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Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk b-acute lymphoblastic leukemia: a report from children's oncology group study aall0232

Published Ahead of Print on April 25, 2016 as 10.1200/JCO.2015.62.4544
JOURNAL OF CLINICAL ONCOLOGY Dexamethasone and High-Dose Methotrexate ImproveOutcome for Children and Young Adults With High-RiskB-Acute Lymphoblastic Leukemia: A Report From Children'sOncology Group Study AALL0232Eric C. Larsen, Meenakshi Devidas, Si Chen, Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh,Leonard A. Mattano Jr, Catherine Cole, Alisa Eicher, Maureen Haugan, Mark Sorenson, Nyla A. Heerema,Andrew A. Carroll, Julie M. Gastier-Foster, Michael J. Borowitz, Brent L. Wood, Cheryl L. Willman,Naomi J. Winick, Stephen P. Hunger, and William L. Carroll Author affiliations appear at the end of this Published online ahead of print at on April 25, 2016.
Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved Supported by Children's Oncology Group significantly, but 20% to 25% of patients are not cured. Children's Oncology Group study AALL0232 Chairs Operations grants U10 CA98543 tested two interventions to improve survival.
and U10 CA180886 and Children'sOncology Group Statistics and Data Patients and Methods Center grants U10 CA098413 and U10 Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 3 2 factorial design, N.J.W., S.P.H., and W.L.C. contributed 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone equally to this work.
(28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate Presented at the 2011 Annual Meeting of plus pegaspargase during interim maintenance 1.
the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011.
ResultsPlanned interim monitoring showed the superiority of the high-dose methotrexate regimens, which Authors' disclosures of potential conflicts exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, of interest are found in the article online at . Author contributions are participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus found at the end of this article.
those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% Corresponding author: Eric C. Larsen, versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose MD, Maine Children's Cancer Program, methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased 100 Campus Dr, Scarborough, ME 04074; both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high- dose methotrexate had a superior outcome compared with those who received the other three 2016 by American Society of Clinical regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis.
High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acutelymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during inductionbenefited younger children but provided no benefit and was associated with a higher risk ofosteonecrosis among participants 10 years and older.
J Clin Oncol 34. 2016 by American Society of Clinical Oncology and WBC count.Clinical trials have produced incremental improvements in event-free sur-vival (EFS) and overall survival (OS) for chil- Acute lymphoblastic leukemia (ALL) is the dren with HR B-ALLthrough intensification of most common malignancy in children and a postinduction therapy and more accurate risk major cause of cancer death before age 40 years.
Approximately 85% of pediatric ALL cases are Compared with prednisolone, dexameth- B-acute lymphoblastic leukemia (B-ALL), sub- asone has greater cytotoxic effects on ALL cells in classified as National Cancer Institute (NCI) vitrosuperior CNS penetration, and a longer standard risk and high risk (HR) based on age CSF half-lifeIn clinical trials, dexamethasone 2016 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at University of Minnesota Libraries on April 26, 2016 from Copyright 2016 American Society of Clinical Oncology. All rights reserved.
Copyright 2016 by American Society of Clinical Oncology
has a greater antileukemic effect than prednisonebut is asso- DNA index , 0.81, induction failure, or SER with MLL rearrangement—were ciated with increased toxicities, including induction death, fractures, removed from protocol therapy after induction. Therapy was continued osteonecrosis, and behavioral disturbances for 2 years for females and 3 years for males from the beginning of interimmaintenance 1. Therapy details are provided in Appendix Methotrexate is a critical component of ALL therapy and plays (online only).
an important role in CNS prophylaxis. Worldwide, two different Therapy amendments were made during the conduct of AALL0232.
methotrexate intensification strategies have been studied: High- Patients with Down syndrome were initially eligible, and 44 were randomly dose methotrexate (HD-MTX) regimens of 2 to 5 g/m2 admin- assigned between the DC and PC treatment regimens, but this group istered over 24 hours followed by leucovorin re,and the experienced excessive toxic mortality and were made ineligible for Capizzi regimen with lower, escalating doses of intravenous enrollment in 2006. An increased incidence of osteonecrosis was observed methotrexate (C-MTX) of 100 to 300 mg/m2 through short in children 10 years of age and older assigned to dexamethasone duringinduction. Consequently, AALL0232 was amended in 2008 to exclude infusions, without leucovorin rescue, followed by asparaginase.
patients 10 years of age and older from the corticosteroid assignment.
Both strategies are effective, but they have never been directly Additionally, all subsequently received discontinuous dexamethasone compared in childhood ALL. Children's Oncology Group (COG) during delayed intensification and prednisone during maintenance.
AALL0232 tested the safety and efficacy of dexamethasone versusprednisone during induction and HD-MTX with leucovorin rescue Toxicity Assessment versus C-MTX plus pegaspargase during interim maintenance 1.
