Children 's Oncology Group Acute Lymphoblastic Leukemia Research Articles

Oral Chemotherapy Adherence in Pediatric Acute Lymphoblastic Leukemia (ALL): A Report from the Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 16-001

Background: Successful treatment of pediatric acute lymphoblastic leukemia (ALL) requires 2 years of risk-directed therapy, much of which is built on a backbone of oral chemotherapy including 6-mercaptopurine (6MP) and dexamethasone (DEX). Studies conducted in the Children's Oncology Group (COG) demonstrate that poor adherence to 6MP during the maintenance phase confers increased relapse risk; however, little is known about the rates of 6MP adherence in non-COG ALL regimens. DFCI ALL Consortium protocols utilize 3-week cycles including 14-day pulses of 6MP with weekly intravenous or intramuscular methotrexate. This treatment approach requires more frequent contact between families and healthcare providers and reduces the number of oral chemotherapy agents prescribed. Whether this higher-touch regimen might reduce the frequency of non-adherence as compared to published COG data is not known. Additionally, there remains a paucity of data investigating incidence of non-adherence to DEX, 6MP, and to any medications during the first year of therapy. Methods: Oral chemotherapy adherence was prospectively evaluated as an embedded ancillary study on the DFCI ALL Consortium Protocol 16-001. Eligible participants included English-, Spanish-, or French-speaking caregivers of patients (<22 years) receiving 6MP and DEX (both liquid and tablet formations) and did not utilize a pillbox. Adherence to 6MP and DEX were measured using Medication Event Monitoring Systems (MEMS) caps, which record the date and time of medicine bottle opening. MEMS caps were used to measure adherence for three consecutive cycles during the first year of therapy, and again for three consecutive cycles during the second year of therapy. Caregivers completed surveys reporting sociodemographic determinants of health (SDOH), medication-taking behaviors, and chemotherapy comprehension. MEMS-based medication adherence rates were calculated as a percentage based upon the ratio of the number of days with MEMS cap openings to the number of days 6MP and/or DEX were prescribed. Adherent patients were defined as those with ≥95% adherence based on prior COG trials that observed an excess risk of relapse below this threshold (Bhatia JAMA Onc 2015). Results: Between 2018 - 2022, 252/429 (59%) eligible patients consented to study participation, and adherence data was successfully collected for 207 (82%). Sixty-six (26%) participants were enrolled from Canadian hospital centers, and 186 (74%) participants were enrolled from US hospital centers. Participant age included 159 (77%) <10 years of age, 31 (15%) 10 - 14 years, and 17 (8%) 15 - 21 years (see Table 1). Thirty-four (16%) patients identified as Hispanic, 13 (6%) non-Hispanic Black, 18 (9%) non-Hispanic Other, and 142 (69%) non-Hispanic White. 57 (31%) patients relied on public insurance at time of diagnosis, 61 (34%) patients reported a primary household language other than English, and 36 (20%) patients lived in lone-parent households. A third, 61 (34%) and 62 (34%), of caregivers reported being unsure of what would happen if their child stopped taking 6MP or DEX, respectively. Over the course of six cycles, MEMS-measured adherence rates to 6MP (N = 180) and DEX (N = 195) were 73% (range 21 - 100) and 86% (range 10 - 100), respectively. Preliminary data suggest that adherence rates to 6MP improved during year 2 of treatment (cycles 4-6 of monitoring) (Table 2). In unadjusted analyses, there was a non-significant association between patient age and likelihood of adherence to oral medication: adherence to 6MP was 71% in those <10 years, 80% in those 10 - 14 years, and 71% in those 15 years or older (Jonckheere-Terpstra test p = 0.66). Conclusion: Among a diverse cohort of patients treated with a DFCI ALL Consortium regimen, adherence to oral chemotherapy is suboptimal with rates of 73% to 6MP and 86% to DEX. This finding recapitulates published data from COG ALL trials, suggesting more frequent contact with healthcare providers in the DFCI Consortium protocol does not mitigate non-adherence. Numerical differences between age groups suggest patients ages 10 - 14 years (N=31) have higher adherence compared to patients both younger and older. These preliminary findings suggest that there may be a behavioral component when it comes to medication adherence - with barriers among young children differing from those in both younger and older adolescents.

Distance to Care Predicts Clinical Trial Enrollment on COG ALL Clinical Trials: A Report from the Children's Oncology Group

Introduction: Equitable participation in clinical trials for all populations is essential to ensure the generalizability of clinical trial results. Historical data suggest that the majority of pediatric patients are enrolled on a trial when treated at a cooperative group institution and minoritized patients are proportionally represented. We proposed to evaluate clinical trial enrollment on Children's Oncology Group (COG) acute lymphoblastic leukemia (ALL) studies to determine if among those who participate in registry studies, there are disparities in participation in therapeutic clinical trials. We hypothesized that minoritized children, those living in disadvantaged neighborhoods, and those living distant from trial sites are less likely to enroll on therapeutic ALL studies. Methods: This study leverages the Childhood Cancer Research Network (CCRN), a childhood cancer case recruitment protocol that enrolled patients between 2008 and 2015. Within the CCRN registry cohort, we evaluated predictors of therapeutic and non-therapeutic clinical trial enrollment for patients with ALL. Patients >21 years at diagnosis and those without race or ethnicity reported were excluded. Enrollment on an upfront therapeutic trial (that overlapped with the timeframe during which the CCRN protocol was active) was defined as participation on one of the following 10 ALL trials: AALL0232, AALL0331, AALL0433, AALL0434, AALL0631, AALL0932, AALL1131, AALL1231, AALL1331, AALL1621. Enrollment on a non-therapeutic trial was defined as participation in any biology repository (including AALL03B1, AALL05B1, AALL08B1), supportive care, or late effects COG study. Potential predictors of interest included a composite of self-reported race and ethnicity, age at diagnosis, neighborhood socioeconomic status (SES) as measured by the Yost Index at the census tract, and distance to care (calculated as distance from home address to COG hospital). Poisson regression with log link and robust error variance was used to estimate adjusted risk ratios (aRR) and corresponding 95% confidence intervals (CI) for enrollment on a COG therapeutic clinical trial. Results: Of the 13,392 patients with ALL enrolled in the CCRN registry, 65% (n=8650) enrolled on a therapeutic COG clinical trial, 9% (1199) enrolled on a non-therapeutic trial without enrolling on a therapeutic trial, and 26% (3543) enrolled in the registry, but no other COG clinical trial. The majority of patient were between 1-9 years old and 58% were non-Hispanic (NH) White, 26% were Hispanic, and 7.2% were NH Black. Almost 11% of patients lived more than 100 miles from the COG center where they received treatment. Neither race nor ethnicity was associated with participation on a clinical trial (as shown in Table 1). Similarly, neighborhood SES was not associated with clinical trial participation. In multivariable models, age and distance to care were both meaningful predictors of therapeutic COG clinical trial enrollment with infants (aRR 0.64, 95%CI 0.57, 0.72) and adolescents (aRR 0.76, 95%CI 0.73, 0.80) less likely to enroll. Those that lived 100-250 miles from their COG center were 8% less likely to enroll (aRR 0.92, 95%CI 0.87, 0.97) and those that lived >250 miles from their COG center were 26% less likely to enroll (aRR 0.74, 95%CI 0.67, 0.81). Age was also a predictor of enrollment on non-therapeutic trials, but distance to care was not associated with enrollment on non-therapeutic trials. Conclusion: Among those who enroll on COG registry trials (which previous data suggests accounts for 55% of patients with ALL), race, ethnicity, and neighborhood SES are not associated with participation in therapeutic or non-therapeutic clinical trials. While age impacts risk stratification in ALL and thus may have impacted eligibility for various therapeutic trials, greater distance to care emerged as a relevant barrier to enrollment on therapeutic clinical trials. This novel finding in pediatric oncology suggests that interventions focused on ensuring access to clinical trials among those that live more than 100 miles from a COG site should be implemented. Approaches to address this disparity could include allowing study labs to be drawn locally and study visits to be conducted by telehealth when feasible.

