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• W3030370526 abstract "To the Editor: Sickle cell anemia (SCA) is a recessively-inherited condition resulting from a missense mutation in the beta-globin locus and is characterized by chronic hemolytic anemia, episodic vaso-occlusive crises, and chronic progressive end-organ damage.1 Hydroxyurea therapy reduces the frequency of acute crises, early morbidity, and long-term mortality. Patients have greater benefit from therapy at the maximum tolerated dose (MTD) than fixed dosing, but MTD varies widely between patients, ranging from 15 mg/kg/d to 35 mg/kg/d.2 A means to accurately predict MTD at the time of treatment initiation using readily-determined clinical and laboratory parameters could therefore improve the ease and efficiency of hydroxyurea therapy in pediatric patients. Utilizing data from the HUSTLE trial (NCT00305175), we derived a predictive equation by regression analysis that incorporates baseline body mass index (BMI), creatinine, and absolute reticulocyte count (ARC; ×109/L) to predict a patientʼs MTD prior to initiation of therapy.3 The Novel Dose Escalation to Predict Treatment with Hydroxyurea study (NDEPTH; NCT02042222) was designed to assess the safety and efficacy of this dose-prediction equation in determining hydroxyurea MTD in children with SCA. The primary hypothesis of the study was that using the dose-prediction equation would result in faster escalation to MTD than with a standard dose-escalation regimen without an increase in myelosuppressive or clinical adverse events. Mean starting dose in the dose-prediction arm was 26.2 ± 2.4 mg/kg/d. All subsequent study procedures in both arms were in accordance with our institutional guidelines, following a commonly used dose-escalation algorithm.4 Participants were deemed to be at MTD if their ANC was between 1.0-3.0 × 109/L or ARC was between 80-100 × 109/L on two sequential clinic visits at least a month apart on a stable hydroxyurea dose. Determination of MTD was made by the participantʼs primary clinician and the study primary investigator using the criteria described above. For the primary endpoint of the study, time to MTD between the two arms was compared using intention-to-treat Kaplan-Meier analysis and the log-rank test. The incidence of laboratory and clinical adverse events was compared between the two arms on an intention-to-treat basis. Neutropenia was defined as an ANC <1.0 × 109/L, reticulocytopenia as an ARC <80 × 109/L, and thrombocytopenia as a platelet count <100 × 109/L. Acute chest syndrome (ACS) and splenic sequestration events were identified using previously described definitions.5 Acute pain crises were defined as episodes severe enough to require emergency center visits or in-patient admissions. Changes in laboratory parameters were compared using the independent, two-sample T-test. Categorical variables were compared using the Fisherʼs exact test. The degree of correlation between predicted and actual MTDs was determined using Spearmanʼs correlation coefficient. A total of 70 participants consented to participate in the study between December 2013 and August 2018. Of these, two were excluded before enrollment, one due to incorrect genotyping and the other to abnormal TCD screening before study treatment was initiated. The remaining 68 participants were randomized to the dose-escalation and dose-prediction arms. There were no significant differences between the two groups in age, gender, genotype, or starting laboratory characteristics (Table S1). Two patients did not return after the baseline visit. Of the 34 participants treated in each arm, eight in the standard arm and seven in the alternative arm were censored before reaching MTD. Two participants on the standard arm completed all study procedures but did not meet criteria for reaching MTD and were censored at the end of the study. The remaining 26 participants on the standard arm and 27 on the alternative arm were successfully escalated to MTD (Figure S1). There was a statistically significant difference in Kaplan-Meier curves between treatment arms (Figure 1; P = .038). The median time to MTD in the standard dose-escalation arm was 17.9 weeks (95% CI: 14, 31), while in the dose-prediction arm it was 16.4 weeks (95% CI: 13, 20). The 75th percentiles were 36.7 (28, 48) and 24.1 (19, 35), respectively. The actual MTD was 22.6 ± 3.4 mg/kg/d in the standard arm and 27.3 ± 3.0 mg/kg/d in the alternative arm (P < .0001). Study participants in the dose-prediction arm required significantly fewer escalations from the starting dose than those in the dose-escalation arm (Table S2). Four participants in the dose-prediction arm required dose escalations compared to 12 in the dose-escalation arm. Two participants in the dose-escalation arm and four in the dose-prediction arm required dose reductions before reaching MTD. The rates of cytopenias were similar between the two treatment arms, with no increases in toxicity in the dose-prediction arm. There was also a trend towards fewer clinical adverse events in the dose-prediction arm (Table S3). Despite the higher mean dose recorded in the dose-prediction arm, laboratory response to treatment was similar between the two arms at the time of MTD and at study exit (Table S4). Predicted MTD correlated moderately with actual MTD for the entire cohort (Spearman R = 0.41, P = .002). Post hoc analysis of correlation between the variables constituting our dose-prediction equation and actual MTD for our entire study cohort revealed that MTD correlated best with baseline serum creatinine level (R = −0.29, P = .035), modestly with baseline ARC (R = 0.26, P = .06), and weakly with BMI (R = −0.12, P = .38). Our novel method to escalate children to