Induction Therapy For Acute Lymphoblastic Leukemia Research Articles

Risk factors and clinical impact of thrombosis during induction chemotherapy for pediatric acute lymphoblastic leukemia: A report from CYP-C.

Thromboembolism (TE) is associated with reduced survival in pediatric acute lymphoblastic leukemia (ALL). It has been hypothesized that TE might signal leukemic aggressiveness. The objective was to determine risk factors for TE during ALL induction (TEind ) therapy and whether TEind is associated with treatment refractoriness. This retrospective cohort study using the population-based Cancer in Young People Canada (CYP-C) registry included children <15 years of age diagnosed with ALL (2000-2019) and treated at one of 12 Canadian pediatric centers outside of Ontario. Univariate and multivariable logistic regression models were used to determine risk factors for TEind and whether TEind predicted induction failure and ALL treatment intensification. The impact of TEind on overall and event-free survival was estimated using Cox proportional hazard regression models. The study included 2589 children, of which 45 (1.7%) developed a TEind . Age (<1 year and ≥10 years vs. 1-<10 years), T-cell phenotype, high-risk ALL, and central nervous system involvement were all associated with TEind in univariate analysis. Age and T-cell phenotype remained independent predictors of TEind in multivariable analysis. Induction failure occurred in 53 patients (2.1%). TEind was not associated with induction failure (OR: not estimable) or treatment intensification (adjusted OR [95% CI]: 0.66 [0.26-1.69]). TEind was independently associated with overall survival (adjusted HR [95% CI]: 2.54 [1.20-5.03]) but not event-free survival (adjusted HR [95% CI] 1.86 [0.98-3.51]). In this population-based study of children treated with contemporary chemotherapy protocols, TEind was associated with age and T-cell phenotype and mortality but did not predict induction failure.

Central Retinal Vein Occlusion (CRVO) in Acute Lymphoblastic Leukaemia (ALL) Adult Patient Treated with Peg Asparaginase

ntroduction Asparaginase, available as native asparaginase or polyethylene glycol (Peg-aspa), is an essential component of multi-agent treatment protocols for Acute Lymphoblastic Leukaemia (ALL). It works by deaminating L-asparagine, leading to apoptosis and cell cycle arrest in leukemic cells. However, peg-asp is associated with various toxicities, including thrombotic complications mainly cavernous sinuses thrombosis and venous thrombosis. Methods and Results: We report a 48-year-old Indian gentleman, known to be hypertensive, diagnosed to have Precursor T-Lymphoblastic leukaemia/ lymphoma (NOS), when he presented with bicytopenia and a mediastinal mass. He was treated as per ALL protocol for adult at National centre for cancer care and research (NCCCR)Doha, which is adopted from UKALL-14 protocol. He received induction treatment (1A&amp; 1B) and has achieved a morphological remission. He received prophylactic anticoagulation with low molecular weight heparin (LMWH) which was stopped only in the cytopenic nadir. During the ascending phase of induction 1B, He presented with acute onset of floaters and blurred vision in the left eye. Urgent CT head scan revealed vitreous haemorrhage. Full blood count was normal except Platelets of 20*10 9ul. Coagulation screen, fibrinogen level and anti-thrombin level was within normal limit. Ophthalmological evaluation revealed vitreous and retinal haemorrhages, indicating Central Retinal Vein Occlusion (CRV). MRI/MRV brain ruled out intracranial venous thrombosis. CSF analysis excluded CNS disease. He received supportive transfusion; however, he has progressed to permanent loss of vision in the left eye. Therapeutic anticoagulation is not indicated in his case. Thrombotic events can occur during induction therapy for ALL mainly cavernous sinuses thrombosis and venous thrombosis, yet CRVO is an unusual site for thrombotic events and associated predominately with age-associated vasculopathies. In the reported case, several factors contribute to thrombosis, including acute leukaemia, prolonged hospitalization, age, presentation with a mediastinal mass, steroid use as well as Peg-aspa and the patient was managed with prophylactic anticoagulation while on therapy. Asparaginase induces a hypercoagulable state by decreasing antithrombin III, protein C, and protein S levels, leading to hypofibrinogenemia and augmenting the risk of thrombotic events. Thrombosis can negatively impact disease-free survival and long-term outcomes, resulting in complications such as therapy delays, post-thrombotic syndrome, and central nervous system-related issues (seizures, neurocognitive deficits, blindness). While these complications may lead to hesitancy or discontinuation of peg-asp use, early recognition and vigilant monitoring of antithrombin III and fibrinogen levels can help to guide management. In cases where the treatment course is complicated by thrombotic events, a high index of suspicion should arise considering strongly the causative agent to be Asparaginase. Thromboprophylaxis with low-molecular-weight heparin (LMWH) is widely accepted as supportive therapy in ALL management. Conclusion: ALL patients receiving Asparaginase therapy are at risk of developing thrombotic events. Early identification of symptoms and risk stratification are essential for improved disease outcomes. Awareness and understanding of peg-asp-induced thrombosis, including unusual site thrombosis can help guide treatment decisions and improve patient outcomes in ALL therapy.