Data on adverse events and clinically significant laboratory findings were collected using the NCI Common Terminology Criteria for AdverseEvents version 3.0 until December 2010 and version 4.0 thereafter. Adverse PATIENTS AND METHODS event reporting was supplemented with the NCI Adverse Event ExpeditedReporting System and MedWatch reports.
Patient Characteristics AALL0232 enrolled participants between January 2004 and January Statistical Analysis 2011. Patients with newly diagnosed B-ALL age 1 to 9 years with initial The study was originally designed as a 2 3 2 randomized factorial WBC $ 50,000/mL or 10 to 30 years with any WBC were eligible. The design, with the first factor comparing the induction corticosteroid diagnosis was determined by morphologic, biochemical, and immunologic (prednisone versus dexamethasone) and the second comparing metho- ,CNS status was defined based on CSF obtained before therapy trexate approaches (HD-MTX versus C-MTX) during interim main- as follows: CNS1 (no blasts), CNS2 (CSF WBC , 5/mL with blasts), or tenance 1. Random assignment occurred at study entry. Power calculations CNS3 (CSF WBC $ 5/mL with blasts and/or clinical signs of CNS leu- are based on log-rank test, with 10 planned interim analyses monitoring kemia). AALL0232 was approved by NCI and the institutional review for efficacy. Two-sided log-rank tests were to be used for EFS comparisons.
boards of participating institutions. Informed consent was obtained from Interim monitoring in January 2011 revealed that the predefined participants or a parent/guardian in accordance with Department of efficacy monitoring boundary had been crossed by showing increased Health and Human Services guidelines.
efficacy for HD-MTX compared with C-MTX, which led to early closure ofaccrual. All patient assigned to C-MTX who had not yet finished the first cycle of maintenance therapy crossed over to the HD-MTX regimen.
AALL0232 used a 2 3 2 factorial design with a COG-modified EFS was defined as the time from study entry to first event (induction augmented intensity Berlin-Frankfurt-M¨unster backbone.Eligible par- failure, induction death, relapse, second malignancy, remission death) or ticipants were randomly assigned at study entry to receive dexamethasone date of last follow-up for event-free patients. Those who crossed over to the (10 mg/m2/day) on days 1 to 14 versus prednisone (60 mg/m2/day) on days HD-MTX arm were censored at the time of crossover. OS was defined as 1 to 28 during induction and HD-MTX versus C-MTX during interim the time from study entry to death or date of last follow-up. Survival rates maintenance 1. Treatment regimens PC, PH, DC, and DH were designated were estimated by using the Kaplan-Meier method with standard by the corticosteroid (prednisone [P], dexamethasone [D]) and metho- errors.Survival curves were compared by using the log-rank test.
trexate (Capizzi [C], high dose [H]) assignments. Early response was used Cumulative incidence rates between regimens were computed by using the to refine treatment.
cumulative incidence function for competing risks, and comparisons were Rapid early responders (RERs) had an M1 marrow (, 5% blasts) by conducted with the K-sample P ,.05 was considered significant for induction day 15 and , 0.1% minimal residual disease (MRD) in the day all comparisons. All analyses were performed with SAS software (version 29 marrow by flow cytometry.Slow early responders (SERs) had an M1 9.4; SAS Institute, Cary, NC). Graphics were generated with R version marrow on induction day 29 but with either an M2 (5% to 25% blasts) or M3 (. 25% blasts) marrow on induction day 15 or MRD $ 0.1% on day29 marrow. They received a second interim maintenance with C-MTX, asecond delayed intensification, and 12-Gy cranial irradiation. Patients with an M2 marrow or $ 1% MRD at day 29 received 2 additional weeks ofinduction therapy and were considered SERs if their day 43 marrow was M1 with , 1% MRD; otherwise, they were considered induction failuresand removed from protocol therapy, as were those with an M3 marrow at AALL0232 enrolled 3,154 participants—48 were ineligible; day 29. Patients with CNS3 status were nonrandomly assigned to receive 44 had Down syndrome; and 148 were nonrandomly assigned to HD-MTX and 18-Gy cranial irradiation. Those with testicular leukemia at specific regimens due to CNS3 status, testicular involvement, or diagnosis and those who received . 48 hours of corticosteroid therapy in extensive corticosteroid pretreatment ). The remaining the week before diagnosis participated in the induction corticosteroid 2,914 participants were randomly assigned to the four treatment random assignment but were nonrandomly assigned to HD-MTX with regimens—PC (n = 926), PH (n = 926), DC (n = 535), DH two interim maintenance and delayed intensification phases. If testicularinvolvement was not resolved at end induction, 24-Gy testicular irradiation (n = 527). Randomly assigned participants with VHR ALL was given during consolidation. Patients with very-high-risk (VHR) features—BCR-ABL1 (n = 135), hypodiploidy (n = 81), MLL ALL—BCR-ABL1 fusion, hypodiploidy with , 44 chromosomes, and/or rearrangement with SER (n = 24)—were removed from protocol 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by at University of Minnesota Libraries on April 26, 2016 from Copyright 2016 American Society of Clinical Oncology. All rights reserved.
