 72% of the time. CONCLUSIONS: OmR were able to be safely placed and administer intraventricular methotrexate with and without boost doses in patients from 7 days to 22 years old. Boosting strategies are predicted to increase CSF methotrexate concentrations ≥ 1 µM for 72 h.

Adalimumab Clearance, Rather Than Trough Level, May Have Greatest Relevance to Crohn's Disease Therapeutic Outcomes Assessed Clinically and Endoscopically.

OBJECTIVE: We postulated that adalimumab [ADA] drug clearance [CL] may be a more critical determinant of therapeutic outcome than ADA concentration. This was tested in Crohn's disease [CD] patients undergoing ADA maintenance treatment. METHODS: CD patients from four cohorts received ADA induction and started maintenance therapy. Therapeutic outcomes consisted of endoscopic remission [ER], sustained C-reactive protein [CRP] based clinical remission [defined as CRP levels below 3 mg/L in the absence of symptoms], and faecal calprotectin [FC] level below 100 µg/g. Serum albumin, ADA concentration, and anti-drug antibody status were determined using immunochemistry and homogeneous mobility shift assay, respectively. CL was determined using a nonlinear mixed effect model with Bayesian priors. Statistical analysis consisted of Mann-Whitney test and logistic regression with calculation of odds ratio. Repeated event analysis was conducted using a nonlinear mixed effect model. RESULTS: In 237 enrolled patients [median age 40 years, 45% females], median CL was lower in patients achieving ER as compared with those with persistent active endoscopic disease [median 0.247 L/day vs 0.326 L/day, respectively] [p <0.01]. There was no significant difference in ADA concentration between patients in endoscopic remission compared with those with recurrence [median 9.3 µg/mL vs 11.7 µg/mL, respectively]. Sustained CRP-based clinical remission and FC levels below 100 µg/g were generally associated with lower CL and higher ADA concentration. Repeated event analysis confirmed those findings with better performances of CL than concentration in associating with ER and other outcomes. CONCLUSION: Lower ADA clearance is associated with an improved clinical outcome for patients with Crohn's disease and may be a superior pharmacokinetic measure than concentration.

Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.

A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk ß-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with ß-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.

The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn's Disease with Infliximab.

Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn's disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108). Concentrations were measured using homogeneous mobility shift assay. Clearance was estimated using the nonlinear mixed effects methods with Bayesian priors. C-reactive protein-based clinical remission (<3 mg/L in the absence of symptoms) was used for the disease control outcome measure. Longitudinal changes in disease control due to factors including time, IFX concentration, and Clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and Clearance. The results indicated that lower baseline Clearance and proactive dosing associated with enhanced disease control during induction (p < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance (p < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = -19.2; p < 0.001), and the combination of both further minimized OFV (p < 0.001) with markedly improved clinical yield in the presence of both PF of PK origin. We conclude that the combination of IFX concentration and Clearance are better predictors of therapeutic outcome compared with either one alone.

Pharmacokinetics and safety of bendamustine in the BEABOVP regimen for the treatment of pediatric patients with Hodgkin lymphoma.

PURPOSE: The Stanford V chemotherapy regimen has been used to treat Hodgkin lymphoma (HL) patients since 2002 with excellent cure rates; however, mechlorethamine is no longer available. Bendamustine, a drug structurally similar to alkylating agents and nitrogen mustard, is being substituted for mechlorethamine in combination therapy in a frontline trial for low- and intermediate-risk pediatric HL patients, forming a new backbone of BEABOVP (bendamustine, etoposide, doxorubicin, bleomycin, vincristine, vinblastine, and prednisone). This study evaluated the pharmacokinetics and tolerability of a 180 mg/m2 dose of bendamustine every 28 days to determine factors that may explain this variability. METHODS: Bendamustine plasma concentrations were measured in 118 samples from 20 pediatric patients with low- and intermediate-risk HL who received a single-day dose of 180 mg/m2 of bendamustine. A pharmacokinetic model was fit to the data using nonlinear mixed-effects modeling. RESULTS: Bendamustine concentration vs time demonstrated a trend toward decreasing clearance with increasing age (p = 0.074) and age explained 23% of the inter-individual variability in clearance. The median (range) AUC was 12,415 (8,539, 18,642) µg hr/L and the median (range) maximum concentration was 11,708 (8034, 15,741) µg/L. Bendamustine was well tolerated with no grade 3 toxicities resulting in treatment delays of more than 7 days. CONCLUSIONS: A single-day dose of 180 mg/m2 of bendamustine every 28 days was safe and well tolerated in pediatric patients. While age accounted for 23% of inter-individual variability observed in bendamustine clearance, the differences did not affect the safety and tolerability of bendamustine in our patient population.

Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia.

LCK is a novel therapeutic target in ~40% of T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib can act as LCK inhibitors with therapeutic effects. We herein report a comprehensive preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib in LCK-activated T-ALL. In 51 human T-ALL cases, these two drugs showed similar patterns of cytotoxic activity, with ponatinib being slightly more potent. Given orally in mice, ponatinib was associated with slower clearance with a longer Tmax and higher AUC0-24 h, although maximum pLCK inhibition was comparable between the two drugs. After establishing the exposure-to-response models, we simulated the steady-state pLCK inhibitory effects of each drug at currently approved dosages in humans: dasatinib at 140 mg and ponatinib at 45 mg once daily are both sufficient to achieve >50% pLCK inhibition for 13.0 and 13.9 h/day, respectively, comparable to pharmacodynamic profiles of these agents in BCR::ABL1 leukemias. Moreover, we developed a dasatinib-resistant T-ALL cell line model with LCK T316I mutation, in which ponatinib retained partial activity against LCK. In conclusion, we described the pharmacokinetic and pharmacodynamic profiles of dasatinib and ponatinib as LCK inhibitors in T-ALL, providing critical data for the development of human trials of these agents.

Preclinical evaluation of proteolytic targeting of LCK as a therapeutic approach in T cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and there is an unmet need for targeted therapies, especially for patients with relapsed disease. We have recently identified pre-T cell receptor and lymphocyte-specific protein tyrosine kinase (LCK) signaling as a common therapeutic vulnerability in T-ALL. LCK inhibitor dasatinib showed efficacy against T-ALL in preclinical studies and in patients with T-ALL; however, this is transient in most cases. Leveraging the proteolysis targeting chimera (PROTAC) approach, we developed a series of LCK degraders using dasatinib as an LCK ligand and phenyl-glutarimide as a cereblon-directing moiety. Our lead compound SJ11646 exhibited marked efficiency in cereblon-mediated LCK degradation in T-ALL cells. Relative to dasatinib, SJ11646 showed up to three orders of magnitude higher cytotoxicity in LCK-activated T-ALL cell lines and primary leukemia samples in vitro, with drastically prolonged suppression of LCK signaling. In vivo pharmacokinetic and pharmacodynamic profiling indicated a 630% increase in the duration of LCK suppression by SJ11646 over dasatinib in patient-derived xenograft models of T-ALL, which translated into its extended leukemia-free survival over dasatinib in vivo. Last, SJ11646 retained a high binding affinity to 51 human kinases, particularly ABL1, KIT, and DDR1, all of which are known drug targets in other cancers. Together, our dasatinib-based phenyl-glutarimide PROTACs are promising therapeutic agents in T-ALL and valuable tools for developing degradation-based therapeutics for other cancers.

Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases.

Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings's regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming's slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7−30.2; OR = 21.0 CI95%: 3.4−127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.

Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development.