Vincristine Side Effects With Concomitant Fluconazole Use During Induction Chemotherapy in Pediatric Acute Lymphoblastic Leukemia.

As a mainstay of treatment for acute lymphoblastic leukemia (ALL), vincristine's side effect profile is well known. Parallel administration of the antifungal fluconazole has been shown to interfere with the metabolism of vincristine, potentially resulting in increased side effects. We conducted a retrospective chart review to determine whether concomitant administration of vincristine and fluconazole during pediatric ALL induction therapy impacted the frequency of vincristine side effects, namely, hyponatremia and peripheral neuropathy. We also evaluated whether the incidence of opportunistic fungal infections was impacted by fluconazole prophylaxis. Medical charts of all pediatric ALL patients treated with induction chemotherapy at Children's Hospital and Medical Center in Omaha, NE, from 2013 to 2021 were retrospectively reviewed. Fluconazole prophylaxis did not significantly impact the rate of fungal infections. We found no correlation between fluconazole use and increased incidence of hyponatremia or peripheral neuropathy, which supports the safety of fungal prophylaxis with fluconazole during pediatric ALL induction therapy.

Effects of age, obesity, and body surface area on asparaginase-associated toxicities during acute lymphoblastic leukemia induction therapy: A report from the Children’s Oncology Group.

7000 Background: Asparaginase is integral to pediatric-inspired regimens (PIR) to treat acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). However, asparaginase-associated toxicities (AAT) often preclude delivery of planned therapy. Older age, obesity and/or large body surface area (BSA) have been associated with higher risk of AAT in PIR, but data are conflicting, and the impact of dose modification based on these factors is unknown. Methods: We examined induction toxicity data from patients ages 1-30 years enrolled in the frontline Children’s Oncology Group (COG) trials for high-risk B-ALL (AALL0232, 2004-2011) and T-ALL (AALL0434, 2007-2014). During Induction, patients received pegaspargase (2,500 IU/m2 without prescribed dose-capping) plus daunorubicin, vincristine, and prednisone or dexamethasone. AAT were defined as CTCAE v4 hyperbilirubinemia (Grade ≥3), elevated alanine aminotransferase (ALT) (Grade ≥4), thrombosis (any), or pancreatitis (any, included consolidation phase). Obesity was classified using population norms as body mass index (BMI) ≥30 (or ≥95th percentile for age/sex). BSA was analyzed continuously and dichotomized at 1.5 m2 (equivalent to pegaspargase 3,750 IU, the threshold for permissible dose-capping in PIR). The association of AAT with end-Induction minimal residual disease (MRD) ≥0.01% was assessed. Results: Among 4,925 patients, 25% were ≥15 years, 39% had BSA &gt;1.5m2, and 18% had obesity. Multivariable logistic analyses inclusive of BMI and BSA together found increased risk for any AAT in age groups ≥10 years (10-15y, odds ratio (OR) 2.0, 15-20y OR 2.2, ≥21 OR 3.3, p=0.002). Only patients with both obesity and high BSA (&gt;1.5m2) were at additional risk (OR 3.3, p&lt;0.0001). Similarly, risks for hyperbilirubinemia, ALT elevations, and thrombosis were increased in patients with both high BSA and obesity (OR 3.5, 95% confidence interval [CI] 2.2-5.7), OR 3.3, 95%CI 1.7-6.6, and OR 3.1 95%CI 1.5-6.5, respectively), but not in those with high BSA without obesity. The risk of hyperbilirubinemia was greater with increasing obesity (p&lt;0.0001) and was also higher in all age groups ≥10 years (OR 6.3-7.9, p&lt;0.0001). Age was not associated with thrombosis or ALT elevation; risk for pancreatitis was associated with Hispanic ethnicity, but not with age, BMI, or BSA. AAT were not associated with pooled trial MRD ≥0.01%. Conclusions: We report here the largest dataset of AAT in children and AYAs receiving ALL Induction therapy without routinely prescribed dose-capping of pegaspargase. Risk for AAT was increased in patients &gt;10 years and in those with obesity, but not high BSA alone. Dose capping may not be necessary for children and AYAs with high BSA without obesity. Prospective studies of AAT pharmacogenomics and modifiable risk factors will support safer dosing in PIR. Clinical trial information: NCT00075725, NCT00408005.