MTD predicts the individualized MTD before the initiation of treatment using a patientʼs baseline BMI, serum creatinine, and ARC. To test this method, the NDEPTH study randomized children to this dosing equation against a standard dose-escalation algorithm and identified faster escalation to MTD in the dose-prediction arm. Importantly, the dose-prediction equation estimated actual MTD accurately, was comparable to standard dose-escalation for safety, and resulted in a higher final hydroxyurea dose than the standard treatment arm. All participants achieving MTD had a strong and sustained response to hydroxyurea therapy, with marked improvement in hemoglobin levels and a low rate of clinical complications. The primary endpoint of this study was time to MTD. Our power calculations were predicated on a median time to MTD of 35 weeks for the standard dose-escalation arm, but the actual median time to MTD was only 17.9 weeks. This discrepancy may be due in part to relatively low ANC values in this young population, which precluded dose escalations in many study participants beyond their starting hydroxyurea dose of 20 mg/kg/d in this arm. Specifically, 14 of 26 children in the standard arm had baseline ANC <3.0 × 109/L at hydroxyurea initiation, or achieved the target ANC (1.0-3.0 × 109/L) with their starting hydroxyurea dose. Notably, a similar proportion of participants on the dose-prediction arm also had low starting ANC values, but tolerated significantly higher starting hydroxyurea doses without excessive myelosuppression. A recent study to prospectively validate a PK-guided approach for MTD prediction (TREAT, NCT02286154) was successful in rapidly escalating children with SCA to MTD without excessive dose changes or toxicities.6 Strikingly, the median time to MTD of 4.8 months in this study was very similar to the median of 3.9 months in the dose-prediction arm of our study. Similarly, the mean hydroxyurea MTD in the TREAT study was 26.7 ± 4.8 mg/kg/d, compared to 27.3 ± 3.0 mg/kg/d in our study. This congruence between the two studies supports the conclusion that targeted myelosuppression is unreliable in determining hydroxyurea MTD in young children with SCA. In summary, the results of the NDEPTH study confirm that a simple dose-prediction equation developed from HUSTLE data was feasible and safe for establishing an optimal hydroxyurea dose for children with SCA. Additionally, this dose-prediction method was clinically superior to standard step-wise dose escalation, with more rapid escalation to MTD, higher final hydroxyurea dose, and equivalent toxicity profile. The simplicity of our dose-prediction equation supports its potential use in countries with limited medical resources, where frequent clinic visits and laboratory monitoring are impractical. We thank the clinicians, nursing staff, and support personnel of the Texas Childrenʼs Hospital Sickle Cell Center and the staff of the Texas Childrenʼs Clinical Research Office, without whose support we would not have been able to conduct this study. We also acknowledge with deep gratitude the patients and families who participated in this study. This project was supported by a Baylor College of Medicine Department of Pediatrics Pilot Award to Alex George. AG has research support from Pfizer, Novartis, Sancilio Pharmaceuticals, and Global Blood Therapeutics; is on an advisory board for Global Blood Therapeutics; has received speakerʼs fees from Pfizer and Global Blood Therapeutics; and receives royalties from Wolters Kluwer. DHM has royalties from Wolters Kluwer. AMY has research support from Novartis and royalties from Wolters Kluwer. TF has research support from Pfizer, is a consultant for Novartis, and provided staff education for Global Blood Therapeutics. REW has research support from Bristol Myers-Squibb, Addmedica, and Hemex; is a medical advisor for Global Blood Therapeutics, Behring, and Nova Laboratories; and serves on a Data Safety Monitoring Board for Novartis. None of the other authors have pertinent disclosures. Figure S1. CONSORT diagrams of study outcomes. Table S1. Baseline characteristics of participants in the dose-escalation (STD) and dose-prediction (ALT) study arms. HbF: Fetal hemoglobin. Table S2. Comparison of dose modifications between the dose-escalation (standard) and dose-prediction (alternative) arms of the study. Data are presented only for participants who reached the MTD endpoint within the protocol-directed 12 months of study monitoring. The number of affected participants is presented with the number of dose changes in parentheses. Table S3. Comparison of myelosuppressive events and adverse clinical events between the dose-escalation and dose-prediction arms of the study. Data are presented for all study participants from time of study entry to study exit or censoring as the total number of participants affected, with events per patient-year in parentheses. Neutropenia: ANC <1 × 109/L; reticulocytopenia: ARC <80 × 109/L; thrombocytopenia: platelets <100 × 109/L. Table S4. Changes in laboratory parameters from baseline between the dose-escalation (STD) and dose-prediction (ALT) arms of the study at the time of MTD (Baseline to MTD) and at study exit 12 months after initiating treatment (Baseline to Study Exit). Data are presented for the study participants who successfully escalated to MTD (N = 26 for the STD arm and 27 for the ALT arm). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W3030370526 title "Novel dose escalation to predict treatment with hydroxyurea ( <scp>NDEPTH</scp> ): A randomized controlled trial of a dose‐prediction equation to determine maximum tolerated dose of hydroxyurea in pediatric sickle cell disease" @default.
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