Delayed Intensification Phase Research Articles

Abstract 3636: Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Abstract Introduction: Methotrexate (MTX) is a key component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL). However, delivery of MTX is often interrupted by dose-limiting acute neurotoxicity, which manifests as seizures, stroke-like symptoms, or altered mental status. Because incidence and risk factors for MTX neurotoxicity are poorly defined, we evaluated clinical and demographic predictors of MTX neurotoxicity using the multi-ethnic REDIAL Consortium. Methods: The REDIAL cohort includes pediatric patients diagnosed with ALL at six treatment centers in the southwestern U.S. This interim analysis evaluated 756 patients age 1-21 years diagnosed with B-ALL (2005-2018). Electronic health records were reviewed to determine race/ethnicity (Latino, non-Latino White, non-Latino Black, or Other), body mass index, sex, age, and intravenous (IV) MTX dose. Applying Ponte di Legno criteria, acute MTX neurotoxicity was defined as neurologic episodes occurring <21 days from intrathecal or IV MTX, which resulted in MTX treatment modifications. The proportion of patients who experienced MTX neurotoxicity and corresponding 95% confidence interval (CI) was calculated overall and within the induction, post-induction, and maintenance treatment phases. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) for the association between clinical factors and MTX neurotoxicity. Results: The study population was 56.6% Latino, 52.8% male, 41.4% treated with >5g/m2 IV MTX, and diagnosed at a median age of 5 years. Overall, 15.5% (95% CI: 12.9-18.3%) of patients experienced neurotoxic events (n=117), including 1.9% (n=14, 95% CI: 1.0-3.1%) during induction, 13.0% (n=98, 95% CI: 10.7-15.6%) during post-induction, and 0.7% (n=5, 95% CI: 0.2-1.5%) during maintenance therapy. Ethnic differences were not statistically significant during induction or maintenance phases. Compared to non-Latinos, post-induction neurotoxicity was significantly more frequent among Latinos (aOR = 2.87, 95% CI: 1.68-5.10), with disparities observed during consolidation, interim maintenance and delayed intensification phases. Exposure to >5g/m2 IV MTX (aOR = 2.16, 95% CI: 1.08-3.24) and older age at diagnosis (aOR = 1.16, 95% CI: 1.08-1.24) were also associated with a significantly more post-induction neurotoxicity. No factors evaluated were significantly associated with neurotoxicity during induction and maintenance therapy. Conclusions: MTX neurotoxicity disproportionally affects Latino children during ALL post-induction therapy. Additional work is warranted to identify risk factors for neurotoxicity during induction and maintenance therapy as well as the specific clinical and host biological factors responsible for post-induction ethnic differences in MTX neurotoxicity. Citation Format: Austin L. Brown, Rachel D. Harris, Olga A. Taylor, Melanie B. Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Kathleen Ludwig, Avner Meoded, Sandi L. Pruitt, Philip J. Lupo, Karen R. Rabin, Michael E. Scheurer. Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3636.

Absence of Silent Inactivation Using Intravenous Pegaspargase in Pediatric Acute Lymphoblastic Leukemia

BACKGROUNDAsparaginase (ASNase) is an integral part of therapy for pediatric acute lymphoblastic leukemia (ALL). Pegylated E. coli ASNase (pegaspargase, PEG) and Erwinia ASNase (crisantaspase) are the two formulations currently in use in the USA. An ASNase activity of at least 0.1 IU/mL is the target necessary for adequate asparagine depletion from cells. Hypersensitivity reactions are the most common adverse events associated with ASNase. Two patterns of hypersensitivity are observed: acute, symptomatic allergic reaction or silent inactivation. In silent inactivation, there is in no clinically observed reaction, but immunologic clearance results in inadequate ASNase activity (< 0.1 IU/ml). Silent inactivation has been reported to occur in approximately 25% of patients receiving ASNase. However, these data are primarily from protocols where patients received native E. coli ASNase in induction before switching to PEG. Also, PEG was typically given via intramuscular injection in these studies. Our institution has exclusively used intravenous (i.v.) PEG for patients with ALL and lymphoblastic lymphoma (LLy) since 2012, and began monitoring ASNase activity in 2014. Our objective was to evaluate the incidence and pattern of hypersensitivity to PEG.PATIENTS AND METHODSWe conducted a retrospective chart review of 221 patients with newly diagnosed ALL or LLy treated at our institution between 2014 and 2016. Of those, 96 were eligible for analysis based on the availability of at least 1 ASNase level, including B-ALL patients classified as high / very high-risk after induction, and all T-ALL / LLy patients (Table 1). PEG 2500 IU/m2 was given via 1-hour i.v. infusion per the schedule used in COG protocols. Routine premedication with antihistamines was not given. 125 patients were excluded due to low / average risk B-ALL, no ASNase levels, or having received alternate chemotherapy. ASNase activity was measured 1 week after PEG in the consolidation and delayed intensification phases of therapy. Silent inactivation was defined as an ASNase activity <0.1 IU/ml without a recorded allergic reaction. In addition to ASNase levels, we recorded the weight and body surface (BSA) for each patient before induction, and before and after the consolidation phase. We also recorded common adverse events associated with ASNase such as hyperglycemia (CTCAE > grade 3), liver dysfunction (CTCAE > grade 3), hypertriglyceridemia (CTCAE > grade 3), pancreatitis (CTCAE > grade 2), and thrombosis (CTCAE > grade 2). Descriptive statistics were created for patient and disease features, and Pearson correlation was used to evaluate association of ASNase levels to patient characteristics (SAS v9.4 Cary NC).RESULTSPatients included in the analysis had a mean age of 9.1 years; the majority had B-ALL (79.2%). Twenty patients (20.8%) had an overt allergic reaction after PEG. There were no patients (95% CI = 0 - 3.8%) with silent inactivation (Table 1). A total of 260 ASNase levels were recorded for an average of 2.7 ASNase levels per patient, with a maximum of 5 levels. The mean ASNase activity in patients without allergic reaction was 1.36 IU/ml (SD = 0.37). Age (rp = -0.41, p<0.001), weight (rp = -0.36, p < 0.001), and BSA (rp = -0.40, p < 0.001) all significantly correlated with lower ASNase activity (Figure 1). The most common ASNase associated adverse event was hepatotoxicity (N=70, 72.9%) with either an ALT >150 U/L and/or total bilirubin > 3 mg/dL, followed by hyperglycemia (N=22, 22.9%) with a glucose level >250 mg/dL, and thromboembolic event (N=11, 11.5%). Pancreatitis (N=4, 4.2%) and hypertriglyceridemia (N=5, 5.2%) were also observed.CONCLUSIONSPediatric patients with ALL/LLy who receive i.v. PEG on the dose/schedule used in COG protocols do not experience silent inactivation. The mean ASNase activity in our experience is higher than reported previously. The incidence of overt allergic reaction is consistent with prior reports. Older patient age at diagnosis and higher baseline weight/BSA correlated with lower, but still therapeutic, ASNase activity. Hepatotoxicity was frequently noted in our series. These data suggest that routine monitoring of ASNase activity may not be warranted for pediatric patients receiving i.v. PEG as given on current COG protocols. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Invasive Fungal Infections in Pediatric Patients with High-Risk Acute Lymphoblastic Leukemia during Initial Phases of Therapy: A Retrospective Evaluation