Hyperglycemia during induction therapy for acute lymphoblastic leukemia is temporally linked to pegaspargase administration.

Chemotherapy regimens containing glucocorticoids and pegaspargase are associated with hyperglycemia; however, the pattern and underlying risk factors are not well characterized. We determined the pattern of hyperglycemia and associated factors in children with acute lymphoblastic leukemia (ALL) receiving glucocorticoids and pegaspargase during induction. Retrospective analysis of patients treated between 2010 and 2020 at a single institution. Pretreatment data, glucose values, and insulin regimens were abstracted from the record. Hyperglycemia was defined as two or more random glucose measurements ≥200mg/dl. Analyses of demographic and clinical factors were conducted with logistic regression. Two hundred thirteen patients, median age 6years (range 1.0-18.9years), 47% female, were included. The prevalence of hyperglycemia was 23% (n=48). Mean glucose levels peaked 3days following administration of pegaspargase. In multivariable analysis, age ≥10years (odds ratio [OR] 6.2, 95% confidence interval [CI]: 2.9-13.4), female sex (OR 2.7, 95% CI: 1.2-6.2), and family history of diabetes (OR 3.2, 95% CI: 1.4-7.3) were predictive of hyperglycemia. Age ≥10years (OR 19.4, 95% CI: 5.5-68.4), family history of diabetes (OR 8.2, 95% CI: 2.7-25.3), and higher body mass index (BMI) (OR 1.8, 95% CI: 1.1-2.9) were associated with insulin treatment. Onset of hyperglycemia in children receiving induction chemotherapy for ALL is temporally linked to administration of pegaspargase. Older age, female sex, and family history of diabetes are predictive of hyperglycemia during induction; older age, family history of diabetes, and higher BMI are associated with insulin treatment. Frequent glucose monitoring is indicated during induction therapy for ALL.

1155. Covering Your Tracts? The Effect of Antibiotic Prophylaxis on Respiratory Tract Infections in Pediatric Acute Lymphoblastic Leukemia

BackgroundAntibiotic prophylaxis decreases rates of febrile neutropenia and systemic infection in children with acute lymphoblastic leukemia (ALL). However, it is unknown whether prophylaxis prevents or ameliorates the severity of specific types of infections like upper respiratory tract infections (URTI) or lower respiratory tract infections (LRTI). MethodsThis is a retrospective, observational convenience cohort study of children with newly-diagnosed ALL, comparing respiratory tract infections (RTI) in participants receiving no antibiotic prophylaxis, levofloxacin prophylaxis, or non-levofloxacin prophylaxis. Information regarding the presence of URTI or LRTI, identified respiratory viruses, hospitalization, oxygen supplementation, and ICU admission was collected through medical record review. The proportion of participants in each group was estimated and compared between groups using Fisher’s exact test and the Kruskal-Wallis test.ResultsOf 262 evaluable participants, 126 received no antibiotic prophylaxis, 59 received levofloxacin prophylaxis, and 77 received non-levofloxacin prophylaxis, with a total of 136 children getting any antibiotic prophylaxis regimen. In the no-prophylaxis group, 22/126 (17.4%) had RTI, compared to 23/136 (16.9%) in the prophylaxis group. There was no significant difference in the numbers of LRTI and URTI, with or without an identified respiratory virus, regardless of the presence or type of antibiotic prophylaxis. Participants receiving prophylaxis did not have a significantly different risk of hospitalization, oxygen supplementation, or ICU admission.Participant Characteristics Comparisons of levofloxacin prophylaxis, other prophylaxis, any prophylaxis, and no prophylaxis ConclusionThere was no observed difference in RTI, hospitalization, oxygen supplementation, or ICU admission for RTI between participants receiving or not receiving antibiotic prophylaxis in this cohort. Because of the relatively low number and severity of respiratory infections, and the high proportion that are viral in etiology, it would likely take a very large sample size to determine the impact of antibacterial prophylaxis on respiratory infections during induction therapy for pediatric ALL.Disclosures Joshua Wolf, MBBS, PhD, FRACP, Karius Inc. (Research Grant or Support) Joshua Wolf, MBBS, PhD, FRACP, Nothing to disclose