High-Density Data Mining to Identify Unique Toxicities of Adolescent/Young Adult Cancer Treatment: A Report from the Children's Oncology Group

Background: Adolescent and young adult (AYA) cancer patients, 15-39 years of age, experience excess treatment-related toxicity compared to children. However, the relatively low number of AYAs enrolled on individual Children's Oncology Group (COG) clinical trials limits thorough toxicity analyses. Our objective was to delineate a detailed signature of drug- and dose-specific toxicities experienced by AYAs. We created a novel high-density data informatic method of clustering and analyzing toxicity data across multiple clinical trials that permits the comparison of outcomes in large populations of AYA versus younger cancer patients. In this pilot study, we aggregated four different COG acute lymphoblastic leukemia (ALL) trials to identify new and previously described toxicities that correlated with age and drug exposure, and validated our findings with previously published toxicity data as traditionally reported.Methods: Toxicity data from four recent COG trials for newly-diagnosed high-risk (CCG-1961, AALL0232) and standard-risk (CCG-1991, AALL0331) ALL trials were analyzed (n=13,436). First, disparate toxicity scoring systems were harmonized and re-mapped to a unified system based on the Common Terminology Criteria of Adverse Events (v.4.0), and then clustered in hierarchical fashion to enhance the power analysis. Differential rates of age-specific toxicities were determined in phases of treatment that were common to all protocols. AYA was defined as per NCI (15-39 y). Fisher's exact test was used to determine significant toxicity differences by treatment and age. Grade 3-5 events were included for all toxicities except osteonecrosis (ON), which included grade 2-5.Results: Across all phases of treatment, toxicity rates among AYAs vs children are summarized in Table 1. During Induction, hyperglycemia and hyperbilirubinemia were more common among AYAs (25.3% vs 8.1% and 10.4 vs 2.4%, respectively; both p < 0.0001). Metabolic disorders, including hypoalbuminemia, were also more common in AYA patients for both dexamethasone and prednisone in Induction (AYA: 8.7% vs 2.2%; children: 2.7% vs 1.5; both p < 0.05). Post-Induction, mucositis and peripheral neuropathy were more common among AYAs (15.5% vs. 4.5% and 6.1% vs 2.9%, respectively, both p<0.0001). ON appeared as a delayed manifestation during Maintenance in patients who received dexamethasone in Induction; patients (≥10 y) showed increased rates (21.4% (dex) vs 12% (pred), p< 0.0001). In addition, this large-scale cross-study analysis identified novel AYA toxicity signatures not previously described, including pancreatitis and thrombosis, which were more common in the AYAs compared to children (8.5% vs 5% and 3.9% vs 1.2 %, respectively; both p < 0.0001).Conclusions: We used high-density bioinformatics analysis to identify unique and novel toxicity signatures of AYA leukemia patients. We identified side effects previously published using traditional biostatistical analyses in individual trials, validating this approach. In addition, we identified novel toxicities. These findings suggest that large-scale data analyses are a sensitive and powerful method for simultaneous analyses of outcomes across multiple clinical trials, and in otherwise small populations. It provides a framework for a comprehensive understanding of toxicity and outcome differences among AYAs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Infectious Outcomes of Pediatric Acute Lymphoblastic Leukemia Patients Presenting with Non-Neutropenic Fever