BACKGROUND Patients with newly diagnosed acute lymphoblastic leukemia (ALL) are at increased risk of infection. While previously published guidelines recommend primary antifungal prophylaxis in patients with T-cell ALL, we sought to determine the pattern of invasive fungal disease (IFI) at our center so as to assess risk factors for IFI, beyond the diagnosis of T-ALL, with the administration of dexamethasone and an anthracycline during induction. The current practice at Children's Health Children's Medical Center Dallas is to provide primary antifungal prophylaxis with micafungin during induction therapy for hospitalized patients with T-cell ALL and those with Down Syndrome. Additionally, we recently decided to provide primary antifungal prophylaxis to patients with HR B-ALL with hyperglycemia who remain hospitalized during induction. The primary objective of this study was to capture the institution-specific five-year incidence of IFI prior to the start of delayed intensification (DI) phase chemotherapy among pediatric patients with ALL. Secondary objectives were to identify potential IFI risk factors specifically amongst pediatric patients with HR ALL. METHODS This retrospective chart review included patients younger than 21 years with newly diagnosed ALL between July 1, 2014 and June 30, 2019. Patients with secondary leukemia, infantile leukemia, or those receiving treatment for a fungal infection at presentation were excluded. The primary outcome was the development of probable or proven IFI, as defined by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria, prior to the start of the DI phase of therapy. Statistical methods included Chi-square test, t-test, and Wilcoxon Rank Sum test, as appropriate to the variable's level of measurement and distribution. Time series analyses were used to assess overall and seasonal trends of IFI incidence over the study period. RESULTS Of 220 included patients, there were 13 cases of IFI diagnosed during the induction and consolidation phases of therapy during the five-year period. IFI occurred in 15.3% of the HR group (11/72), 5.9% of the T-cell ALL group (1/17), and 0.8% of the standard risk (SR) group (1/131). Among individuals with HR ALL, the majority of cases occurred in the absence of primary antifungal prophylaxis (90.9%). The most common sites of IFI included the lungs (n=6) and sinuses (n=4). Implicated fungal pathogens included Aspergillus, Candida, Curvularia, Exserohilum, and Bipolaris. Univariate analysis of the potential IFI risk factors in HR ALL patients did not identify any significant differences between those patients that did or did not develop IFI, with respect to pre-existing comorbidities, body mass index, laboratory results at diagnosis, or hospital exposures during induction including length of stay, intensive care admissions, and receipt of systemic antibiotics (Table). Race and ethnicity was significantly different likely due to the skewed distribution of IFI among patients who identified as Asian (p = 0.03; 8/8 identified as Asian and did not develop IFI). With respect to seasonality of ALL diagnosis, the percent of patients in each group (winter, spring, summer, and fall) that developed IFI were 7.4%, 18.2%, 20%, and 31.2%, respectively. However, time series analysis did not show an association between seasonality of diagnosis and development of IFI (p=0.89). During the induction phase of therapy, hyperglycemia, defined as blood glucose 140-200 mg/dL for ≥ 2 days or &amp;gt;200 mg/dL for 1 day, was present in 100% of the HR patients that developed IFI and 74% of the HR patients that did not develop IFI (p=0.12). CONCLUSION In this pediatric population, patients with HR B-ALL developed more fungal infections during the early phases of therapy then those with SR disease (15.6% versus 0.8%). In analysis of potential risk factors, there were no significant differences between HR ALL groups that did or did not develop IFI. Larger-scale studies are needed in order to identify potential risk factors that will guide decisions on the routine use of primary antifungal prophylaxis in patients with HR ALL during induction therapy. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Micafungin use for primary antifungal prophylaxis during induction phase of therapy.

Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331.

Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% (P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% (P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

Successful Toxicity Reduction in Ma-Spore ALL 2010 in Standard/Intermediate Risk Childhood ALL: Replacing Cytarabine/Doxorubicin with More Vincristine and L-Asparaginase during Consolidation and Delayed Intensification

As ~90% children with Acute Lymphoblastic Leukemia (ALL) are now cured, the next challenge of contemporary ALL therapy is curing with less toxicity. To reduce toxicity, the Malaysia-Singapore ALL 2003 (MS2003) study lowered the intensity of induction in Standard(SR)/Intermediate Risk(IR) patients by removing Daunorubicin. However, toxicities causing prolonged delays during Consolidation and Delayed-Intensification(DI) remained major problems. To address these delays, the MS2010 study: (1) Replaced half of all cytarabine blocks with 2 doses of Vincristine(VCR) per block (2) Implemented Doxorubicin-free DI Protocol V (3) Added 1 dose of L-Asparaginase(L-Asp) to each DI block. Here, we report the significant improvements in MS2010 compared to MS2003 in terms of treatment-related toxicities. Methods MS2003 (Yeoh AEJ et al. J Clin Oncol 2012) started with a 3 drug induction for non-HR patients in a BFM ALL-IC 2002 backbone where SR consisted of 2x Protocol III and IR consisted of 3x Protocol III. In MS2010 (Yeoh AEJ et al. J Clin Oncol 2018), SR consisted of 2x Protocol V and IR consisted of 2x Protocol III + 1x Protocol V (Table 1). We performed a per-protocol analysis of 315 children with de novo SR/IR ALL, treated on MS2003 (n=183) and MS2010 (n=132) in 2 centers in Singapore, with a median follow up of 10.7 and 6.4years respectively. We analyzed clinical toxicity data, focusing on hospitalizations for fever (regardless of neutrophil count). Mean differences were adjusted for baseline characteristics including sex, race, age and Down syndrome. Results Overall decreased hospitalization stay and phase delays. In MS2010, the total duration of hospitalization for fever are fewer and shorter; this is most apparent for DI phases. For SR group, total length of stay during DI decreased from 13.7 to 6.1 days with adjusted(adj.) δ=7.0 days (95% CI 3.5-10.5, p&lt;0.001). For IR group, this was from 19.1 to 11.5days with adj.δ=5.2 days (95% CI 0.2-10.3, p=0.042). In MS2010, overall delays in treatment are significantly reduced -- SR: From 65.9 to 16.4days, adj.δ=48.8 days(95% CI 39.8-57.8, p&lt;0.001); IR: From 106.9 to 23.6days, adj.δ=80.9days (95% CI 68.4-93.5, p&lt;0.001). The reduction in delays are mainly seen during Consolidation and DI. Overall, patients also completed intensive chemotherapy in a much shorter duration of time in MS2010 (see Table.1). Total ICU admissions were decreased (SR: 9.0% to 4.7% p=0.346 ; IR: 13.5% to 5.9% p=0.57). Total episodes of bacteremia were also decreased (SR: 31.2% to 18.75% p=0.708 ; IR 31.4% to 26.5% p=0.23). MS2010 Protocol III had 5 doses of L-Asp compared to 4 doses of L-Asp in MS2003 Protocol III. Although L-Asp is generally considered less myelosuppressive, there was a significant increase in the number of hospitalizations during MS2010 Protocol III blocks. This translated to longer hospitalizations per patient in MS2010 during those specific phases (III#1: adj.δ=-1.6 days 95% CI -2.8 to -0.3 p=0.017; III#2: adj.δ=-1.9 days 95% CI -3.2 to -0.6 p=0.006). These increases in hospitalizations in MS2010 Protocol IIIa were most likely due to an additional single dose of L-Asp. Equivalent survival outcomes Based on a per-protocol analysis, 5 year Event-Free survival(EFS) outcomes between the cohorts were equivalent. In the SR cohort, 5yr EFS was 93.6% (MS2003) vs. 95.5% (MS2010) p=0.685. In the IR cohorts, 5yr EFS improved from 89.4% (MS2003) to 95.6% (MS2010) p=0.151, although statistical significance was not reached. Overall, significant improvements: reduction in hospitalisation stays and reduction in treatment delays were observed in MS2010. This was achieved through a combination of (1) Replacing half of all cytarabine blocks with 2 doses of VCR per block; and (2) New DI Protocol V with no Anthracyclines. Despite the AIEOP-BFM 2000 experience of increased toxicity with Protocol III, our modifications to consolidation Ib and Protocol III have led to less phase delays, tolerable toxicities with comparable outcomes. Disclosures No relevant conflicts of interest to declare.

Invasive fungal infections in children with acute lymphoblastic leukaemia: Results from four Australian centres, 2003-2013.

Invasive fungal infections (IFI) are an important complication of acute lymphoblastic leukaemia (ALL) treatment. Our study describes the prevalence and outcomes of IFI in children with ALL. IFI episodes in children with primary or relapsed ALL, identified for The Epidemiology and Risk Factors for Invasive Fungal Infections in Immunocompromised Children study, were analysed. IFI were classified according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria with a 'modified-possible' category included. A total of 123 IFI episodes in 119 patients with ALL were included. A proven, probable, possible and modified-possible IFI was diagnosed in 56 (45.5%), 22 (17.9%), 39 (31.7%) and six (4.9%) episodes, respectively. The prevalence was 9.7% (95% confidence interval [CI] 8-11.4%) overall and 23.5% (95% CI 14.5-32.5%) for relapsed/refractory ALL. For non-relapsed ALL, the IFI prevalence was significantly higher for children with high-risk compared to standard-risk ALL (14.5% vs 7.3%, P=.009), and IFI were more common during induction, consolidation and delayed intensification phases. Mould infections occurred more frequently than non-mould infections. Thirteen children (10.9%) died within 6 months of IFI diagnosis with five deaths (4.2%) attributable to an IFI. IFI is more common in children with high-risk ALL and in relapsed disease. Overall survival was encouraging, with IFI contributing to very few deaths.

Treatment of higher risk acute lymphoblastic leukemia in young people (CCG-1961), long-term follow-up: a report from the Children's Oncology Group.