Barriers to Care and Outcomes of Pediatric Acute Lymphoblastic Leukemia Treatment in the Gaza Strip.

Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer worldwide. Although children in high-income countries enjoy survival rates of ~90%, children in countries with limited resources suffer from survival rates of <35%. No published data on pediatric cancer incidence, management, or outcomes in the Gaza Strip are available. A retrospective cohort study was undertaken for pediatric (below 12 y of age) ALL diagnoses admitted to the only pediatric cancer ward in the Gaza Strip between 2010 and 2015. Outcomes included event-free survival (EFS) and overall survival (OS) calculated by Kaplan-Meier estimates. Events were defined as induction failure, relapse, and death. The 3-year EFS estimate was 80% (95% confidence interval [CI], 66%-89%). The EFS at 1 and 3 years for high-risk ALL was 55% (95% CI, 27%-76%) and 23% (95% CI, 4%-51%), respectively. The 3-year OS was 93% (95% CI, 82%-97%). The 3-year OS for high-risk ALL was 69% (95% CI, 30%-90%). All 84 (100%) patients required referral to an outside hospital for definitive ALL diagnoses and induction therapy. Forty-four (52%) patients required at least one additional referral. The overall outcomes demonstrated relatively high survival rates at 3 years which may be artificially elevated due to exclusion of adolescents, limited follow up, and deceased patient charts unavailable. Structural determinants of health in Gaza lead to limited diagnostic and treatment capabilities, limited access to advanced medical training, and reliance on out-of-territory transfers for care. These barriers impact the access to comprehensive pediatric care within the Gaza Strip.

Levocarnitine for pegaspargase-induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia.

BackgroundPegaspargase (PEG‐ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG‐ASP‐associated hepatotoxicity.MethodsWe collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity.ResultsFifty‐two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG‐ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event‐free survival.ConclusionsThis real‐world data on levocarnitine supplementation during ALL induction highlights the risk of PEG‐ASP‐associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.

Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository.

Acute lymphoblastic leukemia (ALL) is among the most common cancers in children. With improvements in combination chemotherapy regimens, the overall survival has increased to over 90%. However, the current challenge is to mitigate adverse events resulting from the complex therapy. Several chemotherapies intercept cancer metabolism, but little is known about their collective role in altering host metabolism. We profiled the metabolomic changes in plasma of ALL patients initial- and post- induction therapy. We exploited a biorepository of non-fasted plasma samples derived from the Dana Farber Cancer Institute ALL Consortium; these samples were obtained from 50 ALL patients initial- and post-induction therapy. Plasma metabolites and complex lipids were analyzed by high resolution tandem mass spectrometry and differential mobility tandem mass spectrometry. Data were analyzed using a covariate-adjusted regression model with multiplicity adjustment. Pathway enrichment analysis and co-expression network analysis were performed to identify unique clusters of molecules. More than 1200 metabolites and complex lipids were identified in the total of global metabolomics and lipidomics platforms. Over 20% of those molecules were significantly altered. In the pathway enrichment analysis, lipids, particularly phosphatidylethanolamines (PEs), were identified. Network analysis indicated that the bioactive fatty acids, docosahexaenoic acid (DHA)-containing (22:6) triacylglycerols (TAGs), were decreased in the post-induction therapy. Metabolomic profiling in ALL patients revealed a large number of alterations following induction chemotherapy. In particular, lipid metabolism was substantially altered. The changes in metabolites and complex lipids following induction therapy could provide insight into the adverse events experienced by ALL patients.

