For this study, 118 children with standardrisk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population. (Blood.

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Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 ؋ 2 factorial design to receive dexamethasone (6 mg/m 2 /d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m 2 /d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m 2 /d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous systemdirected therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous systemrelapse rate of 3.7% ؎ 0.8%, compared with 7.1% ؎ 1.1% for prednisone (P ‫؍‬ .01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% ؎ 2% for dexamethasone and 77% ؎ 2% for prednisone (P ‫؍‬ .002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse. (Blood. 2003;101:3809-3817)

A B S T R A C T PurposeDespite improvements in treatment, approximately 20% of patients with acute lymphoblastic leukemia (ALL) experience relapse and do poorly. The Therapeutic Advances in Childhood Leukemia (TACL) Consortium was assembled to assess novel drugs for children with resistant leukemia. We hypothesize that novel agents and combinations that fail to improve baseline complete remission rates in comparable populations are unlikely to contribute to better outcomes and should be abandoned. We sought to define response rates and disease-free survival (DFS) rates in patients treated at TACL institutions, which could serve as a comparator for future studies. Patients and MethodsWe performed a retrospective cohort review of patients with relapsed and refractory ALL previously treated at TACL institutions between the years of 1995 and 2004. Data regarding initial and relapsed disease characteristics, disease response, and survival were collected and compared with those of published reports. ResultsComplete remission (CR) rates (mean Ϯ SE) were 83% Ϯ 4% for early first marrow relapse, 93% Ϯ 3% for late first marrow relapse, 44% Ϯ 5% for second marrow relapse, and 27% Ϯ 6% for third marrow relapse. Five-year DFS rates in CR2 and CR3 were 27% Ϯ 4% and 15% Ϯ 7% respectively. ConclusionWe generally confirm a 40% CR rate for second and subsequent relapse, but our remission rate for early first relapse seems better than that reported in the literature (83% v approximately 70%). Our data may allow useful modeling of an expected remission rate for any population of patients who experience relapse.

• Adherence rates were significantly lower in African Americans (87%) and Asian Americans (90%), as compared with non-Hispanic whites (95%).• Adherence to 6MP at ,90%was associated with a 3.9-fold increased risk of relapse in a multiracial cohort of children with ALL.Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP . Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P 5 .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials. gov as #NCT00268528. (Blood. 2014;124(15):2345-2353

Importance Variability in prescribed 6-mercaptopurine and lack of adherence to 6-mercaptopurine could result in intra-individual variability in systemic exposure to 6-mercaptopurine (measured as erythrocyte thioguanine nucleotide levels) in children with acute lymphoblastic leukemia. The impact of intra-individual variability in systemic exposure to 6-mercaptopurine on relapse risk is unknown. Objective To determine impact of high intra-individual variability in 6-mercaptopurine systemic exposure on relapse risk in children with acute lymphoblastic leukemia. Design Prospective longitudinal design; daily adherence monitoring, 6-mercaptopurine dose-intensity and erythrocyte thioguanine nucleotide levels (pmol/8*10^8 erythrocytes) measured for 6 consecutive months per patient; cohort followed for a median of 6.7 years from diagnosis. Setting Children’s Oncology Group study (COG-AALL03N1); 94 participating institutions; ambulatory care setting. Participants Participants included 742 children meeting the following eligibility criteria: diagnosis of acute lymphoblastic leukemia at ≤21 years; in first continuous remission at study entry; receiving self/parent/caregiver-administered oral 6-mercaptopurine during maintenance. Median age at diagnosis: 5 years; 68% were male; 43% with NCI-based high-risk disease. Main Outcome Measures Adherence measured electronically using Medication Event Monitoring System that recorded date/time of each 6-mercaptopurine bottle opening; adherence rate defined as ratio of days of 6-mercaptopurine bottle opened to days when 6-mercaptopurine prescribed. 6-mercaptopurine doses actually prescribed were divided by planned protocol doses (75mg/m2/day) to compute average monthly dose-intensity. Electronically-monitored adherence (68,716 person-days), 6-mercaptopurine dose-intensity (120,439 person-days) and monthly erythrocyte thioguanine nucleotide levels (n=3,944 measurements) contributed to the analysis. Using intra-individual coefficients of variation (CV %), patients were classified as having stable (CV % <85th percentile) vs. varying (CV % ≥85th percentile) indices. Results Adjusting for clinical prognosticators, patients with 6-mercaptopurine non-adherence (mean adherence rate <95%) were at a 2.7 fold increased risk of relapse (95% confidence interval [CI], 1.3 to 5.6, p=0.01). Among adherers, high intra-individual variability in thioguanine nucleotide levels contributes to increased relapse risk (HR=4.4, 95% CI, 1.2 to 15.7, p=0.02). Furthermore, adherers with varying thioguanine nucleotide levels had varying 6-mercaptopurine dose-intensity (OR=4.5, p=0.006) and 6-mercaptopurine drug interruptions (OR=10.2, p=0.003). Conclusions and Relevance These findings emphasize the need to maximize 6-mercaptopurine adherence and maintain steady thiopurine exposure to minimize relapse in children with acute lymphoblastic leukemia.

Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n ‫؍‬ 20) or T-cell ALL (n ‫؍‬ 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best,

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