Background: Despite advances in cure rates for pediatric acute lymphoblastic leukemia (ALL), infections remain a significant cause of treatment-related morbidity and mortality. Patients with a central venous catheter (CVC) who develop fever while severely neutropenic (absolute neutrophil count (ANC) &amp;lt; 500) are known to be at high risk for serious infections such as blood stream infections (BSIs). However, on Children's Oncology Group (COG) ALL protocols, the majority of a patient's therapy course is in the maintenance phase, during which patients are typically not severely neutropenic. While the BSI rate in all pediatric oncology patients presenting with non-neutropenic fever has been reported to be around 5 to 10% (Allaway et al Pediatr Blood Cancer 2019), minimal data are available regarding BSI and other infections in pediatric ALL patients with non-neutropenic fever. Objective: The objective of this study was to describe the infectious outcomes of children with ALL who developed non-neutropenic fever. Methods: A single institution retrospective chart review collected data on all non-neutropenic pediatric ALL patients (age 0-25 years) with a CVC who were evaluated for fever (temperature ≥ 38ºC) and had a blood culture drawn at the time of presentation from April 2019 through June 2020. Febrile events occurring within 7 days of a prior febrile episode, during administration of empiric or treatment antibiotics, and in patients within 30 days after stem cell transplant (SCT) were excluded. The primary outcome was documented infection from the day of fever evaluation including BSI, positive respiratory viral panel (RVP) result, or other clinically identified infection. The following demographic and clinical variables were abstracted to evaluate risk factors for infection: age, sex, race, ethnicity, CVC type, maximum presenting temperature, ANC, exposure to chemotherapy agents known to be associated with fever (cytarabine or anti-thymocyte globulin), patient location at presentation, history of SCT, sedation event within the prior 24 hours, and COG ALL protocol risk stratification. Institutional review board approval was obtained. Descriptive and inferential statistics, including chi-square or Fisher's exact test as appropriate, were calculated. Analyses were performed using SAS Enterprise Guide v7.1. Results: Data were collected on 299 non-neutropenic febrile episodes experienced by 150 patients. Eighty-eight (29.4%) episodes (61 patients) had at least one identified infection. Thirteen (14.8%) infections were a BSI; the overall BSI rate was 4.3%. Seven BSIs were gram-positive organisms and the remainder were gram-negative organisms. The other infections included 57 (64.8%) respiratory viral infections, 15 (17.0%) pneumonias, 6 (6.8%) ear, nose and throat infections, 3 (3.4%) gastrointestinal infections, and 5 (5.7%) other infections. There was more than one identified infection in 11 episodes (12.5% of infectious episodes) with respiratory viral infection and pneumonia as the most common co-infections (n=6). Presenting temperature ≥ 39ºC was associated with having an identifiable infection (p=0.003). Documented infections occurred less frequently in patients with an exposure to a drug associated with fever (p=0.004), who were inpatient at presentation (p=0.042), or who had a sedation in the prior 24 hours (p=0.003). Conclusion: In this single institution cohort of children with ALL, 29.4% of non-neutropenic febrile episodes were due to a documented infection. The BSI rate of 4.3% is similar to other published reports of pediatric oncology patients with a CVC who developed non-neutropenic fever. Not surprisingly, the most common type of infection was respiratory viral infection. Notably, infections occurred more frequently in patients with a presenting temperature ≥ 39ºC while having had a sedation event within the past 24 hours or having received a chemotherapy agent associated with development of fever were less likely to be associated with an infection. These results provide data that may be useful in determining need for empiric antimicrobial therapy in pediatric ALL patients with non-neutropenic fever based on height of fever and recent treatment exposures. Further evaluation of these initial results in larger, multi-institutional studies are ongoing in order to guide future approaches to treatment of children with ALL who develop non-neutropenic fever. Disclosures No relevant conflicts of interest to declare.

Premedication and Longer Infusion Time Do Not Reduce the Incidence of Hypersensitivity Reactions to Pegaspargase

Introduction Pegaspargase (PEG) is a critical component of therapy for pediatric acute lymphoblastic leukemia (ALL); however, complete asparaginase treatment may be hampered by the development of hypersensitivity reactions. Inadequate exposure to asparaginase has been shown to result in inferior outcomes (Gupta 2020). Although Erwinia asparaginase can be utilized as a replacement in patients with PEG allergy, recent shortages of Erwinia leave some patients who develop allergy to PEG without an alternative. Premedication with antihistamines and corticosteroids, as well as decreasing the pegaspargase infusion rate have been proposed as approaches to reduce hypersensitivity reactions (Cooper 2019, Bade 2019, Stock 2019). We evaluated the episodes of hypersensitivity reactions to PEG during three time periods with differing premedication and infusion practices at a single institution. Methods We utilized pharmacy records to conduct a retrospective chart review on PEG administration at Children's Healthcare of Atlanta from June 2017 to May 2020. Abstraction captured data on clinical hypersensitivity reactions to PEG over 3 time periods. PEG 2500 units/m2 was delivered as an intravenous infusion according to the schedules used in Children's Oncology Group ALL protocols. In the first time period (P1, June 22, 2017 to June 21, 2018) PEG was infused over 1 hour without premedication. In the second period (P2, June 22, 2018 to May 19, 2019) PEG was infused over 1 hour following premedication with ranitidine and diphenhydramine. In the final period (P3, May 20, 2019 to May 19, 2020) PEG was infused over 2 hours with normal saline piggyback intravenous fluids following premedication with ranitidine (or famotidine), diphenhydramine and hydrocortisone. Asparaginase activity was measured 7-10 days after PEG doses in consolidation and subsequent phases in P1 and P2, and also after induction in P3. Silent inactivation was defined as asparaginase activity &amp;lt;0.1 IU/ml. A likelihood ratio test was used to compare the probability of a hypersensitivity reaction per dose of PEG between periods. Results The cohort included 277 recipients of at least one dose of PEG during the review period. Some patients received PEG across multiple periods. During P1, 121 patients received 298 PEG doses. Of these, fifteen patients (12.4%) had hypersensitivity reactions; 1 patient (0.8%) had silent inactivation. During P2, 94 patients received 235 PEG doses. Seventeen (18.1%) of these patients had hypersensitivity reactions, with no cases of silent inactivation cases. During P3, 125 patients received 332 PEG doses. Sixteen (12.8%) had hypersensitivity reactions and one (0.8%) had silent inactivation (Figure 1). The majority of reactions occurred with each patient's second (56%) or 3rd (38%) PEG dose. The probability of reaction per dose across all periods was 0.054 (95% CI: 0.039, 0.069). The reaction probability for the three phases are estimated to be 0.050, 0.068, and 0.048 for P1, P2, and P3 respectively (Figure 2). There was no statistically significant difference in the probability of PEG hypersensitivity reactions between the three different time periods (p = 0.56). Conclusions Premedication with antihistamines and corticosteroids or prolongation of infusion time did not affect the incidence of hypersensitivity reactions to PEG over a three-year period at our institution. The rate of silent inactivation was extremely low, and did not increase after premedication was instituted. These results contrast with prior single institution reports regarding reductions in hypersensitivity reactions and indicate that larger, multi-center trials are needed to determine the efficacy of premedication or prolongation of infusion time on reducing hypersensitivity reactions to PEG during pediatric ALL therapy. Disclosures No relevant conflicts of interest to declare.