Children's Cancer Group CCG-1882 improved outcome for 1-21-year old with high risk acute lymphoblastic leukemia and Induction Day 8 marrow blasts ≥25% (slow early responders, SER) with longer and stronger post induction intensification (PII). This CCG-1961 explored alternative PII strategies. We report 10-year follow-up for patients with rapid early response (RER) and for the first timedetails our experience for SER patients. A total of 2057 patients were enrolled, and 1299 RER patients were randomized to 1 of 4 PII regimens: standard vs. augmented intensity and standard vs. increased length. At the end of interim maintenance, 447 SER patients were randomized to idarubicin/cyclophosphamide or weekly doxorubicin in the delayed intensification phases. The 10-year EFS for RER were 79.4 ± 2.4% and 70.9 ± 2.6% (hazard ratio = 0.65, 95% CI 0.52-0.82, p < 0.001) for augmented and standard strength PII; the 10-year OS rates were 87.2 ± 2.0% and 81.0 ± 2.2% (hazard ratio = 0.64, 95% CI 0.48-0.86, p = 0.003). Outcomes remain similar for standard and longer PII, and for SER patients assigned to idarubicin/cyclophosphamide and weekly doxorubicin. The EFS and OS advantage of augmented PII is sustained at 10 years for RER patients. Longer PII for RER patients and sequential idarubicin/cyclophosphamide for SER patients offered no advantage. CCG-1961 is the platform for subsequent COG studies.

Treatment of children with acute lymphoblastic leukemia with risk group based intensification and omission of cranial irradiation: A Korean study of 295 patients.

Recent studies indicate 70-80% event-free survival (EFS) for pediatric acute lymphoblastic leukemia (ALL). In this study, we report the outcome of 295 children and adolescents treated at our institution, with stratification into four risk groups, and omission of cranial irradiation in all patients. Patients were diagnosed from January 2005 to December 2011 and classified and treated as low, standard, high, and very high risk groups. A delayed intensification phase was given twice for high and very high risk groups. None of the patients received cranial irradiation for central nervous system (CNS) prophylaxis. The 10-year EFS and overall survival (OS) were 78.5 ± 2.5% and 81.9 ± 2.7%, respectively. EFS according to risk group was as follows: low risk 91.2 ± 3.7%, standard risk 98.1 ± 1.9%, high risk 81.5 ± 4.3%, very high risk 59.4 ± 5.3%. In a multivariate analysis, high hyperdiploidy and infant ALL were significant predictors of EFS. Cumulative incidence of any relapse, isolated CNS relapse, and any CNS relapse were 17.1 ± 2.3%, 1.5 ± 0.7%, and 2.3 ± 0.9%, respectively. Other events included infection-related deaths during remission induction chemotherapy (3), primary refractory disease (2), and treatment-related deaths in first complete remission (8). In this single-institution study of Korean pediatric ALL patients, risk group based intensification with omission of cranial irradiation resulted in EFS comparable to previous studies, excellent survival of low- and standard-risk patients, and a low rate of CNS relapse.

Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232

AbstractMinimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children’s Oncology Group study.

10001 Background: Response to initial therapy is a powerful prognostic factor in pediatric ALL. Traditionally, slow early response (SER) has been defined by marrow morphology 8 or 15 days after start of induction therapy. More recently, MRD has been identified as the most important predictor of adverse outcome. The value of morphologic assessment of response in the setting of MRD has not been established. Methods: In COG studies AALL0331 (for NCI Standard Risk (SR) B ALL patients (pts)) and AALL0232 (High Risk (HR) B ALL pts), SER was defined by morphology as either ≥5% blasts in a day 15 marrow, or by flow cytometry as ≥0.1% MRD in a d29 marrow (SER MRD). Assignment to treatment arms also depended upon cytogenetic findings and extramedullary disease; each protocol had randomized treatment questions. SER pts were non-randomly assigned to receive augmented BFM therapy (ABFM) with 2 interim maintenance and delayed intensification phases (and CNS radiation for HR SER pts only). All pt treatment groups were combined for these analyses. Rapid early responders (RER) had a better outcome than SER pts (Table). However, pts who were SER only by morphology had a 5y DFS that was not significantly different from that of RER pts, and superior to that of pts who were SER MRD, or SER by both morphology and MRD. In multivariate analysis, SER by morphology was not an adverse prognostic factor after adjusting for risk group and MRD, or separately in SR or HR pts after adjusting for MRD. However, pts with .01-.1% MRD who were SER by morphology had a better 5y DFS than the.01-.1% MRD pts who were RER (90±6%, n=91 vs 77±3%, n=592). Only the former group received ABFM, suggesting intensification based on response rescues some poor risk pts. We conclude that a day 15 marrow is not needed to assess response if MRD is measured at end induction, provided that SER MRD is defined using a .01% cutoff, the threshold for intensifying therapy in current COG ALL trials. Clinical trial information: NCT00103285, NCT00075725. [Table: see text]

Dose-Intensity Impacts On Survival of Adolescents and Young Adults with Acute Lymphoblastic Leukemia Treated in Adult Departments by a Pediatric Protocol (FRALLE 2000BT)