Dietary Antioxidant Micronutrient Intake and Toxicity during Remission Induction in Children with Acute Lymphoblastic Leukemia (ALL): Results from Dana-Farber Cancer Institute (DFCI) ALL Consortium Trial 05-001

Introduction: Treatment related toxicities are a major contributor to morbidity during induction therapy in childhood ALL. Our prior study in 103 children with ALL suggested that low intakes of antioxidant micronutrients were associated with toxicity and delays in chemotherapy administration (Am J Clin Nutr 79:1029, 2004). The objective of this study was to examine whether inadequate antioxidant micronutrient dietary intake in children with ALL is associated with episodes of infection or ≥grade 3 mucositis during Remission Induction.Methods: Assessment of dietary intake was collected in patients (pts) ages 1-17.9 years enrolled on the DFCI ALL Consortium Protocol 05-001 from 2005-2011. Institutional review board approval was obtained by each of the 9 participating centers. Grade 3 or higher (NCI CTCAEvs) mucositis, culture positive bacteremia and fungemia, and radiographic invasive fungal disease were prospectively collected. Dietary intake was assessed with the Harvard Service Food Frequency Questionnaire (FFQ) for children ages 1-5 years and the Youth and Adolescent Harvard FFQ for children ages 5-18 years and queried about intake in the past 30 days at the end of induction. Dietary antioxidant intake from food sources ± supplementation was examined by comparing consumption above and below recommended intake for age and sex as per the Dietary Reference Intake (DRI). Micronutrient intake was summarized with descriptive statistics and plotted by the presence/absence of a given toxicity in induction. Categorical and continuous variables were compared between group with the Fisher's exact test and the Wilcoxon rank sum test respectively. Logistic regression was used to model the probability of a given toxicity univariately and with a multivariable adjustment for sex and age.Results: Among 794 eligible pts, 561 (71%) had analyzable FFQs. The sample with dietary surveys responses was marginally younger (p=0.06) and more often classified as initial standard risk (p=0.01) than those with no end of induction survey. DRI recommendations were not met for vitamin C (18%), vitamin E (67%) and zinc (12%); 39% of pts reported zinc overconsumption. 141 (25%) of pts with dietary data had ≥1 bacterial and/or fungal infection, 131 (23%) had ≥1 bacterial infection, and 19 (3%) had ≥1 fungal infection. 24 (4%) pts experienced at least 1 event of ≥grade 3 mucositis. Female sex was associated with overall and bacterial infection (p=0.02) and marginally with mucositis (p=0.06). The proportion of patients with ≥Grade 3 mucositis was marginally higher (p=0.06) for those not meeting the vitamin C recommendation (OR=2.3; 95% CI 1.0-5.5), but was not significant (p=0.10) in a multivariable model. Supplementation was reported by 88 (16%) for zinc, vitamins C, E, and A in combination, 16 (3%) for β-carotene and total carotene, and 87 (15%) for vitamin E alone. Intake levels of vitamins C, E, and A, zinc and total carotenoids from food sources and total (food + supplementation) were compared for pts with and without infection and mucositis (unadjusted for age/sex) (Figure 1). Bacterial infection was associated with low intake from food only of zinc (p=0.02), vitamin A (p=0.01), and vitamin E (p=0.049). Mucositis was associated with the following: low intakes of vitamin C from food (p=0.04), vitamin E from food (p=0.03), total lycopene (p=0.03), total α-carotene (p=0.01), total β-carotene (p=0.007) and from food (p=0.008), total carotene (p=0.005) and carotene from food (p=0.006), and total vitamin A (p=0.01) and vitamin A from food (p=0.004). Females age <10 had higher rates of bacterial infection with low β-carotene (p=0.05) and vitamin A from food (p=0.004). In males age ≥10, low vitamin E from food was observed in those with bacterial infections (p=0.05). Supplementation did not confer an added benefit for most nutrients.Conclusions: Confirming our pilot study, data from a large prospective cohort show that low dietary intakes of antioxidant vitamins, carotenoids and zinc primarily from food sources predict risk for bacterial infection or mucositis during induction therapy for childhood ALL. Dietary supplementation for most vitamins and minerals did not confer an added benefit for prevention of infection or mucositis over levels obtained from food. Our results suggest a possible modifiable dietary intervention to reduce toxicity during induction therapy for ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Are Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL) Receiving Pediatric or Adult ALL Regimens: A Population-Based Statewide Evaluation of the Approach to AYA ALL across Pediatric and Adult Cancer Centers