BACKGROUND: SJ733, a newly developed inhibitor of P. falciparum ATP4, has a favorable safety profile and rapid antiparasitic effect but insufficient duration to deliver a single-dose cure of malaria. We investigated the safety, tolerability, and pharmacokinetics of a multidose SJ733 regimen and a single-dose pharmacoboost approach using cobicistat to inhibit CYP3A4, thereby increasing exposure. METHODS: Two multidose unboosted cohorts (n = 9) (SJ733, 300 mg and 600 mg daily for 3 days) followed by three single-dose boosted cohorts combining SJ733 (n = 18) (75-, 300-, or 600-mg single dose) with cobicistat (150-mg single dose) as a pharmacokinetic booster were evaluated in healthy volunteers (ClinicalTrials.gov: NCT02661373). FINDINGS: All participants tolerated SJ733 well, with no serious adverse events (AEs), dose-limiting toxicity, or clinically significant electrocardiogram or laboratory test findings. All reported AEs were Grade 1, clinically insignificant, and considered unlikely or unrelated to SJ733. Compared to unboosted cohorts, the SJ733/cobicistat-boosted cohorts showed a median increase in area under the curve and maximum concentration of 3·9 × and 2·6 ×, respectively, and a median decrease in the ratio of the major CYP3A-produced metabolite SJ506 to parent drug of 4·6 × . Incorporating these data in a model of parasite dynamics indicated that a 3-day regimen of SJ733/cobicistat (600 mg/150 mg daily) relative to a single 600-mg dose ± cobicistat would increase parasite clearance from 106 to 1012 parasites/µL. INTERPRETATION: The multidose and pharmacoboosted approaches to delivering SJ733 were well-tolerated and significantly increased drug exposure and prediction of cure. This study supports the further development of SJ733 and demonstrates an innovative pharmacoboost approach for an antimalarial. FUNDING: Global Health Innovative Technology Fund, Medicines for Malaria Venture, National Institutes of Health, and American Lebanese Syrian Associated Charities.

Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication.

PURPOSE: To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD). PATIENTS AND METHODS: After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with or without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times per day on days 1-28) and two dose levels of sorafenib (150 and 200 mg/m2/day on days 8-28) in 9 pediatric patients with refractory/relapsed FLT3-ITD-positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both preclinical and clinical studies. RESULTS: The combination of crenolanib and sorafenib in preclinical models showed synergy without affecting pharmacokinetics of each agent, inhibited p-STAT5 and p-ERK for up to 8 hours, and led to significantly better leukemia response (P < 0.005) and survival (P < 0.05) compared with single agents. Fewer FLT3-KD mutations emerged with dose-intensive crenolanib (twice daily) and low-intensity sorafenib (three times/week) compared with daily crenolanib or sorafenib (P < 0.05). The crenolanib and sorafenib combination was tolerable without dose-limiting toxicities, and three complete remissions (one with incomplete count recovery) and one partial remission were observed in 8 evaluable patients. Median crenolanib apparent clearance showed a nonsignificant decrease during treatment (45.0, 40.5, and 20.3 L/hour/m2 on days 1, 7, and 14, respectively) without drug-drug interaction. Only 1 patient developed a FLT3-KD mutation (FLT3 F691L). CONCLUSIONS: The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.

Changes in body mass index, weight, and height in children with acute myeloid leukemia and the associations with outcome.

Little is known about body composition changes in patients with acute myeloid leukemia (AML) during and after treatment or their associations with outcomes. Z-scores for body mass index (BMI), weight, and height at diagnosis, their longitudinal changes from diagnosis to 5 years off therapy, and their associations with adverse effects and outcomes were evaluated in 227 pediatric patients with AML enrolled in the AML02 and AML08 trials at St. Jude Children's Research Hospital between 2002-2017. The median Z-scores for baseline weight, height, and BMI were 0.193, 0.209, and 0.170, respectively, and those for weight and height decreased significantly during therapy to -0.038 and -0.163, respectively, at off-therapy (P < .001 for both). At 5 years off therapy, the Z-scores for weight and BMI had increased significantly to 0.492 (P = .003) and 0.911 (P < .001), respectively, whereas the height Z-score remained significantly lower at -0.066 (P < .001) compared with baseline. The height Z-score of transplant recipients decreased further from -0.211 at transplant to -0.617 12 months later (P < .001). Baseline BMI category and Z-score were not associated with outcomes, but higher weight Z-scores were associated with lower incidences of refractory or relapsed disease (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.67-0.99) and higher incidences of death in remission (HR, 1.31; 95% CI, 1.01-1.70). Furthermore, weight Z-score decrease during induction therapy was associated with gastrointestinal, hepatic, and infection toxicities during subsequent therapy and with death in remission (HR, 2.66; 95% CI, 1.11-6.45). Multidisciplinary monitoring for weight changes and short stature is required from diagnosis to the off-therapy period.

Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy.

Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities for all drugs on the low-risk or standard-risk arms, analyzing 504,039 dosing records. The median dose intensity for each drug ranged from 61-100%. Dose intensities for several drugs were more than 10% higher on T15 than on T16: cyclophosphamide (P<0.0001 for the standard- risk arm), cytarabine (P<0.0001 for the standard-risk arm), and mercaptopurine (P<0.0001 for the low-risk arm and P<0.0001 for the standardrisk arm). We attributed the lower dosages on T16 to the higher asparaginase dosages on T16 than on T15 (P<0.0001 for both the low-risk and standard-risk arms), with higher dose-intensity for mercaptopurine in those with anti-asparaginase antibodies than in those without (P=5.62x10-3 for T15 standard risk and P=1.43x10-4 for T16 standard risk). Neutrophil count did not differ between protocols for low-risk patients (P=0.18) and was actually lower for standard-risk patients on T16 than on T15 (P<0.0001) despite lower dosages of most drugs on T16. Patients with low asparaginase dose intensity had higher methotrexate dose intensity with no impact on prognosis. The only dose intensity measure predicting a higher risk of relapse on both studies was higher mercaptopurine dose intensity, but this did not reach statistical significance (P=0.03 T15; P=0.07 T16). In these intensive multiagent trials, higher dosages of asparaginase compromised the dosing of other drugs for acute lymphoblastic leukemia, particularly mercaptopurine, but lower chemotherapy dose intensity was not associated with relapse.

Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase.

PURPOSE: We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL). METHODS: We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m2 IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m2 or 3500 IU/m2 IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms. A pharmacokinetic-pharmacodynamic model was used to estimate the duration of CSF asparagine depletion below 1 uM. RESULTS: During induction, CSF asparagine depletion after two doses of pegaspargase was twice as long as one dose (median 30.7 vs 15.3 days, p < 0.001). During continuation, the higher dose increased the CSF asparagine depletion duration by only 9% on the LR and 1% in the SHR arm, consistent with the nonlinear pharmacokinetics of serum asparaginase. Pegaspargase caused a longer CSF asparagine depletion duration (1.3-5.3-fold) compared to those who were switched to erwinase (p < 0.001). The median (quartile range) serum asparaginase activity needed to maintain CSF asparagine below 1 µM was 0.44 (0.20, 0.99) IU/mL. Although rare, CNS relapse was higher with decreased CSF asparagine depletion (p = 0.0486); there was no association with relapse at any site (p = 0.3). CONCLUSIONS: The number of pegaspargase doses has a stronger influence on CSF asparagine depletion than did dosage, pegaspargase depleted CSF asparagine longer than erwinase, and CSF asparagine depletion may prevent CNS relapses.

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study.

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady-state exposures (area under the concentration curve from 0 to 12-h [AUC0->12 h ]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m2 /dose) or a pharmacokinetically guided dose targeting an AUC0->12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in-target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

Association between obesity and neurocognitive function in survivors of childhood acute lymphoblastic leukemia treated only with chemotherapy.