AbstractAbstract ▪3561▪This icon denotes a clinically relevant abstract Background:Adolescents (15–19y) with acute lymphoblastic leukemia (ALL) markedly benefit from pediatric rather than adult chemotherapy regimens, as highlighted by many retrospective studies (Boissel et al., JCO 2001). In young adults with ALL, there are now strong evidences that pediatric or pediatric-inspired protocols may also improve long-term outcome (Huguet et al., JCO 2009). However, whether care environment (adult vs pediatric unit) may impact this outcome remains an open issue. To address this question, we explored the outcome of adolescents and young adults (AYA, 15–29y) treated in adult hematology departments by the pediatric FRALLE 2000-BT protocol. Methods:From February 2001 to June 2011, 89 AYAs with Ph-negative ALL including 60 adolescents (15–19y) and 29 YAs (20–29y) were treated according to the pediatric FRALLE 2000-BT protocol in 13 French and Belgian adult hematology units (median follow-up, 5 years). After a prednisone prephase and a four-drug induction (prednisone, daunorubicin, vincristine and L-asparaginase), patients achieving CR received four 8-week phases of treatment: consolidation, 1st delayed intensification (DI), interphase, 2nd DI, and maintenance. According to FRALLE protocol recommendations, each phase should begin after hematological recovery of previous phase (ANC>1 G/L, Platelets>100 G/L). Twenty-five patients (18 adolescents and 7 YAs) underwent allogeneic transplantation after consolidation phase or 1stDI. Results:Apart age (median age, 18 vs 23y; p<.0001), adolescent and YAs cohorts had similar characteristics, including WBC, B/T lineage distribution, and high-risk karyotype (t(4;11)/MLL-AF4, hypodiploidy)), except for initial CNS involvement (1/60 vs 4/29 respectively, p=.02). Initial peripheral response to prednisone (PDN) at D7 and bone marrow response to chemotherapy at D21 were better in the adolescent subgroup, without reaching significance (slow PDN-responders: 30% vs 38%, p=.42; slow chemo-responders: 13% vs 21%, p=.37). Overall CR rate was 99% and did not differ between both cohorts (98% in adolescents, 100% in YAs). 5y-OS and 5y-EFS were estimated respectively at 66% and 61%. Despite similar CR rates, 5-year EFS was significantly shorter in adolescents than in YAs (47% vs 79%, p=.02). A non significant shorter 5y-OS was also observed in adolescents (58% vs 81%, p=.11). To explain this difference, we looked at dose-intensity disparities between both subgroups. During induction phase, no differences in drug cumulative doses were observed. To further explore potent difficulties to respect protocol schedules in younger patients, we compared intervals from induction D1 to start of different trial phases between both subgroups. In comparison to YAs, intervals from induction D1 to consolidation, 1st DI, 2nd DI and maintenance phases were progressively delayed in adolescents: 4 days for consolidation (p=.24), 6 days for 1st DI (p=.19), 9 days for 2nd DI (p=.005), and finally 25 days for maintenance phase (p=.0002). In univariate analysis, among age (adolescents vs YAs), B/T lineage, WBC, cytogenetics, and time to 1st DI, only age and time to 1st DI significantly affected EFS (p=.05 and p=.001 respectively). In bivariate analysis, age and time to 1st DI were identified as independent prognostic factors for EFS (p=.03 and p=.004, respectively). The same observation was done with interval time to 2ndDI. Conclusion:The outcome of AYAs treated in adult units with the pediatric FRALLE 2000 protocol is encouraging, particularly in YAs. The poorer outcome observed in adolescents may be related to increasing intervals from initial induction to the different phases of treatment. Prospective trials are required to register individual reasons that lead physicians and patients to progressively delay therapy. This study suggests that trial itself is not sufficient to improve the outcome in adolescents with cancer and that AYA programs are needed to explore the difficulties encountered by patients and care teams to adhere to therapy. Disclosures:No relevant conflicts of interest to declare.

A Genome-Wide Analysis of Variants Influencing Methotrexate Clearance Replicates SLCO1B1.

AbstractAbstract 2466High-dose methotrexate (HDMTX) is an important element of chemotherapy for acute lymphoblastic leukemia (ALL) and other malignancies. Methotrexate clearance influences cure and toxicity in children with acute lymphoblastic leukemia (ALL). HDMTX schedules and doses vary widely among treatment protocols. The Children's Oncology Group (COG) tested the efficacy of 6 courses of 2 g/m2 over 4 hours versus 1 g/m2 over 24 hours (P9904 and P9905 protocols). Patients were assigned to one of four arms for consolidation: A, 24-hour methotrexate infusion (1 g/m2) and no delayed intensification (DI); B, 4-hour methotrexate infusion (2 g/m2) with no DI; C, 24-hour methotrexate infusion with DI; D, 4-hour methotrexate infusion with DI. We estimated methotrexate clearance for 1279 patients treated on these protocols, with two plasma MTX concentrations per course, using a Bayesian pharmacokinetic modeling approach. Germline genetic variation was assessed using the Affymetrix 6.0 array, and other single nucleotide polymorphisms (SNPs) were imputed based on 1000 Genomes reference data, yielding 5.2 million SNP genotypes evaluable per patient.Average MTX clearance was highly variable, with a median (range) of 164 (65–355) and 109 (49–290) ml/min/m2 for the 24-hour and 4-hour infusions, respectively. Methotrexate clearance was lower in older children (p = 7 × 10−7), girls (p = 2.7 × 10−4), and patients who received a delayed intensification phase during consolidation (p = 0.0022). Adjusting for age, gender, race, and treatment arm, a genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in SLCO1B1(p = 2.1 × 10−11), a gene that encodes for an organic anion transporter that is known to transport methotrexate. This replicates our previous findings (Trevino et al, J Clin Oncol. 2009;27(35):5972-8) that polymorphisms in SLCO1B1 influence methotrexate clearance in ALL patients treated on St. Jude protocols with three different HDMTX schedules. In a combined meta-analysis including the 1279 COG patients and 699 St. Jude patients, and adjusting for age, gender, race, and treatment arm, the association of methotrexate clearance with SLCO1B1 SNP rs4149056 yields a p-value of 3.1 × 10−19 (Figure). Even after adjustment for the rs4149056 SNP, other polymorphisms in SLCO1B1 remained significantly related to methotrexate clearance, indicating that there are multiple variants in SLCO1B1 that can influence methotrexate clearance. Validation of the association of this gene with five different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial

Acute lymphoblastic leukaemia (ALL) is curable in more than 80% of children and adolescents who exhibit high-risk features. However, treatments are associated with symptomatic osteonecrosis that disproportionately affects adolescents. Based on the findings from the CCG-1882 trial, the CCG-1961 trial was designed to assess whether dexamethasone dose modification would reduce the risk of osteonecrosis. We therefore compared use of continuous versus alternate-week dexamethasone within standard and intensified post-induction treatments. In the CCG-1961 trial, a multicohort cooperative group trial, 2056 patients (aged 1-21 years) with newly diagnosed high-risk ALL (age ≥10 years, white blood cell count ≥50×10(9) per L, or both) were recruited. To address osteonecrosis, a novel alternate-week schedule of dexamethasone (10 mg/m(2) per day on days 0-6 and 14-20) was compared with standard continuous dexamethasone (10 mg/m(2) per day on days 0-20) in computer-generated randomised regimens with permuted blocks within double or single delayed intensification phases, respectively. Masking was not possible because of the differences in the treatments. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002812. Symptomatic osteonecrosis was diagnosed in 143 patients at 377 confirmed skeletal sites, resulting in 139 surgeries. In patients aged 1-21 years, the overall cumulative incidence of osteonecrosis at 5 years was 7·7% (SE 0·9), correlating with age at ALL diagnosis (1-9 years, 1·0% [0·5]; 10-15 years, 9·9% [1·5], hazard ratio 10·4 [4·8-22·5]; 16-21 years, 20·0% [4·3], 22·2 [10·0-49·3]; p<0·0001) and sex of the patients aged 10-21 years (girls 15·7% [2·5] vs boys 9·3% [1·7], 1·7 [1·2-2·4]; p=0·001). For patients aged 10 years and older with a rapid response to induction treatment, the use of alternate-week dexamethasone during phases of delayed intensification significantly reduced osteonecrosis incidence compared with continuous dexamethasone (8·7% [2·1] vs 17·0% [2·9], 2·1 [1·4-3·1]; p=0·0005), especially in those aged 16 years and older (11·3% [5·3] vs 37·5% [11·0], p=0·0003; girls 17·2% [8·1] vs 43·9% [14·1], p=0·05; boys 7·7% [5·9] vs 34·6% [11·6], p=0·0014). Alternate-week dexamethasone during delayed intensification phases, a simple dose modification, reduces the risk of osteonecrosis in children and adolescents given intensified treatment for high-risk ALL. Its use is being evaluated in children with standard risk ALL. US National Cancer Institute at the National Institutes of Health.

Strength capacity in young patients who are receiving maintenance therapy for acute lymphoblastic leukemia: a case-control study

The treatment for children and adolescents with acute lymphoblastic leukemia (ALL) can lead to multiple adverse effects, including a poor physical capacity. Accordingly, several studies have reported that survivors of ALL may experience muscle weakness, even years following their remission.1,2 However, it has not yet been determined whether patients who are currently receiving treatment for ALL present with impaired strength. To date, only a single pilot study compared muscle strength in ALL with healthy controls.3 Using an isometric strength assessment, the authors found that the ALL patients were weaker than their healthy peers. Importantly, the children with ALL demonstrated a progressive weakening from the initiation of delayed intensification phase through the next 28 days, suggesting that muscle strength may fluctuate during ALL treatment. Understanding the time course of treatment-induced muscle strength impairments can help to determine the timing of exercise training intervention,3 which is known to benefit ALL patients.4-6 The present case-control study aimed to characterize muscle strength in children who were receiving maintenance therapy for ALL and to compare this strength to that of age-, gender-, and BMI-matched healthy controls.

Nelarabine May Be Safely Incorporated Into a Phase III Study for Newly Diagnosed T-Lineage Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

AbstractAbstract 865With dose-intensified, multi-agent therapy, 80 to 85% of patients with T-lineage acute lymphoblastic leukemia (T-ALL) are cured. Nelarabine (Compound 506U78; IND# 52611) has shown impressive single agent clinical activity in relapsed T-ALL, but has been associated with significant neurotoxicity. We previously showed that Nelarabine could be added safely to an intensive multi-agent chemotherapy backbone in the COG AALL00P2 pilot study without excess neurotoxicity. The Phase III AALL0434 T-ALL study was designed to assess the safety and efficacy of adding Nelarabine to a COG-augmented BFM chemotherapy regimen. In the Safety Phase of the study, 600 patients with newly-diagnosed T-ALL were accrued from January 2007 to June 2010. Patients with high-risk T-ALL, defined by bone marrow (BM) minimal residual disease (MRD) level >1% or >5% BM blasts at day 29 of Induction, were randomized to receive backbone chemotherapy +/− five 5-day courses of Nelarabine 650 mg/m2/day once in Consolidation, once in Delayed Intensification and at the start of the first three Maintenance cycles. Patients were also randomly assigned to treatment arms that contained either high-dose methotrexate (HD-MTX) plus leucovorin rescue or Capizzi style escalating intravenous MTX without rescue during Interim Maintenance. Fifty-seven patients were assigned to the High-risk arm and were equally randomized to each of the MTX regimens +/− Nelarabine; their progress was followed for at least 8 weeks after receiving cranial radiation in the Delayed Intensification Phase (week 34) to assess for neurotoxicities. Toxicities were compared between patients who were randomized to regimens with Nelarabine (n= 28) and without Nelarabine (n= 29). There were no differences in the incidence of pre-defined targeted neurotoxicities of peripheral motor neuropathy (10 Nelarabine vs 6 no Nelarabine p= 0.38), sensory neuropathy (10 Nelarabine vs 7 no Nelarabine p = 0.78) and central neurotoxicity (0 Nelarabine vs 3 no Nelarabine; p=0.11 [two-tailed Fisher's Exact Test]). Additional toxicities including febrile neutropenia (24 vs 29 p= 0.058), and AST/ALT elevations (24 vs 20; p=0.36) were similar in the regimens with/without Nelarabine. The only difference in toxicities between the regimens was increased AST and ALT (unrelated to Nelarabine) within the escalating MTX treatment arms, as compared to arms containing HD-MTX (34 vs 10 p=0.003). Adverse events were reported for 8 of 28 patients on Nelarabine-containing and 7 of 29 patients on the non-Nelarabine containing treatment arms. There were two CNS adverse events reported for the 29 patients treated without Nelarabine. There were no CNS adverse events on the Nelarabine treatment arms. There were 3 PNS adverse events reported among the 28 patients that received Nelarabine: two events in the same patient included abdominal pain and constipation, and one patient had a transient Grade 2 motor neuropathy following a course of Nelarabine. These results show that the addition of Nelarabine to the backbone chemotherapy is safe and feasible. The AALL0434 Efficacy phase has now opened, and both intermediate and high-risk patients will be randomly assigned to all four treatment arms. The COG experience with Nelarabine demonstrates that this agent may have significant toxicity in heavily pre-treated T-ALL patients, but may be well-tolerated in newly diagnosed patients. AALL0434 will determine whether or not Nelarabine treatment improves outcome of children, adolescents and young adults with newly diagnosed T-ALL. Disclosures:Borowitz:genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Hunger:bristol myers squibb: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Longer Time to the Start of Continuation Therapy Is Associated with Improved Survival In High Risk Pediatric Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group (COG)