Dexamethasone and High-Dose Methotrexate Improve Outcome in High-Risk B-ALL Randomly assigned Not randomly assigned Fig 1. Consort diagram for Children's Oncology Group AALL0232. DC, dexamethasone plus Capizzi escalating-dose methotrexate regimen; DH, dexamethasone plus high-dose methotrexate regimen; IF, induction failure; ID, induction death; PC, prednisone plus Capizzi escalating-dose methotrexate regimen; PH, prednisone plus high-dose methotrexate regimen; RER, rapid early responder; SER, slow early responder; Unk, unknown; VHR, very high risk.
therapy after induction and are excluded from this report. Of the Methotrexate Random Assignment randomly assigned participants with complete data at the end of Interim monitoring in January 2011 showed that the pre- induction (n = 2,554), 80.3% were classified as RERs (n = 2,051) defined efficacy monitoring boundary had been crossed, with and 19.7% were classified as SERs (n = 503). These include superior outcomes for participants assigned to HD-MTX versus 35 RERs and 111 SERs classified as induction failures or induction C-MTX, and AALL0232 accrual was halted. At that time, the estimated 5-year EFS rates were 82 6 3.4% (HD-MTX) versus Age distribution ranged from 12 months to 30 years, with 33% 75.4 6 3.6% (C-MTX; P = .006). Therapy changes were recom- 1 to 9 years old, 47% 10 to 15 years old, and 20% 16 to 30 years old, mended to provide HD-MTX to all participants who had not yet including 2% age 21 years and older. Fifty-four percent were male completed course 1 of maintenance or received cranial irradiation.
and 46% female. African American enrollment was 6.7%, and For the final analyses, the outcome of those assigned to C-MTX Hispanic enrollment was 23.8%. The presenting WBC distribution who subsequently received HD-MTX was censored at the time of was 37.6% , 10,000/mL, 18.9% 10 to 49,999/mL, 23.9% 50 to therapy crossover (n = 127). These analyses showed 5-year EFS 99,999/mL, 12.6% 100 to 199,999/mL, and 7.0% $ 200,000/mL.
rates of 79.6 6 1.6% for the HD-MTX regimens versus 75.2 6 The distribution of CNS status at entry was 85.9% CNS1 and 1.7% for the C-MTX regimens (P = .008; ) and 5-year OS 14.1% CNS2 for the randomized cohort.
rates of 88.9 6 1.2% for HD-MTX and 86.1 6 1.4% for C-MTX(P = .025; Appendix ). For RERs, the 5-year EFS rates Treatment Outcome were 84.9 6 1.6% for HD-MTX versus 82.8 6 1.7% for C-MTX The 5-year EFS and OS for the 2,979 participants eligible and (P = .202; and OS rates were 91.8 6 1.2% versus 90.7 6 evaluable for postinduction therapy was 75.2 6 1.1% and 85.0 6 1.3% (P = .531; Appendix ). For SERs, the 5-year EFS rates 0.9%, respectively ). For the 2,573 participants considered were 57.8 6 4.6% for HD-MTX and 49.4 6 4.2% for C-MTX in the evaluation of the randomized questions (eligible, evaluable (P = .095; ), and OS rates were 77.9 6 3.8% versus 71.2 6 for postinduction therapy, not VHR, and not Down syndrome), 3.9% (P = .048; Appendix For patients 10 years of age and the 5-year EFS was 77.5 6 1.2%, and OS was 87.5 6 0.9% older nonrandomly assigned to receive prednisone during induction As expected, RERs had better 5-year EFS (83.9 6 1.1% v 53.3 6 after April 2008, those randomly assigned to receive HD MTX had 3.1%, P ,.001; Appendix ) and OS (91.3 6 0.9% v 74.3 6 a nonsignificant trend towards improved outcome (4-year EFS 2.8%, P , .001; Appendix ) than SERs.
79.1% v 77% with C-MTX; P = .569; ). Five-year 2016 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at University of Minnesota Libraries on April 26, 2016 from Copyright 2016 American Society of Clinical Oncology. All rights reserved.
Fig 2. (A) Event-free survival (EFS) and overall survival (OS) for eligible, evaluable enrolled participants. The 5-year EFS and OS rates were 75.3 6 1.1% and 85.0 6 0.9%, respectively. (B) EFS and OS for non–Down syndrome, non–very-high-risk randomly assigned participants. The 5-year EFS and OS rates were 77.5 6 1.2% and 87.5 60.9%, respectively.
cumulative incidence rates for HD-MTX versus C-MTX were 7.0 6 induction deaths and 51 (1.7%) remission deaths. Among all 0.8% and 8.6 6 0.9% for marrow relapse (P = .089), 2.9 6 0.5% eligible, evaluable, randomly assigned participants (n = 2,573), versus 4.1 6 0.6% for CNS relapse (P = .09), and 2.0 6 0.4% versus 97 experienced death as a first event, with 48 (1.9%) induction 2.1 6 0.4% for remission deaths (P = .89). provides the raw deaths and 49 (1.9%) remission deaths. Induction deaths occurred number of events by methotrexate regimen.
in 1.7% (18 of 1,062) participants assigned to dexamethasone and1.7% (30 of 1,852) of those assigned to prednisone. The 5-yearcumulative incidence rate for remission deaths was 2.0 6 0.3%.