▪Background:Abundant evidence suggests that AYA with ALL have improved outcomes when treated following pediatric-inspired, as opposed to adult, ALL chemotherapy regimens. Given the complexity of pediatric ALL protocols, it is unclear whether this approach has been universally accepted by medical oncologists treating AYA ALL patients across the population.Methods:The population-based California Cancer Registry (CCR) was used to evaluate socio-demographics, location of ALL induction therapy (adult- vs pediatric-setting), and therapies administered to AYAs (15-39 years) with ALL newly diagnosed and treated in the state of California between 2004-2014. Specific ALL regimens were determined through abstraction of registry treatment text fields. Facility volume was defined as AYA ALL inductions per year and categorized by quartiles (≥7/year highest and <1/year lowest). Chi-square and student t-tests characterized differences by patient demographics, treating facilities, and treatment regimens. Multivariable logistic regression was performed to examine the association of the sociodemographic and clinical factors with receipt of pediatric-inspired ALL regimen at an adult cancer center, adjusted for clustering by induction facility. Results are presented as adjusted odds ratios (OR) and associated 95% confidence intervals (CI).Results:Of 1591 AYAs with ALL, 61% were treated in an adult oncology-setting and 28% were treated in a pediatric-setting. Treatment setting could not be determined in 11% (n=175) of patients who were excluded from additional analyses. 32% of patients were 15-18 years, 39% were 19-29 years, and 29% were 30-39 years. The majority of patients were males (64%), of Hispanic race/ethnicity (64%), and had public (46%) or private (44%) insurance. AYAs who were younger (P<0.001), diagnosed in more recent years (P=0.03), and those with public insurance (P= 0.01) were more likely to receive induction treatment in a pediatric-setting. 59% and 41% of AYAs treated in a pediatric- versus adult-setting, respectively, received induction therapy at an NCI-designated cancer center (P<0.001). Only 5% of AYAs treated in the pediatric-setting received care at low volume (<1 AYA ALL case per year) facilities, whereas 27% of AYAs treated in the adult setting received care at low volume facilities (P<0.001). ALL treatment regimen was evaluable in 1131 (79%) of patients and revealed that amongst AYAs treated in the adult-setting, 22% received pediatric-inspired and 78% received adult ALL regimens over the decade. Although pediatric-inspired regimens were administered more frequently by medical oncologists over-time, 62% of AYAs treated by medical oncologists from 2013-2014 received adult ALL regimens, with Hypercvad used most commonly (70%). Multivariable regression revealed that younger patient age (19-24 vs 35-39 years: OR 2.1, 95% CI 1.4-3.2), treatment at an NCI-designated cancer center (OR 5.3, 95% CI 2.5-11.3), and treatment at higher volume AYA ALL facility (mid quartile versus lowest quartile: OR 2.3, 95% CI 1.0-5.2; highest quartile versus lowest quartile: OR 7.4, 95% CI 2.7-20.4) were significantly associated with receipt of pediatric-inspired ALL regimens by medical oncologists; whereas, year of diagnosis, sex, race/ethnicity, and insurance had no significant association.Conclusions:Our population-level findings demonstrate that AYAs with ALL across the state of California are most commonly treated in adult oncology community settings where the volume of AYA ALL patients seen on a yearly basis is frequently very low. Strikingly, as recently as 2014, AYAs with ALL continue to be treated predominantly with adult ALL regimens. Receipt of pediatric-inspired ALL regimens is significantly more likely if AYAs with ALL receive treatment at NCI-designated cancer centers and/or centers that treat a higher yearly volume of AYA ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Diagnosis and treatment efficacy analysis of 29 children with mixed phenotype acute leukemia