Enhanced Risk Stratification of 21,178 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia (ALL) Incorporating White Blood Count (WBC), Age, and Minimal Residual Disease (MRD) at Day 8 and 29 As Continuous Variables: A Children's Oncology Group (COG) Report

Current risk stratification for COG ALL patients (pts) relies on National Cancer Institute (NCI) risk group (RG) at diagnosis, somatic genetics, and early response to therapy as measured by specific thresholds of minimal residual disease (MRD) using flow cytometry on day 8 peripheral blood (D8 PB) and day 29 bone marrow (D29 BM). NCI RG is defined as age 1-10 years (yrs) and white blood cell count (WBC) &amp;lt;50,000/uL (Standard Risk, SR); all other non-infant patients are high risk (HR). Using COG risk stratification, current therapies for SR and HR patients are based on 5-year projected event-free survival (EFS) of 92-97%, and 65-86%. Currently, two subsets, Ph-like and very high risk (VHR) ALL are identified with additional assays-genomic sequencing for Ph-like, and persistent BM MRD on D29 and at end of consolidation for VHR, and are eligible for different treatments. However, as UK investigators recently published (O'Connor, JCO 2018; Enshaei, Blood 2020), using multiple continuous variables as threshold-defined categorical data may diminish the power of accurately predicting relapse, and thus prescribe inappropriate post induction therapy. We tested the UK approach of transforming categorical variables into continuous data on 13,870 NCI SR and 7308 NCI HR B-ALL pts treated on two generations of COG trials: AALL0331 (SR; n=5094), AALL0932 (SR; n=8776), AALL0232 (HR; n=2883), and AALL1131 (HR; n=4425). Down syndrome and Ph+ pts were excluded from analysis. Clinical characteristics are listed in Table 1. ETV6-RUNX1 (25.24%) and double trisomies of chromosome 4, 10 (DT) (23.77%) comprised the favorable risk genetic RG (FRG) group (48.15% of risk classified) while KTM2A rearranged (1.71%), hypodiploidy (1.67%), and iAMP21 (2.56%) comprised the unfavorable risk genetic RG (URG) (6.26%). All others with genetic information were classified as intermediate risk genetic RG (IRG) (45.59% of risk classified). Among 4873 pts tested, 20.46% had Ph-like ALL. D8 PB and D29 BM MRD data were available for 76.42% and 96.69% pts, respectively. We first log transformed WBC, D8 and D29 MRD and displayed these by treatment protocol, NCI RG, and FRG/URG (separating out Ph-like independently). Age and WBC followed the normal expected distribution with the median age of SR pts 4.0 yrs (range 1-9) and HR 12 yrs (range 1-30). Transformed MRD was displayed as a variable t(MRD), corresponding to the negative log; max t(D29 MRD) was 13.82, corresponding to MRD &amp;lt;1.0 x 10-5.The great majority of pts were MRD-positive at D8 (mean t(D8 MRD) 7.42); but there was broad distribution of values, with NCI SR and FRG pts having lower t(D8 MRD) (mean 7.52 and 8.08) than NCI HR and URG pts (mean 7.20 and 6.56) (p &amp;lt; 0.001) . The great majority of pts were D29 MRD-negative (mean t(D29 MRD) 12.08), with NCI SR and FRG pts achieving lower D29 MRD (mean t(D29 MRD) 12.43 and 12.73) than NCI HR and URG pts (mean 11.40 and 10.95) (p&amp;lt; 0.0001). Ph-like ALL pts had a mean t(D8 MRD) and t(D29 MRD) of 6.22 and 9.37. We next conducted a univariate analysis for risk factors for relapse, including sex, age, WBClog, CNS status, protocol-defined rapid early response status, FRG, URG, t(D8 MRD), and t(D29 MRD); all variables except CNS status were significant p &amp;lt; 0.0001). Multivariable modeling showed that WBClog, FRG, URG, t(D8 MRD), t(D29 MRD) retained significance (p &amp;lt; 0.0001). Finally, we applied the UK Prognostic Index (PIUKALL) equation [t(d29 MRD) x -0.218 + CYTO-GR x -0.440 + CYTO-HR x 1.066 + WBClog x 0.138] to the COG data using protocol, NCI RG, FRG, URG, IRG, or Ph-like RG in the model and validated the trends for relapse-free survival (RFS), which were similar in our groups with an overall median PIUKALL of -2.63 (mean -2.32, SD -.90, min -3.54, max 1.79). We next added in t(D8 MRD) to define a PICOG and determined that D8 PB MRD added significantly to the model, mostly through discriminating between the hazard ratios of the FRG and the URG RGs. Importantly, the D8 PB MRD led to a qualitatively more distinctive group with a potentially lower predicted RFS in NCI SR pts, a group that has been more difficult to predict in the past, and yet comprises nearly half of all relapse events. Our analyses of 21,178 COG B-ALL pts confirm and extend the utility of integrating WBC and MRD as continuous rather than categorical values to refine risk stratification for patient treatment and trial design. Disclosures Loh: Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. Mattano:Melinta Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Hunger:Amgen: Current equity holder in publicly-traded company, Honoraria; Novartis: Consultancy. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; AbbVie, Inc.: Research Funding.

Minimal Residual Disease Risk-Stratification in Pediatric Mixed Phenotype Acute Leukemia: Results of a Multi-Center Cohort Study