Corticosteroid Random Assignment The 5-year cumulative incidence rates of remission deaths among Participants 1 to 9 years of age (n = 851) were randomly all randomly assigned participants were as follows: DC, 1.8 6 assigned to the corticosteroid and methotrexate regimens—DH 0.6%; DH, 1.4 6 0.6%; PC, 2.3 6 0.6%; and PH, 2.3 6 0.6% (P = (n = 206), DC (n = 218), PH (n = 213), PC (n = 214). Because there .77). The higher rates observed on the prednisone induction arms was a significant qualitative interaction between the corticosteroid are due to nonrandom assignment of older patients to these arms and methotrexate assignments (P = .048), EFS comparisons were made among the four regimens. The DH regimen was superior, Methotrexate random assignment. There was a higher rate of with a 5-year EFS rate of 91.2 6 2.8% compared with 83.2 6 3.4% febrile neutropenia during interim maintenance 1 in the C-MTX (DC), 80.8 6 3.7% (PH), and 82.1 6 3.5% (PC; P = .015; ) regimens (8.3% v 5.1% with HD-MTX; P = .003; and a nonsignificant trend toward improved 5-year OS (P = .444; Ischemic cerebrovascular toxicity was observed in five patients who Appendix ). Five-year cumulative incidence rates for the received HD-MTX, whereas no patients who received C-MTX had four regimens were 3.2 6 1.3% (DH), 7.3 6 2.0% (DC), 3.5 6 this toxicity (P =.03). No other statistically significant differences 1.4% (PH), and 4.8 6 1.7% (PC) for marrow relapse (P = .024) were found in toxicity between the methotrexate regimens during and 2.0 6 1.0% (DH), 4.9 6 1.5% (DC), 5.0 6 1.6% (PH), and interim maintenance 1, including mucositis, neurotoxicity, 5.4 6 1.6% (PC) for CNS relapse (P = .28).
osteonecrosis, and death in remission.
Before June 2008, when the induction corticosteroid random Corticosteroid random assignment. During induction, dex- assignment was closed to older patients due to excess rates of amethasone was associated with higher rates of febrile neutropenia osteonecrosis with dexamethasone, 1,048 participants 10 years of (18.2% v 11.0% with prednisone; P , .001) and infections/ age and older were randomly assigned to dexamethasone (n = 523) infestations (29.4% v 20.3% with prednisone; P ,.001; ).
and prednisone (n = 525). The 5-year EFS rates for the older Despite higher rates of infection on the dexamethasone arms, there participants were virtually identical at 73.1 6 2.1% (dex- was no difference in the induction death rate compared with the amethasone) and 73.9 6 2.2% (prednisone; P = .78; ) as were prednisone regimens (18 of 946 [1.9%] v 17 of 952 [1.8%] with 5-year OS rates (P = .97; Appendix Appendix dexamethasone and prednisone, respectively; P = .87). Among provides the raw number of events by corticosteroid regimen.
patients younger than 10 years of age, induction deaths were threeof 424 (0.71%) for dexamethasone and four of 427 (0.94%) for prednisone (P = .71). For those 10 years of age and older, induction Nonrelapse mortality. Among the 3,106 eligible and evaluable deaths occurred in 15 of 522 (2.9%) assigned to dexamethasone participants, 104 experienced death as a first event, with 53 (1.7%) versus 13 of 525 (2.5%) assigned to prednisone (P = .69).
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Dexamethasone and High-Dose Methotrexate Improve Outcome in High-Risk B-ALL C-MTX (n = 1,291) C-MTX (n = 1,012) HD-MTX (n = 1,282) HD-MTX (n = 1,039) Fig 3. (A) Event-free survival (EFS) comparisons by methotrexate regimen, all randomly assigned participants. The 5-year EFS rates for Capizzi escalating-dose methotrexate (C-MTX) and high-dose methotrexate (HD-MTX) were 75.2 6 1.7% and 79.6 6 1.6%, respectively. (B) EFS comparisons by methotrexate regimen, randomlyassigned participants with a rapid early response. The 5-year EFS rates for C-MTX and HD-MTX were 82.8 6 1.7% and 84.9 6 1.6%, respectively. (C) EFS comparisons bymethotrexate regimen; randomly assigned participants with a slow early response. The 5-year EFS rates for C-MTX and HD-MTX were 49.4 6 4.2% and 57.8 6 4.6%,respectively.
Among patients 10 years of age and older who participated in AALL0232 improved survival further for these patients and has the induction corticosteroid arm before it was closed in 2008, the changed clinical practice in North America.