AbstractAbstract 3223 Background:Delays in treatment are common in pediatric ALL and may occur more often in high risk ALL (HR-ALL). Delays during maintenance therapy have adverse impact on survival, but the significance of delays prior to maintenance is unknown (Schmiegelow, et al, American Journal of Pediatric Hematology Oncology 1990 and Dibenedetto et al, Pediatric Hematology Oncology 1994). We studied the effect of delays in therapy prior to maintenance by analyzing data from two HR-ALL clinical trials, CCG1961 and POG9906. The objective was to determine the association between time to maintenance (TTM) from starting induction therapy and event-free survival (EFS) in children with high-risk ALL. Methods:CCG1961 enrolled 2078 patients from September 1996 to May 2002 with B- and T-lineage ALL with high-risk features, defined as those aged 1–9 years with initial white blood cell count (WBC) ≥ 50,000/μl, any patient aged ≥ 10 years and ≤ 21 years, and those with central nervous system (CNS) leukemia or overt testicular leukemia. Rapid early responders (RERs), those with < 25% blasts in the bone marrow on day 7 of therapy, were randomized to receive standard or augmented BFM therapy with either a single interim maintenance and delayed intensification phase (SDI) or two interim maintenance and delayed intensification (DDI) courses as outlined in Table 1. Slow early responders (SERs) were randomized to augmented BFM with DDI with either doxorubicin or idarubicin and cyclophosphamide in the DI courses. POG9906 enrolled 276 patients from March 2000 to April 2003 with high-risk B-precursor ALL, defined as all patients with CNS disease, testicular disease, MLL rearrangement, age ≥ 16 years, or WBC ≥ 100K. In addition, it included selected patients aged 12–15 with high-risk disease based on the Shuster criteria for age and initial WBC. Patients with favorable cytogenetic features (ETV6-RUNX1 fusion or trisomy of chromosomes 4 and 10) were excluded unless they had CNS or testicular leukemia. Patients were treated with augmented BFM with DDI. Patients who made it to start of maintenance are included in this report. TTM was calculated as time from start induction until start of maintenance therapy. Expected TTM for those with B-lineage ALL is shown in Table 1. TTM was dichotomized by plotting the Akaike information criterion (AIC) versus all possible cutoff values of TTM and identifying the cut-point which best discriminated between groups who did and did not fail. The identified threshold was then examined as a predictor of EFS using the Kaplan Meier method and log rank test. The outcomes were 5-year EFS for CCG1961 and 4-year EFS for POG9906. Results:Among the B-lineage patients, longer TTM was significantly associated with improved EFS in CCG1961 Std BFM DI and SER Aug BFM Doxo arms, as well as on POG 9906. For example, in Std BFM DI, 5-year EFS was 83% in those with longer TTM and 71.9% in those with shorter TTM (P=.036). Among the T lineage cohort enrolled on CCG1961, similar results were seen with longer TTM being significantly associated with improved EFS in Std BFM DDI and SER Aug BFM Ida, and a trend toward improved EFS with longer TTM in each of the other arms. Conclusions:These data suggest that longer TTM may be associated with superior EFS in pediatric high-risk ALL. Multiple factors may contribute to this association. For instance, pharmacogenetic differences resulting in more treatment toxicity and delays may also be associated with more potent anti-leukemic effects, or patients with infectious complications may have an endogenous immune response that also has an anti-leukemia effect. Further research is needed to validate the association between TTM and EFS and to characterize the timing and causes of these delays in protocol therapy. Disclosures:No relevant conflicts of interest to declare.

The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers

Glucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL), but usage differs between cooperative group protocols. All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone. Issues to consider in the choice of induction steroid include impact on event-free and overall survival, acute morbidity such as infection risk, diabetes, and behavioural disturbances and long-term complications such as avascular necrosis. It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase, but dosing schedules (intermittent versus continuous) vary. There is no consensus on the potential benefit of steroid administration during maintenance therapy. This review will summarize the current available data on steroid use in paediatric ALL, highlighting outcomes as well as major toxicities.

Young Adults With Acute Lymphoblastic Leukemia Have an Excellent Outcome With Chemotherapy Alone and Benefit From Intensive Postinduction Treatment: A Report From the Children's Oncology Group

Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002. CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count > or = 50,000/microL and/or age > or = 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL. Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/microL was an adverse prognostic factor. Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.

Failure of Asparagine (ASN) Depletion, Not Inadequate Asparaginase (ASNase) Activity, Predicts Relapse in Standard Risk (SR) Childhood Acute Lymphoblastic Leukemia (ALL): A Children's Oncology Group (COG) Report.