BACKGROUNDMixed phenotype acute leukemia (MPAL) is a rare form of leukemia in children. Current evidence supports the use of acute lymphoblastic leukemia (ALL)-directed regimens as initial therapy for MPAL; Children's Oncology Group (COG) ALL regimens are commonly used for pediatric ALL in the United States. Data for the predictive value of minimal residual disease (MRD) to risk-stratify therapy for pediatric MPAL is sparse overall and currently unknown in the context of COG ALL regimens. The primary objective for this study was to therefore examine the predictive value of MRD for event-free and overall survival (EFS, OS) in a centrally-reviewed, strictly-defined pediatric MPAL cohort treated according to COG ALL regimens. METHODSA retrospective cohort of pediatric MPAL treated from 2008-2016 was assembled from six institutions in the United States. All sites submitted primary diagnostic flow cytometry for central review. Two independent hematopathologists blinded to clinical outcomes confirmed the diagnosis of MPAL according to the WHO2008 and/or WHO2016 classification and assigned a MPAL phenotype. MRD was assessed by multi-parameter flow cytometry (“negative” defined as <0.01%). Endpoints of interest included presenting features of MPAL, MRD levels at end of induction and consolidation (EOI, EOC), role of hematopoietic stem cell transplantation (HSCT) in complete remission (CR), EFS, and OS. Kaplan-Meier analyses were performed stratified by predictors of interest. Stepwise multivariable Cox proportional hazard models inclusive of MRD and candidate predictors were used to evaluate EFS and OS for patients with complete data. Analyses were repeated in the subset of patients with “neutral” cytogenetics (i.e. no favorable [double trisomy, ETV6-RUNX1] or adverse [hypodiploid, BCR-ABL1, KMT2Ar, Ph-like, iAMP21, FLT3-ITD] features). All tests were 2-sided with significance set at p <0.05. RESULTSOf the 112 cases diagnosed by institutions as MPAL, 94 (84%) fulfilled strict WHO criteria. The majority of MPAL patients were B/Myeloid (89%), with a single blast population (87%), and without hyperleukocytosis (WBC≥50K/uL) or central nervous system involvement at presentation (Table 1). Within the cohort, 85/94 were treated with a COG ALL regimen with EOI MRD available (1/85 suffered an induction death prior to MRD assessment). ALL induction therapy resulted in a MRD-negative CR in 72% (61/85); three MRD-negative patients nonetheless converted to non-ALL therapy. Of those EOI MRD+ (≥0.01%), 12 of 14 who continued with COG ALL therapy achieved an EOC MRD-negative CR (i.e. 70/85 [82%] were MRD-negative by EOC). Induction failure (IF) occurred in 7% (6/85) and was defined as disease progression prior to EOI (n=2) or by EOI MRD ≥5% (n=4). The two patients with early disease progression were successfully “salvaged” with AML therapy (<21 days from initial diagnosis) and achieved a MRD-negative CR following one cycle. Patients achieving MRD-negative remissions at EOI and/or EOC with ALL chemotherapy had excellent EFS and OS (Figure 1). Multivariable analysis confirmed the predictive value of MRD at EOI (hazard ratio ±SE for EFS and OS = 3.77±1.67 and 3.54±2.09; p=0.032 and p=0.024 respectively). Only a few patients receiving ALL therapy proceeded to HSCT in CR1, all were alive at time of reporting. Use of HSCT was not associated with improved EFS or OS (p>0.50 for both); five-year EFS and OS for ALL chemotherapy without HSCT (n=73) were 78±6% and 90±4%, respectively. The presence of multiple blast populations of distinct lineages at diagnosis was similarly rare and was potentially associated with worse OS on multivariable analysis (p=0.024). No other candidate predictors were associated with EFS or OS. No difference in the predictive value of MRD was present when analyses were limited to patients with “neutral” cytogenetics. CONCLUSIONIn a retrospective analysis of pediatric MPAL, the majority of patients treated with ALL chemotherapy achieved a MRD-negative CR by EOC (~week 12 of therapy); overall survival in this group was excellent. Further prospective validation of MRD is essential to refine risk-stratified therapy for pediatric MPAL. Optimal salvage for those who fail to achieve remission with ALL chemotherapy is unknown and requires further study. DisclosuresO'Gorman:Becton Dickinson: Consultancy.

Age but Not Adiposity Predicts Asparaginase-Induced Hepatotoxicity during Induction Therapy for Adolescent and Young Adults with Acute Lymphoblastic Leukemia

INTRODUCTIONObesity is associated with increased treatment-related toxicity during therapy for acute lymphoblastic leukemia (ALL). During induction, hepatotoxicity due to L-asparaginase results in significant morbidity and chemotherapy delays/modifications. While hepatotoxicity is more common in older adolescent and young adult (AYA) patients, it cannot be predicted with high accuracy. Obesity defined by the surrogate marker of body mass index (BMI) has been shown to be a risk factor for hepatotoxicity; however, BMI does not accurately reflect body adiposity during ALL therapy due to concurrent muscle loss and adiposity gain. Because excess adiposity is generally believed to be responsible for most of the comorbidities of obesity, we hypothesized that body fat measured by direct assessment would be a better predictor of asparaginase-induced hepatotoxicity, and that non-obese patients with increased adiposity might be identified as an at-risk population which would not otherwise be recognized. METHODSWe conducted an interim analysis of a prospective trial for an obesity intervention in pre-adolescent and AYA patients ≥10 years old newly diagnosed with B-ALL (NCT02708108). Whole-body dual-energy x-ray absorptiometry (DXA) performed at diagnosis and end of induction (EOI) directly quantified adiposity as total body fat percentage (TBF%) and fat mass (FM). Overweight or obesity (OW/OB) was defined using CDC-norms as a BMI percentile (BMI%) ≥85%. All patients were treated with Children's Oncology Group ALL regimens using a four-drug induction inclusive of glucocorticoids, daunorubicin, vincristine, and pegylated L-asparaginase. Obese and/or patients ≥15 years were considered at-risk for hepatotoxicity and thus eligible to receive exogenous supplementation with levocarnitine for hepatoprotection per provider discretion. The primary endpoint for the analysis was CTCAE Grade 3+ hepatotoxicity. Stepwise multivariable logistic regression models were constructed for the primary endpoint inclusive of TBF% and FM at diagnosis, change in FM during induction, and demographic candidate predictors. All tests were two-sided and significance was set at p<0.05. RESULTSWe analyzed a cohort of 25 subjects enrolled on trial with DXA results at diagnosis. The cohort was divided equally by age ≥15 years (48%) and sex (44% female). The majority were of Hispanic ethnicity (64%) consistent with institutional demographics. Over half the cohort was OW/OB at diagnosis with mean TBF% of 39.5±1.3% and FM 31.7±2.5kg. In this AYA population, Grade 3+ hepatotoxicity occurred in 10/25 (40%) overall; all episodes included transaminitis (10/10) ± concurrent hyperbilirubinemia (2/10). Two of these patients met criteria for CTCAE Grade 4 hepatotoxicity (2/25, 8%); both were older, obese, with TBF% >40% at diagnosis. After accounting for age, radiographic measures of adiposity at diagnosis were not significant predictors of hepatotoxicity on multivariable analyses (FM at diagnosis p=0.299; TBF% at diagnosis p=0.599). Similarly, gain or loss of FM was not significantly associated with hepatotoxicity after adjusting for age or starting BMI category (p=0.818). Successful loss of fat due to the intervention occurred in 7/13 (54%) of OW/OB patients (mean loss -3.9±8.9kg) but was similarly not associated with decreased risk of hepatotoxicity (p=0.734). Only age ≥15 years was significantly associated with risk for Grade 3 hepatotoxicity across all models. Levocarnitine supplementation was prescribed by the primary providers to five of six eligible at-risk patients; no reported adverse events occurred. No severe, CTCAE Grade 4 hepatotoxicity occurred in the four patients adherent to levocarnitine supplementation. CONCLUSIONContrary to our hypothesis, neither directly measured adiposity at diagnosis nor changes in adiposity during ALL induction predicted hepatotoxicity for this AYA cohort. Older AYA patients were at significant risk for hepatotoxicity irrespective of level of adiposity. However, the potential impact of extreme obesity on hepatotoxicity requires further investigation. Validation of these results is necessary in a larger cohort; should they be confirmed, future trials targeting hepatotoxicity reduction from ALL induction should focus on age-related differences in drug metabolism and effects. DisclosuresNo relevant conflicts of interest to declare.