5-year cumulative incidence of osteonecrosis was 24.3 6 2.3% forthose assigned to 14 days of dexamethasone and 15.9 6 2.0% forthose assigned to 28 days of prednisone (P = .001). There were no Methotrexate Random Assignment other significant differences in toxicities during induction between Intravenous methotrexate is a key component of ALL post- the two corticosteroid regimens.
induction intensification strategies. When this study was under-taken, the COG used escalating C-MTX without leucovorin rescueplus asparaginase and vincristine, whereas most other groups used HD-MTX plus leucovorin rescue with mercaptopurine withsimilar outcomes. However, the impact of the HD-MTX regimen Survival for children and young adults with HR-ALL has improved remained uncertain. AALL0232 establishes that the HD-MTX over time due to more precise risk stratification and refinement regimen is superior to C-MTX for the treatment of HR B-ALL, of postinduction therapy through serial clinical trials.- with mature data showing significant improvements in both 5-year 2016 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at University of Minnesota Libraries on April 26, 2016 from Copyright 2016 American Society of Clinical Oncology. All rights reserved.
Table 1. Event Summary by Randomly Assigned Regimen Methotrexate Regimen Corticosteroid Regimen Induction failure Second malignant neoplasm Abbreviations: C-MTX, Capizzi escalating-dose methotrexate; Dex, dexamethasone; HD-MTX, high-dose methotrexate.
*x2 test.
EFS (80% v 75%; P = .008) and OS (88.9 6 1.2% v 86.1 6 1.4%; Ischemic cerebrovascular toxicity was observed in five patients who P = .025) rates. The improved outcome associated with HD-MTX received HD-MTX compared with none who received C-MTX.
occurred in all subgroups analyzed, was due to decreased rates of Although this reached statistical significance, the small numbers both marrow and CNS relapse, and was especially evident in SERs.
preclude any definite conclusion on the clinical significance of In contrast to RERs, all SERs received a second interim maintenance these observations. On the basis of these findings, we conclude that phase with C-MTX. AALL0232 cannot be considered a direct HD-MTX is both efficacious and safe and should be the standard of comparison of methotrexate doses and schedules alone because care during interim maintenance for children and adolescents with each regimen contained additional agents (eg, 6-mercaptoputine in HD-MTX, pegaspargase in C-MTX).
Close monitoring revealed no statistically significant differ- ence in occurrence of mucositis, neurotoxicity, osteonecrosis, or Corticosteroid Random Assignment other toxicities, including death, during remission between the Prior studies showed that dexamethasone had greater anti- methotrexate regimens during interim maintenance 1. C-MTX leukemic activity compared with prednisone but was also asso- was associated with a greater frequency of febrile neutropenia ciated with higher rates of several toxicities.Due to concern for than HD-MTX (8.3% v 5.1%; P = .003). This may be due to the serious acute infectious toxicity associated with 4 weeks of dex- myelosuppressive effects of MTX given without leucovorin rescue amethasone combined with an anthracycline in a four-drug ALL or to the additive myelosuppressive effect of asparaginase.
induction, AALL0232 compared dexamethasone 10 mg/m2/day for For steroid × MTX interaction: P = .0478 Dexamethasone (n = 523) Prednisone (n = 525) Fig 4. (A) Event-free survival (EFS) comparisons by treatment regimen, randomly assigned participants age 1 to 9 years. The 5-year EFS rates by regimen were prednisone plus Capizzi escalating-dose methotrexate regimen (PC), 82.1 6 3.5%; prednisone plus high-dose methotrexate regimen (PH), 80.8 6 3.7%; dexamethasoneplus Capizzi escalating-dose methotrexate regimen (DC), 83.2 6 3.4%; and dexamethasone plus high-dose methotrexate regimen (DH), 91.2 6 2.8%. (B) EFS comparisonsby steroid regimen, participants age 10 years or older. The 5-year EFS rates for dexamethasone regimens and prednisone regimens were 73.1 6 2.1% and 73.9 6 2.2%,respectively.
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Dexamethasone and High-Dose Methotrexate Improve Outcome in High-Risk B-ALL Table 2. Interim Maintenance and Induction Toxicities by Treatment Regimen Methotrexate Regimen Corticosteroid Regimen Prednisone, No. (%) Interim maintenance 1 toxicity No. of participants Febrile neutropenia Ischemia cerebrovascular Induction toxicity No. of participants Febrile neutropenia Interim maintenance 1 toxicity No. of participants Febrile neutropenia Ischemia cerebrovascular Induction toxicity No. of participants Febrile neutropenia Interim maintenance 1 toxicity No. of participants Febrile neutropenia Ischemia cerebrovascular Induction toxicity No. of participants Febrile neutropenia Abbreviations: C-MTX, Capizzi escalating-dose methotrexate; Dex, dexamethasone; HD-MTX, high-dose methotrexate.