Objective: To analyze the clinical characteristics and prognosis of mixed phenotype acute leukemia (MPAL) in children. Methods: The data of 29 children diagnosed as MPAL in the Pediatric Blood Disease Center, Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences from January 1, 2005 to December 1, 2019 were collected retrospectively. The morphology, immunophenotypes, cytogenetics, molecular biological characteristics, induction chemotherapy regimen, and prognosis were analyzed. Kaplan-Meier Method was used to draw survival curve. Log-Rank was used for univariate analysis. Results: (1) Among 29 MPAL cases, there were 1 case with KMT2A rearrangement, 1 case with BCR-ABL1, 13 cases with B/myeloid(B-M) type, 12 cases with T/myeloid(T-M) type and 2 cases with acute undifferentiated leukemia. (2) The common immunophenotypes were CD33 (23 cases, 79%), CD34 (25 cases, 86%) and HLA-DR (20 cases, 69%), and CD19 was positive in 17 cases (59%). (3) In molecular genetics analysis, 8 cases were detected to have abnormal gene fusion, including 1 case with MLL-AF4 fusion gene, 1 case with BCR-ABL1 fusion gene, 3 cases with TEL-AML1 fusion gene, 2 cases with WT1 and 1 case with FLT3-ITD. (4) In cytogenetics analysis, 27 cases obtained chromosome karyotypes, including 14 cases with abnormal karyotypes and 10 cases were complex karyotypes. (5) In treatment efficacy analysis, 27 cases received induction chemotherapy and the complete remission(CR) rate was 85%（23/27）.The 5-year disease free survival(DFS) rate was (71±10)% and 5-year overall survival(OS) rate was (74±10)%. Thirteen of 14 cases received acute lymphoblastic leukemia（ALL） induction therapy achieved CR, while 10 of 12 cases received hybrid induction therapy achieved CR. No significant difference was found in 5 year-OS rates between cases with ALL induction therapy and hybrid induction therapy ((77±15)% vs. (80±13)%, χ²=0.027，P=0.870). Conclusions: MPAL is a rare childhood leukemia and is prone to incorporate complex karyotypes. Induction therapy with ALL or hybrid regimens is a good choice to obtain favorable prognosis.

3064 – PREDICTIVE VALUE OF MIRNA 181A IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA

<h3>Context</h3> Acute lymphoblastic leukemia (ALL) represents the most common type of pediatric malignant neoplasm. The miRNAs play an important role in the regulation of normal hematopoiesis and their disruption contributes to leukemogenesis and considered novel candidates with diagnostic, predictive and prognostic potential value. Recently, specific miRNAs have been discovered to be involved in the pathogenesis of ALL serving as a biomarker for detection of leukemia at diagnosis and relapse. <h3>Objective</h3> To study the associations between miR181a expression and the outcome after induction so the possibility of using miR-181a expression as a predictive marker for children with ALL. <h3>Methods</h3> This study was carried out in Oncological Clinical Pathology Department, South Egypt Cancer Institute and included 40 newly diagnosed pediatric ALL. MiR-181a expression was assessed at diagnosis and before start of treatment. MiR-181a was extracted from peripheral blood or bone marrow sample by miRNeasy Mini kit, then revers transcription of miRNA to cDNA using TaqMan® MicroRNA Reverse Transcription (RT) Kit, and finally, real-time PCR(q-PCR) using 7500 Fast Real-Time PCR System by TaqMan® Universal Master Mix. Patients have been evaluated for the response after induction therapy clinically, by complete blood picture and bone marrow aspirate examination. <h3>Results</h3> The expression level of miR-181a was significantly higher in remission group than in non-remission group. (P< 0.001). <h3>Conclusions</h3> High expression of miRNA-181a is associated with remission and good outcome after induction therapy in pediatric ALL. So miR-181a could be considered as a predictive marker in pediatric ALL. We recommended further studies to work on the use of miR-181a as a prognostic and predictive non-invasive marker in childhood ALL.

Fluoroquinolone prophylaxis does not increase risk of neuropathy in children with acute lymphoblastic leukemia.