Abstract 222: Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome

Abstract Purpose: Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) compared to children without DS. While genome-wide association studies (GWAS) have identified several susceptibility loci in childhood ALL, studies of ALL in children with DS are lacking. Therefore, we conducted the first GWAS of DS-ALL. Methods: We analyzed independent cohorts of: 1) 226 newly diagnosed DS-ALL cases from Children's Oncology Group (COG) ALL trials (2000-2013) and 436 DS controls from the National Down Syndrome Project (NDSP), 2) 124 additional COG ALL cases (2011-2015) and 336 additional NDSP DS controls, 3) 20 DS-ALL cases and 275 DS controls from Michigan neonatal bloodspots, and 4) 157 DS-ALL cases and 145 DS controls largely from neonatal bloodspots from California and Washington. Genotyping was performed with Affymetrix or Illumina single nucleotide polymorphism (SNP) arrays. STRUCTURE software was used to define European (372 cases, 1,056 controls), Hispanic (140 cases, 136 controls), and African (15 cases, 62 controls) genetic ancestry. After genome-wide imputation and quality control, ancestry- and cohort-specific associations were evaluated at &amp;gt;6,000,000 autosomal SNPs with minor allele frequency ≥1%. Associations were meta-analyzed across cohort and ancestry groups, assuming additive allelic effects. Results: Genome-wide significant (p&amp;lt;5x10-8) association signals were identified for known ALL susceptibility loci, including rs58923657 near IKZF1 (Odds Ratio [OR]=2.02, p=5.32x10-15), CDKN2A missense mutation rs3731249 (OR=3.63, p=3.91x10-10), rs3781093 near GATA3 (OR=1.73, p=2.89x10-8), and rs7090445 near ARID5B (OR=1.57, p=2.93x10-8). A novel potential risk locus was identified at chromosome 20q11.21 (rs78019519, OR=3.17, p=5.11x10-7) with consistent effects observed across each cohort and ancestry group. This SNP is in the promoter region of the oncogene TPX2 and is also associated with expression of HM13 in whole blood in the Genotype-Tissue Expression (GTEx) Portal. Conclusion: We confirmed that known ALL susceptibility loci in children without DS, including IKZF1, CDKN2A, GATA3, PIP4K2A and ARID5B, also confer risk of ALL in children with DS, with CDKN2A showing the largest effect size. We also identified a potentially novel locus associated with ALL susceptibility in DS at chromosome 20q11.21. Additional investigation of these loci is ongoing and may advance our understanding of DS-ALL etiology and biology. Citation Format: Austin L. Brown, Adam J. de Smith, Michael E. Scheurer, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Michael E. Zwick, Naomi Winick, Kelly Maloney, Anne L. Angiolillo, Reuven Schore, MIchael M. Burke, Wanda L. Salzer, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Elanor Feingold, Stephanie L. Sherman, Wenjian Yang, Meenakshi Devidas, Kyle Walsh, Andrew T. DeWan, Maria S. Pombo-de-Oliveira, Jeffrey W. Taub, Daniel Sinnett, Jasmine Healy, Jillian M. Birch, Lisa F. Barcellos, Helen Hansen, Ivan Smirnov, Charles G. Mullighan, Stephen P. Hunger, Ching-Hon Pui, Mignon Loh, Joe L. Wiemels, Xiaomei Ma, Catherine Metayer, Beth A. Mueller, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 222.

Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group

AbstractPhiladelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of BCR-ABL1 (n = 46) or ETV6-RUNX1 (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of CRLF2 (IGH-CRLF2 or P2RY8-CRLF2) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients (50.8% of those with CRLF2 rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (ABL1, ABL2, CSF1R, and PDGFRB) in 14.1%, EPOR rearrangements or JAK2 fusions in 8.8%, alterations activating other JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6%, and mutations involving the Ras pathway (KRAS, NRAS, NF1, PTPN11) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.

Improved Survival for Children and Adolescents With Acute Lymphoblastic Leukemia Between 1990 and 2005: A Report From the Children's Oncology Group

To examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's Oncology Group (COG) clinical trials between 1990 and 2005. In total, 21,626 persons age 0 to 22 years were enrolled onto COG ALL clinical trials from 1990 to 2005, representing 55.8% of ALL cases estimated to occur among US persons younger than age 20 years during this period. This period was divided into three eras (1990-1994, 1995-1999, and 2000-2005) that included similar patient numbers to examine changes in 5- and 10-year survival over time and the relationship of those changes in survival to clinical covariates, with additional analyses of cause of death. Five-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with National Cancer Institute (NCI) standard- or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased. This study documents ongoing survival improvements for children and adolescents with ALL. Thirty-six percent of deaths occurred among children with NCI standard-risk features emphasizing that efforts to further improve survival must be directed at both high-risk subsets and at those children predicted to have an excellent chance for cure.