14 days to 60 mg/m2/day of prednisone for 28 days. Participants establishes that children and adolescents 10 years of age or older assigned to dexamethasone experienced higher rates of febrile with HR B-ALL should receive 28 days of prednisone during neutropenia and infections than those assigned to prednisone; however, no significant difference in induction deaths was found.
Because there was a statistical interaction between the cor- Of note, the brief, but continuous exposure to dexamethasone ticosteroid and methotrexate assignments, a direct comparison during induction contributed to a higher rate of subsequent between dexamethasone and prednisone is not possible in the osteonecrosis compared with participants assigned to prednisone patients younger than 10 years. Comparison of the four regimens (24.3% v 15.9%; P = .001) 10 years of age or older. This finding led demonstrated a statistically significant improvement in EFS and a to the termination of the corticosteroid assignment for patients trend toward improved OS with DH compared with the other three 10 years and older in 2008. With consideration of the relative regimens DC, PH, and PC. On the basis of this result, AALL0232 efficacy and toxicity of the corticosteroid regimens, AALL0232 has established a new standard of care for patients 1 to 9 years old 2016 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at University of Minnesota Libraries on April 26, 2016 from Copyright 2016 American Society of Clinical Oncology. All rights reserved.
with HR B-ALL, who should receive 14 days of dexamethasone agents and application of targeted therapies based on novel during induction and HD-MTX during interim maintenance 1.
Dexamethasone intriguingly had more antileukemic efficacy than prednisone in younger patients, but no difference was seenamong those 10 years and older. This observation may be due to AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS age-related differences in corticosteroid pharmacokinetics. Younger patients have more rapid clearance of dexamethasone, and hencedexamethasone, a more potent corticosteroid, may enhance the Disclosures provided by the authors are available with this article at impact of corticosteroid differences in this population.In contrast, older patients have slower clearance of corticosteroids,which might minimize any improvement in efficacy while con-tributing to an increase in bone toxicity with dexamethasone.
AUTHOR CONTRIBUTIONS In conclusion, over the past 50 years, the dramatic improve- ment in survival for children with ALL has been a direct result of Conception and design: Eric C. Larsen, Meenakshi Devidas, Wanda L.
serial clinical trials conducted worldwide. The key strategies that Salzer, Mignon L. Loh, Leonard A. Mattano Jr, Catherine Cole, AlisaEicher, Maureen Haugan, Mark Sorenson, Julie M. Gastier-Foster, Naomi have led to this success have been more accurate risk stratification, J. Winick, Stephen P. Hunger, William L. Carroll prophylactic treatment of the CNS, and refinement of postinduction Collection and assembly of data: Eric C. Larsen, Meenakshi Devidas, intensification. Given the high survival of children with ALL, there Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh, Leonard A. Mattano have been concerns about whether outcome has reached a plateau.
Jr, Nyla A. Heerema, Andrew A. Carroll, Julie M. Gastier-Foster, Michael COG AALL0232 has demonstrated that optimization of conven- J. Borowitz, Brent L. Wood, Naomi J. Winick, Stephen P. Hunger, William tional chemotherapy agents remains a viable strategy by showing superior outcome with HD-MTX for all patients with HR B-ALL as Data analysis and interpretation: Eric C. Larsen, Meenakshi Devidas, SiChen, Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh, Andrew A.
does 14 days of dexamethasone during induction for patients 1 to Carroll, Julie M. Gastier-Foster, Brent L. Wood, Cheryl L. Willman, Naomi 9 years of age. It is likely that continued improvements in the J. Winick, Stephen P. Hunger, William L. Carroll treatment of children, adolescents, and young adults with B-ALL Manuscript writing: All authors will derive from both further refinements in the use of conventional Final approval of manuscript: All authors acute lymphoblastic leukemia performed by the corticosteroids: Possible relationship to the prevention ALL-BFM study group from 1981 to 2000. Leukemia of meningeal leukemia. J Clin Oncol 5:202-207, 1987 17. Silverman LB, Gelber RD, Dalton VK, et al: 1. Smith M, Arthur D, Camitta B, et al: Uniform 9. Conter V, Aric o M, Basso G, et al: Long-term Improved outcome for children with acute lympho- approach to risk classification and treatment assign- results of the Italian Association of Pediatric Hema- blastic leukemia: Results of Dana-Farber Consortium ment for children with acute lymphoblastic leukemia.
tology and Oncology (AIEOP) Studies 82, 87, 88, 91 Protocol 91-01. Blood 97:1211-1218, 2001 J Clin Oncol 14:18-24, 1996 and 95 for childhood acute lymphoblastic leukemia.