Introduction: The mechanisms of treatment failure in ALL are poorly understood. Attention has focused on the intrinsic resistance of the leukemic blast. ASNase contributes importantly to response and outcome in ALL. In about 1/3 of 1st relapse patients, we found inadequate ASN depletion, i.e., ASN > 3 mmoles on Day 14 of Induction (11 days following a single dose of pegylated ASNase) and an inferior re-induction rate (Pediatr Blood Cancer 2006; 47:141). Patients with relapse have a superior re-induction rate with qwk rather than conventional qow pegylated ASNase (Blood 2000; 96:1709). In the present study, we hypothesized that inadequate ASN depletion with standard ASNase dosing leads to relapse in newly diagnosed children with ALL.Methods: Between 1997 and 1998, 118 children with NCI standard risk ALL were enrolled on Children's Cancer Group CCG-1962 study after informed consent (Blood 2002; 99:1986). By random allocation, patients received either native ASNase 6,000 IU/m2 tiw × 9 in Induction and × 6 in each of 2 Delayed Intensification (DI) phases (n=59, 15 relapses, 1 2nd malignancy) or a single dose of pegylated ASNase 2500 IU/m2 (n=59, 10 relapses) in Induction and each of 2 DI phases. All ASNase was administered intramuscularly and begun on Day 3–5 of Induction and each DI phase. Multiple samples were obtained for each patient and cooled promptly to prevent ex-vivo deamination, which may lead to falsely low, not falsely high ASN values. We examined the incidence of relapse by 8 years in patients ranked by ASN concentration and ASNase activity.Results: The overall 4-year EFS is 84%. Overall, 17/ 31 patients (55%) in the highest Day 14 ASN tertile relapsed compared to 7/ 75 (9%) in the lower two tertiles (p<0.001). The median Day 14 ASN for relapse and remission patients was 3.8 and 0.1 [native ASNase] and 4.9 and 0.63 mmoles [pegylated ASNase]. Day 7 ASN was less informative. ASNase activity was not predictive of outcome.Conclusion: In vivo, asparagine (ASN) depletion reflects a balance between ASNase activity and ASN production, which may vary for an individual over time and among individuals. ASN depletion on Induction Day 14, 9–11days after ASNase administration, predicts outcome in children with SR ALL receiving either native or pegylated ASNase. ASNase activity is not predictive. Failure to achieve adequate ASN depletion in Induction may contribute to relapse in childhood ALL.ASN ConcentrationInduction DayPegylated ASNaseNative ASNaseDay 7 ASNμmolesRelapses/ totalμmolesRelapses/ total1st tertile> 1.143/ 16> 0.996/ 162nd tertile0.03–1.124/ 160.04–0.733/173rd tertile0.012/ 190.014/23DAy 14 ASN1st tertile> 2.789/ 17> 2.628/ 142nd tertile0.18–2.680/ 170.23–0.273/ 153rd tertile0.01–0.071/ 170.013/ 26ASNase ActivityInduction DayPegylated ASNaseNative ASNaseDay 7 ActivityIU/mlRelapses/ totalIU/mlRelapses/ total1st tertile≤0.643/17≤0.235/192nd tertile0.65–0.922/180.24–0.513/183rd tertile0.93–1.634/170.52–1.135/19DAy 14 Activity1st tertile≤ 0.312/17≤ 0.235/182nd tertile0.34–0.664/180.24–0.424/193rd tertile0.68–1.254/170.42–1.245/18

Improved Outcome of Children with Down Syndrome (DS) and High Risk Acute Lymphocytic Leukemia (HR-ALL): A Report of CCG-1961.

Down syndrome patients with ALL (ALL-DS) have unique clinical and biologic features which can make treatment a challenge particularly in regards to toxicity. In order to evaluate the optimal treatment for ALL-DS with higher risk ALL we compared the outcomes of ALL-DS patients (n=51) enrolled on the Children's Cancer Group (CCG) 1961 protocol for HR-ALL to those of their non-DS counterparts (n=2001). CCG-1961 was open from November 1996 to May 2002 for patients with ALL age 1–9 years and WBC ≥ 50,000 or age ≥ 10 years with any WBC. Rapid early responders (RER ≤ 25% blasts on day 7 bone marrow after 4 drug induction) were randomized in a 2 × 2 design to receive intensive post-induction intensification therapy (IPII) or standard post-induction intensification therapy (SPII) and 1 or 2 delayed intensification phases. Slow early responders (SER > 25% blasts on day 7 bone marrow) were treated with IPII, and randomized to receive idarubicin or doxorubicin. No up-front therapy modifications were prescribed for DS patients (only for toxicity as per protocol). All DS patients were over 2 years of age. DS patients were more likely to have WBC ≥ 50,000 than non-DS (76% vs 53%) and less likely to have T cell immunophenotype (4% vs 23%), lymphoma syndrome (10% vs 23%) or marked splenomegaly (4% vs 12%) at diagnosis. No differences in gender, race, or extramedullary disease were noted in the DS vs non-DS patients. There were 36 RER DS patients (16 randomized to IPII and 20 SPII) and 16 SER patients. There were 6 deaths in the DS patients: 4 early in induction, 1 in consolidation, and 1 in maintenance. All deaths were associated with toxicity and/or infection and 2 patients had progressive disease. DS patients were more likely to have grade 3–4 stomatitis during intensive treatment phases (15.2% vs 1.8% during induction, 23.1% vs 2.9% during delayed intensification #1). The 5-yr event free survival (EFS) was 69.1% (se 8.4%) for DS patients and 70.4% (se 1.5%) for non-DS patients. The 5-yr overall survival (OS) was equivalent for the two groups: 77.9% (se 7.5%) for DS patients compared to 80.9% (se 1.1%) for non-DS patients. The 5 year death as a first event assessment was 88.2% (se 6.6%) (RHR 2.6) vs 95.5% (se 0.7%) for non-DS patients, consistent with an increased incidence of early toxic deaths in the ALL-DS cohort. IPII therapy for RER DS patients resulted in excellent disease control (0 BM relapses vs 5 with SPII). The 4-yr EFS for the IPII DS patients (RER + SER) was 83.7% (se 6.7%) vs 78.8% (se 11.5%) for the RER DS randomized group only. This difference may be explained by the single event in the 16 SER patients; however the small number precludes a definitive conclusion. In conclusion, HR patients with ALL-DS treated with IPII therapy on CCG-1961 have similar OS and EFS to non-DS patients. These results compare favorably with those of other studies. The early mortality due to toxicity in the DS population does not result in decreased EFS or OS as compared to the non-DS population. IPII therapy is well tolerated and effective in HR ALL-DS, as evidenced by excellent outcomes in the RER and SER groups, and should be considered a reasonable standard of care for this patient population.