Administration of Erwinia Asparaginase (Erwinase®) Following Allergy to PEG-Asparaginase In Children and Young Adults with Acute Lymphoblastic Leukemia Treated on AALL07P2 Achieves Therapeutic Nadir Serum Asparaginase Activity: A Report From the Children's Oncology Group (COG)

AbstractAbstract 2134 Introduction:L-asparaginase is a vital component of multi-agent chemotherapy for children and young adults with acute lymphoblastic leukemia (ALL). In the United States, there are 2 asparaginase preparations approved by the Food and Drug Administration, native E. coli (Elspar®) and PEG-asparaginase (Oncaspar®). PEG-asparaginase is the most commonly utilized asparaginase product due to its longer half-life and decreased immunogenicity. However, the incidence of clinical allergy to PEG-asparaginase approaches 20%, with repeated administration. Due to cross reactivity with native E. coli asparaginase, there is no FDA-approved preparation available for patients who develop clinical allergy to PEG-asparaginase. A third preparation, Erwinia asparaginase (Erwinase®), derived from Erwinia chrysanthemi, is not commercially available in the United States. The optimal dosing of Erwinase® necessary to obtain nadir asparaginase activity > 0.1 IU/mL similar to that obtained after conventional dosing of PEG-asparaginase is unknown. Patients and Methods:We hypothesized that substitution of Erwinase® 25,000 IU/m2 × 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule in children and young adults with ALL would provide a 48 hour nadir serum asparaginase activity ≥ 0.1 IU/mL, and effectively deplete plasma asparagine, a surrogate marker of asparaginase activity. Eligible patients on COG study AALL07P2 were >1 to <30 years of age, concurrently enrolled on a frontline COG ALL treatment study, and had documented ≥ grade 2 allergy (NCI Common Terminology Criteria 3.0) to PEG-asparaginase. Results:A total of 55 eligible/evaluable patients were enrolled from February 2008 to April 2010. Blood samples were obtained at scheduled time points during Erwinase® therapy and assayed for serum asparaginase activity and asparagine concentration in plasma. Nadir serum asparaginase activity ≥ 0.1 IU/mL was achieved in 49/53 patients (92.5%) at 48 hours after dosing and in 46/52 patients (88.5%) at 72 hours after dosing. Plasma asparagine was significantly depleted (<1.0 μM) in all 49 patients for whom samples were satisfactorily obtained. Grade 2–3 allergic reaction and grade 1–2 hyperglycemia related to Erwinase® were reported in 5 and 3 patients, respectively. There were no reports of hemorrhage, thrombosis, pancreatitis, or death. Conclusion:Erwinase® as administered using the AALL07P2 regimen was well tolerated and achieved nadir serum asparaginase activity at both 48 and 72 hours after dosing that was similar to that achieved with PEG-asparaginase. We conclude that following allergy to PEG-asparaginase, Erwinase® 25,000 IU/m2 × 6 doses IM on a Monday/Wednesday/Friday schedule can be substituted for a single dose of PEG-asparaginase. Disclosures:Supko: EUSA Pharma: Research Funding. Plourde: EUSA Pharma: Employment. Winick: EUSA Pharma: EUSA Advisory Board.

A High Frequency of Blasts with the PNH Phenotype in Patients with ALL.

Abstract 1575Poster Board I-601It has been proposed that if more than 2 mutations are required for leukemia to arise, then an elevation in the mutation rate would be necessary for these mutations to coincide in the same cell, based on the rarity of spontaneous mutations (Loeb 1991). Hypermutability could occur transiently, for example, due to mutagens, or permanently, due to inactivation of repair pathways. Genome-wide analysis has indicated that in acute lymphoblastic leukemia (ALL), more than 2 somatic mutations are often found (Mullighan et al 2007), suggesting that hypermutability is likely to occur at least in some cases. To investigate this hypothesis, we have used our method for the detection of rare cells that have acquired a spontaneous inactivating mutation in the PIG-A gene. Expanded populations of stem cells with PIG-A mutations in the setting of bone marrow failure are the hallmark of paroxysmal nocturnal hemoglobinuria (PNH), but under most other circumstances, PIG-A mutations are thought to be growth neutral in vitro and in vivo. PIG-A is on the X-chromosome, and therefore, a single inactivating mutation is sufficient to produce the PNH phenotype, characterized by a lack of glycosylphosphatidylinositol (GPI)-linked proteins and an inability to bind to the FLAER reagent. Furthermore, it is known from patients with PNH and from cell lines that a very broad spectrum of mutations can inactivate PIG-A. This combination of features makes PIG-A uniquely suited as a sentinel gene for spontaneous mutagenesis in humans, which is otherwise very difficult to quantitate. Here we have analyzed a panel of blast cells derived from ficolled marrow samples from patients with B-lineage ALL, obtained from the Children's Oncology Group ALL Cell Bank. To determine the frequency of spontaneous PIG-A mutations, samples were stained sequentially with an Alexa-488 conjugate of the FLAER reagent, a mixture of murine anti-CD55 and anti-CD59 antibodies, FITC-conjugated rabbit anti-mouse immunoglobulin secondary antibody, and PE-conjugated anti-CD45 antibody. The blast population was identified based on forward and side scatter, dim expression of CD45, and exclusion of propidium iodide. Control GPI (+) and GPI (-) cells from a patient with PNH served as a control. Among 19 cases of B lineage ALL studied, the frequency of blast cells with the PNH phenotype varied over a very wide range, and the distribution of mutant frequency values was seen to be bimodal. One group, representing about 40% of the cases of ALL, had a median mutant frequency of 6.8 × 10-6, which is very similar to the proportion of granulocytes that acquire the PNH phenotype due to spontaneous PIG-A mutations in normal individuals (Araten et al, 1999). These values are also close to the frequency of mutants reported for the HPRT, GPA, and XK genes in normal individuals. The other 60% of the samples had a median mutant frequency of 465 × 10-6, which is far above the range of this parameter in normal individuals. Among 6 established cell lines derived from T-ALL, the mutant frequency ranged from 4.1 ×10-6 to 265 × 10-6. Here as well, the distribution suggested that in this subtype of ALL, there may be two distinct phenotypes with respect to this parameter. Based on this data, we believe that an increase in inactivating mutations is not essential for the development of ALL, but that it is a common feature of this condition. We cannot rule out the possibility that samples with a low mutant frequency would demonstrate some form of genomic instability that would not be detected by our assay, such as an increase in gene duplications or translocations. Further investigations are needed to determine whether hypermutability as detected by this assay is associated with distinct cytogenetic abnormalities, clinical features at presentation, and outcome. DisclosuresNo relevant conflicts of interest to declare.