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Clinical significance of minimal residual disease in Ann Stat 16:1141-1154, 1988 35. Roberts KG, Li Y, Payne-Turner D, et al: childhood acute lymphoblastic leukemia and its 32. Merryman R, Stevenson KE, Gostic WJ II, Targetable kinase-activating lesions in Ph-like acute relationship to other prognostic factors: A Children's et al: Asparaginase-associated myelosuppression lymphoblastic leukemia. N Engl J Med 371:1005-1015, Oncology Group study. Blood 111:5477-5485, 2008 and effects on dosing of other chemotherapeutic Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Meenakshi Devidas and Si Chen, University of Florida, Gainesville, FL; Wanda L. Salzer, US Army Medical Research and Materiel Command, Frederick; Michael J. Borowitz, Johns HopkinsMedical Institutions, Baltimore, MD; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT, Mignon L. Loh, University of California,San Francisco, San Francisco, CA; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Catherine Cole, Princess MargaretHospital for Children; University of Western Australia, Perth, Western Australia, Australia; Alisa Eicher, Doernbecher Children's Hospital,Portland, OR; Maureen Haugan, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Mark Sorenson, University of IowaHospitals and Clinics, Iowa City, IA; Nyla A. Heerema and Julie M. Gastier-Foster, The Ohio State University School of Medicine,Columbus, OH; Andrew A. Carroll, University of Alabama at Birmingham, Birmingham, AL; Brent L. Wood, University of Washington,Seattle, WA; Cheryl L. Willman, University of New Mexico, Albuquerque, NM; Naomi J. Winick, University of Texas Southwestern MedicalCenter, Dallas, TX; Stephen P. Hunger, Children's Hospital of Philadelphia; University of Pennsylvania, Philadelphia, PA; and William L.
Carroll, New York University Medical Center, New York, NY.
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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia:A Report From Children's Oncology Group Study AALL0232 The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO's conflict of interest policy, please refer to or .
Andrew A. Carroll No relationship to disclose No relationship to disclose Meenakshi Devidas Julie M. Gastier-Foster No relationship to disclose Research Funding: Bristol-Myers Squibb Michael J. Borowitz No relationship to disclose Consulting or Advisory Role: HTG Molecular DiagnosticsResearch Funding: Becton Dickinson, Amgen, MedImmune, Bristol- No relationship to disclose Elizabeth A. Raetz Honoraria: Amgen, Seattle Genetics No relationship to disclose Cheryl L. Willman No relationship to disclose No relationship to disclose Leonard A. Mattano Jr No relationship to disclose Employment: Pfizer (I)Stock or Other Ownership: Pfizer, Pfizer (I), Amgen, Amgen (I), Stephen P. Hunger Monsanto, Monsanto (I) Stock or Other Ownership: Express Scripts, Amgen, Merck (I), Amgen (I), Consulting or Advisory Role: Pfizer, Mylan, Novartis, Celldex Travel, Accommodations, Expenses: Pfizer, Mylan Honoraria: Jazz Pharmaceuticals, Sigma Tau Pharmaceuticals, SpectrumPharmaceuticals Patents, Royalties, Other Intellectual Property: Coinventor on US patent No relationship to disclose 8,568,974, B2 Identification of Novel Subgroups of High-Risk Pediatric Precursor-B Acute Lymphoblastic Leukemia, Outcome Correlations and No relationship to disclose Diagnostic and Therapeutic Methods Related to Same. It has not beenlicensed, and there is no income.
Travel, Accommodations, Expenses: Amgen No relationship to disclose William L. Carroll No relationship to disclose No relationship to disclose Nyla A. HeeremaNo relationship to disclose 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by at University of Minnesota Libraries on April 26, 2016 from Copyright 2016 American Society of Clinical Oncology. All rights reserved.
Dexamethasone and High-Dose Methotrexate Improve Outcome in High-Risk B-ALL We pay special tribute to and acknowledge the significant contributions that Jim Nachman made to this article. He continually challengedour premises and kept us on task through the entire process. His keen insight, untiring work ethic, and sense of humor will never beforgotten.
P < .001 P < .001 Fig A1. (A) Event-free survival (EFS) comparison of rapid early responders (RERs) and slow early responders (SERs). The 5-year EFS rates for RERs and SERs were 83.9 6 1.1% and 53.3 6 3.1%, respectively. (B) Overall survival (OR) RERs and SERs. The 5-year OS rates for RERs and SERs were 91.3 6 0.9% and 74.3 6 2.8%, respectively.
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C-MTX (n = 1,291) C-MTX (n = 1,012) HD-MTX (n = 1,282) HD-MTX (n = 1,039) Fig A2. (A) Overall survival (OS) comparisons by methotrexate regimen, all randomly assigned participants. The 5-year OS rates for Capizzi escalating-dose methotrexate (C-MTX) and high-dose methotrexate (HD-MTX) were 86.1 6 1.4% and 88.9 6 1.2%, respectively. (B) OS comparisons by methotrexate regimen, randomly assigned rapidearly responders. The 5-year OS rates for C-MTX and HD-MTX were 90.7 6 1.3% and 91.8 6 1.2%, respectively. (C) OS by methotrexate regimen, randomly assigned slowearly responders. The 5-year OS rates for C-MTX and HD-MTX were 71.2 6 3.9% and 77.9 6 3.8%, respectively.