BACKGROUND: Neurocognitive impairment and obesity are common adverse sequelae in survivors of childhood acute lymphoblastic leukemia (ALL); however, the association has not been investigated. METHODS: Neurocognitive function was evaluated once in survivors of ALL who were at least 8 years old and 5 years from their diagnosis. In a cross-sectional analysis, the associations with the body mass index (BMI) category and Z score were examined. A longitudinal analysis used the overweight/obesity area under the curve (AUC), which was determined via the trapezoidal rule by a sum of the integrals defined by the BMI Z score at each time point and the time intervals of the BMI measurement. RESULTS: For 210 survivors, the median BMI Z score at diagnosis was 0.17, which increased to 0.54 at the end of induction and to 0.74 at the neurocognitive assessment. In the cross-sectional analysis, overweight/obese survivors scored significantly lower than others on the measures of executive function (cognitive flexibility, planning, verbal fluency, working memory, and spatial construction; all P < .05), attention (attention span and risk taking; all P < .05), and processing speed (visual motor coordination, visual speed, and motor speed; all P < .05). In the longitudinal analysis, when the treatment period was subdivided into 4 time periods (induction, consolidation, early maintenance, and late maintenance), a greater overweight/obesity AUC during induction therapy was associated with worse cognitive flexibility (P = .01) and slower motor speed (P = .02), which persisted throughout the treatment. CONCLUSIONS: Overweight/obesity was significantly associated with neurocognitive impairment during long-term follow-up, and this association started early in treatment for ALL. Novel early interventions to provide cognitive training and prevent weight gain are required for patients at risk.

Limited sampling strategies for accurate determination of extended half-life factor VIII pharmacokinetics in severe haemophilia A patients.

BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. OBJECTIVE: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose + peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population. CONCLUSIONS: The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.

Identification of small molecules that mitigate vincristine-induced neurotoxicity while sensitizing leukemia cells to vincristine.

Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose-limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR-induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human-induced pluripotent stem cell-derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR's antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.

Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies.

BACKGROUND: A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies. METHODS: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m2 /d) in combination with clofarabine (40 mg/m2 ), etoposide (100 mg/m2 ), and dexamethasone (8 mg/m2 ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5. RESULTS: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m2 /d, 6 were treated at the dose level of 40 mg/m2 /d, and 4 were treated at the dose level of 60 mg/m2 /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m2 /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years. CONCLUSIONS: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509). LAY SUMMARY: Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.

The Heme-Regulated Inhibitor Pathway Modulates Susceptibility of Poor Prognosis B-Lineage Acute Leukemia to BH3-Mimetics.

Antiapoptotic MCL1 is one of the most frequently amplified genes in human cancers and elevated expression confers resistance to many therapeutics including the BH3-mimetic agents ABT-199 and ABT-263. The antimalarial, dihydroartemisinin (DHA) translationally represses MCL-1 and synergizes with BH3-mimetics. To explore how DHA represses MCL-1, a genome-wide CRISPR screen identified that loss of genes in the heme synthesis pathway renders mouse BCR-ABL+ B-ALL cells resistant to DHA-induced death. Mechanistically, DHA disrupts the interaction between heme and the eIF2α kinase heme-regulated inhibitor (HRI) triggering the integrated stress response. Genetic ablation of Eif2ak1, which encodes HRI, blocks MCL-1 repression in response to DHA treatment and represses the synergistic killing of DHA and BH3-mimetics compared with wild-type leukemia. Furthermore, BTdCPU, a small-molecule activator of HRI, similarly triggers MCL-1 repression and synergizes with BH3-mimetics in mouse and human leukemia including both Ph+ and Ph-like B-ALL. Finally, combinatorial treatment of leukemia bearing mice with both BTdCPU and a BH3-mimetic extended survival and repressed MCL-1 in vivo. These findings reveal for the first time that the HRI-dependent cellular heme-sensing pathway can modulate apoptosis in leukemic cells by repressing MCL-1 and increasing their responsiveness to BH3-mimetics. This signaling pathway could represent a generalizable mechanism for repressing MCL-1 expression in malignant cells and sensitizing them to available therapeutics. IMPLICATIONS: The HRI-dependent cellular heme-sensing pathway can modulate apoptotic sensitivity in leukemic cells by repressing antiapoptotic MCL-1 and increasing their responsiveness to BH3-mimetics.