Patients with Early T-Cell Precursor (ETP) Acute Lymphoblastic Leukemia (ALL) Have High Levels of Minimal Residual Disease (MRD) at the End of induction—A Children's Oncology Group (COG) Study.

Abstract 9Current risk stratification algorithms in children with B-lineage ALL have facilitated the identification of subgroups with adverse outcomes that benefit from intensified therapy. However, many of the features that are highly prognostic of outcome in B-precursor ALL, such as the combination of age and white blood cell count (WBC) at diagnosis, have limited ability to predict outcome in T-ALL. In contrast, early response to induction therapy, as measured by bone marrow (BM) morphology at days 8, 15 or 29, and day 29 (end induction) BM MRD are highly predictive of outcome in both B-precursor and T-ALL. Coustan-Smith and colleagues (Lancet Oncology 10:147-156 2009) have recently identified a subset of children with ETP ALL that have an extremely high risk of induction failure or relapse. The ETP ALL blasts exhibit stem cell-like features as defined by the presence of antigens seen on early progenitors including CD117, CD34, HLA-DR and/or CD13/33, the absence of antigens seen on later stage immature T cells including CD1a and CD8, and decreased to absent expression of the early T cell antigen CD5.We analyzed patients enrolled in current generation COG ALL trials, including patients with B-precursor ALL treated on AALL0232 (high risk, n=2129) or AALL0331 (standard risk, n=3747), and 416 patients with T-ALL enrolled on AALL03B1. Clinical features including age, WBC, gender, and CNS status were compared between ETP-positive (n=25) and –negative (n=391) T-ALL patients. We also compared response to four weeks of induction therapy (prednisone, vincristine, PEG-asparaginase, and daunorubicin) as measured by day 15 and 29 BM morphology and day 29 BM MRD determined by flow cytometry. Twenty-five of 416 (6%) T-ALL patients had an ETP phenotype. The ETP-positive patients were older and presented with a lower white blood cell count than the ETP-negative patients (see Table). There was no difference in the gender distribution or the presence of CNS disease at diagnosis between the two groups. Strikingly, the ETP-positive patients had a dramatically inferior early response to therapy with 100% having ≥ 0.01% day 29 MRD (vs. 46% of ETP-negative T-ALL and 23.4% of precursor B-ALL) and 74% having ≥ 1% day 29 MRD (vs. 21% of ETP-negative T-ALL and 5% of precursor B-ALL). These results confirm the poor response of ETP T-ALL and suggest that novel treatment strategies are warranted in this patient subgroup. Disclosures:No relevant conflicts of interest to declare.ETP+ETP−p-valueAge 10+ years (n1 =25, n2 =391)76%45%0.0032WBC ≥ 50,000/mcl (n1 =23, n2 =371)22%63%0.0002Gender (Males) (n1 =25, n2 =391)60%77%0.09CNS status (CNS3) (n1 =23, n2 =368)0%7%0.39Day 15 BM ≥ 5% blasts (n1 =20, n2 =312)75%21%< 0.0001Day 29 BM ≥ 5% blasts (n1 =18, n2 =305)17%4%0.0516Day 29 BM MRD ≥ 0.01% (n1 =19, n2 =303)100%46%< 0.0001Day 29 BM MRD ≥ 1% (n1 =19, n2 =304)74%21%< 0.0001Day 29 BM MRD ≥ 10% (n1 =19, n2 =303)21%7%0.043

Acute Lymphoblastic Leukemia (ALL) with t(8;14)(q11.2;q32): B-Lineage Disease with High Proportion of Down Syndrome. A Children's Oncology Group (COG) Study.

Recurrent chromosome translocations play a critical role in the pathogenesis of ALL and many translocations have important prognostic significance. The t(8;14)(q11.2;q32) is a recurrent translocation that fuses the chromosome 8 CEBPD (CCAAT enhancer binding protein delta) gene to the IgH (immunoglobulin heavy chain) gene, leading most likely to deregulated CEPD expression. We previously reported the clinical data of 10 such patients (Leukemia , 2000; 14:238–240). Using the COG ALL cytogenetics database we expand the report to include 22 patients (13 females and 9 males) with the t(8;14)(q11.2;q32). All patients with available immunophenotyping data (n=20) had B-lineage ALL. The median age at diagnosis was 9.2 years (range: 1.6 months – 17.1 years). Median diagnostic white blood cell count (WBC) was 9,950 (range: 700–172,000). Of the 22 patients, 7 were NCI standard risk and 15 were high risk. The most common additional cytogenetic abnormality was trisomy 21. Of the ten cases with trisomy 21, seven were constitutional (Down Syndrome), thus confirming previous reports that a significant fraction of t(8;14) patients (7/22; 31.8%) have Down Syndrome, which is much higher than the 3% (80/2811) overall rate of children with Down Syndrome in a recent COG ALL trial (p<0.0001). In addition to the Down Syndrome cases, one case with phenotypic Turner syndrome had a mosaic constitutional r(Y)(p11q11.2); thus, eight cases (36%) had constitutional abnormalities. Secondary abnormalities included additional X (n=5); additional 5 (n=3); Philadelphia chromosome (n=1). Two cases had a second der(14)t(8;14) and two had loss of the der(8) t(8;14), consistent with the der(14)t(8;14) as the significant abnormality. Four cases (18%) had 9p deletions compared with 11% in the overall ALL population, and two cases (9%) had abnormalities of 13q compared with 2% in the overall population. Numerically, the cases were pseudodiploid (n=12) and hyperdiploid (n=10). Children with Down Syndrome had superior estimated 5-year event-free survival of 100%, compared to non-Down patients with 50.1±17.7% (p=0.04). Overall survival was also different but did not reach statistical significance: 100% vs. 60.9±17.0% (p=0.088). In summary, the rare t(8;14)(q11.2;q32) is associated with B-lineage phenotype and occurs with greatly increased frequency in children with Down Syndrome, who have an excellent outcome with standard COG therapy as compared to non-Down Syndrome patients with this translocation.