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Dexamethasone and High-Dose Methotrexate Improve Outcome in High-Risk B-ALL For steroid × MTX interaction: P = .2474 Dexamethasone (n = 523) Prednisone (n = 525) Fig A3. (A) Overall survival (OS) comparisons by treatment regimen, randomly assigned participants age 1 to 9 years. The 5-year OS rates by regimen were prednisone plus Capizzi escalating-dose methotrexate regimen (PC), 92.4 6 2.5%; prednisone plus high-dose methotrexate regimen (PH), 92.7 6 2.4%; dexamethasone plus Capizziescalating-dose methotrexate regimen (DC), 92.3 6 2.4%, and dexamethasone plus high-dose methotrexate regimen (DH), 96.3 6 1.9%. (B) OS comparisons by steroidregimen, participants age 10 years or older. The 5-year OS rates for dexamethasone regimens and prednisone regimens were 83.8 6 1.8% and 83.7 6 1.8%, respectively.
Fig A4. Event-free survival (EFS) comparison by methotrexate regimen, ran- domly assigned participants age 10 years and older assigned to prednisone(enrolled after April 2008). The 4-year EFS rates Capizzi escalating-dose metho-trexate (C-MTX) and high-dose methotrexate (HD-MTX) were 77.0 6 4.8% and79.1 6 4.3%, respectively. Note that there was insufficient follow-up to report 5-year EFS.
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Table A1. Therapy Details Phase and Regimen 1.5 mg/m2 (2 mg maximum) Days 1, 8, 15, 22 5 mg/m2/dose twice a day Days 1, 8, 15, 22 Days 8, 29 (CNS3: +15, 22) Extended induction DC/DH 1.5 mg/m2 (2 mg maximum) 5 mg/m2/dose twice a day 1.5 mg/m2 (2 mg maximum) Days 1, 8, 15, 22 30 mg/m2/dose twice a day Days 1, 8, 15, 22 Extended induction PC/PH Days 8, 29 (CNS3: +15, 22) 1.5 mg/m2 (2 mg maximum) 30 mg/m2/dose twice a day Consolidation all Days 1-4, 8-11, 29-32, 36-39 1.5 mg/m2 (2 mg maximum) Days 15, 22, 43, 50 Days 1, 8, 15, 22 Interim maintenance 1 PC/DC 1.5 mg/m2 (2 mg maximum) Every 10 days 3 5 doses Every 10 days 3 5 doses Interim maintenance 1 PH/DH 1.5 mg/m2 (2 mg maximum) Days 1, 15, 29, 43 Days 1, 15, 29, 43 Delayed intensification 1 all 1.5 mg/m2 (2 mg maximum) Days 1, 8, 15, 43, 50 2,500 units/m2/dose Days 29-32, 36-39 Interim maintenance 2 all Same as interim maintenance 1 PC/DCPC/DC start methotrexate 50 mg/m2 less than previous maximum tolerated dosePH/DH start methotrexate at 100 mg/m2 Delayed intensification 2 all Same as delayed intensification 1 Maintenance‡ (12-week cycles) 1.5 mg/m2 (2 mg max) 20 mg/m2/dose twice a day Days 1-5, 29-33, 57-61 Methotrexate (oral) Days 1 (and 29 first four cycles) Abbreviations: DC, dexamethasone plus Capizzi escalating-dose methotrexate regimen; DH, dexamethasone plus high-dose methotrexate regimen; IT, intrathecal; IT- MTX, intrathecal methotrexate; IV-MTX, intravenous methotrexate; PC, prednisone plus Capizzi escalating-dose methotrexate regimen; PH, prednisone plus high-dosemethotrexate regimen.
*IT cytarabine: 1 to 1.99 years, 30 mg; 2 to 2.99 years, 50 mg; $ 3 years, 70 mg. IT-MTX: 1 to 1.99 years, 8 mg; 2 to 2.99 years, 10 mg; 3 to 8.99 years, 12 mg; $ 9 years, †IV-MTX: 100 mg/m2 (dose escalated by 50 mg/m2 every 10 days for a total of five doses, adjusted for toxicity).
‡Total duration of treatment from start of interim maintenance 1: females, 2 years; males, 3 years.
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Dexamethasone and High-Dose Methotrexate Improve Outcome in High-Risk B-ALL Table A2. Events by Corticosteroid Assignment American Indian or Alaska Native Native Hawaiian or other Pacific Islander Black or African American Hispanic or Latino Not Hispanic or Latino 0.01% # MRD , 0.1% 0.1% # MRD , 1.0% 1.0% # MRD , 10.0% Abbreviations: DC, dexamethasone plus Capizzi escalating-dose methotrexate regimen; DH, dexamethasone plus high-dose methotrexate regimen; MRD,minimal residual disease; PC, prednisone plus Capizzi escalating-dose metho-trexate regimen; PH, prednisone plus high-dose methotrexate regimen.
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