BackgroundFluoroquinolone antibiotics are frequently utilized in pediatric oncology patients as prophylaxis or step‐down therapy following broad spectrum beta‐lactam therapy for febrile neutropenia. Concerns regarding neurotoxicity limit the use of these agents. No studies have evaluated the association between fluoroquinolone use and neurotoxicity in pediatric oncology patients receiving other neurotoxic agents such as vincristine.MethodsAn observational cohort study comprising patients aged 0‐18 at diagnosis enrolled on a prospective study for treatment of acute lymphoblastic leukemia (ALL) at a pediatric comprehensive cancer center between October 2007 and November 2018. Data for neuropathic pain and sensory or motor neuropathy were collected prospectively, and a Cox proportional hazards regression model was used to evaluate associations between administration of fluoroquinolone antibiotics during induction therapy and subsequent development of vincristine‐induced peripheral neurotoxicity (VIPN).ResultsA total of 598 participants were enrolled, including 338 (57%) who received fluoroquinolones during induction therapy; of these 470 (79%) were diagnosed with VIPN and 139 (23%) were diagnosed with high‐grade (Grade 3+) VIPN. On unadjusted analyses, and analyses adjusted for age and race, there was no evidence of an association between fluoroquinolone exposure and subsequent VIPN (hazard ratio [HR] 0.8, 95% CI 0.5‐1.04, P = .08) or high‐grade VIPN (HR 1.1, 95% CI 0.4‐2.2, P = .87).ConclusionsThe results of this observational study do not show an association between exposure to fluoroquinolone antibiotics during induction therapy for ALL and subsequent development of vincristine‐induced peripheral neuropathies, and suggest that a large increase in VIPN is unlikely.

Prevalence and predictors of weight loss during induction therapy for childhood acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma often experience significant weight gain during induction therapy. However, a subgroup of patients may experience weight loss, which can impact outcomes; thus, identifying and understanding this underrecognized concern is important. Our aim was to identify the prevalence and predictors for weight loss during ALL induction therapy. This was a single-institution retrospective study of 187 patients, ages 2 to 20 y, diagnosed with ALL or lymphoblastic lymphoma. We analyzed weight trends during induction therapy and predictors of weight loss. Significant weight loss (≥5%) occurred in 17% of patients. Having high-risk disease, trisomy 21, overweight/obese status at the time of diagnosis, and/or hyperglycemia were positively associated with weight loss and negatively associated with weight gain during induction therapy. Future studies should aim to better understand the etiology and importance of weight loss during induction therapy.

Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study.

The rarity of mixed phenotype acute leukemia (MPAL) has precluded adequate data to incorporate minimal residual disease (MRD) monitoring into therapy. Fluidity in MPAL classification systems further complicates understanding its biology and outcomes; this includes uncertainty surrounding the impact of shifting diagnostic requirements even between iterations of the World Health Organization (WHO) classification. Our primary objective was to address these knowledge gaps. To do so, we analyzed clinicopathologic features, therapy, MRD, and survival in a centrally-reviewed, multi-center cohort of MPAL uniformly diagnosed by the WHO classification and treated with acute lymphoblastic leukemia (ALL) regimens. ALL induction therapy achieved an EOI MRD negative (<0.01%) remission in most patients (70%). EOI MRD positivity was predictive of 5-year EFS (HR=6.00, p<0.001) and OS (HR=9.57, p=0.003). Patients who cleared MRD by EOC had worse survival compared to those EOI MRD negative. In contrast to adults with MPAL, ALL therapy without transplantation was adequate to treat most pediatric patients. Earlier MRD clearance was associated with better treatment success and survival. Prospective trials are now necessary to validate and refine MRD thresholds within the pediatric MPAL population and to identify salvage strategies for those with poor predicted survival.

Effects of chemotherapy agents used to treat pediatric acute lymphoblastic leukemia patients on bone parameters and longitudinal growth of juvenile mice

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Therapies for pediatric ALL have improved such that more than 80% of patients survive to 5 years post-therapy, and most survive to adulthood. These ALL patients experience long-term side effects that permanently affect their quality of life, with bone loss and reduced longitudinal growth being the most common skeletal complications. To determine the effects of the chemotherapeutic agents used in ALL induction therapy on bone density and longitudinal growth in mice, we treated juvenile mice with doxorubicin, dexamethasone, vincristine, l-asparaginase, or combination therapy. At adulthood, mice were culled and bones collected and scanned by micro-computed tomography (micro-CT). Mice that received doxorubicin and combination therapy exhibited reduced longitudinal growth and significant reductions in trabecular bone volume, trabecular thickness, and trabecular number, with increased trabecular separation. Mean cortical thickness, cortical area, marrow area, endocortical perimeter, and polar moment of inertia were significantly reduced by doxorubicin and combination therapy. Vincristine treatment significantly decreased trabecular bone volume, trabecular number, and increased trabecular separation but had no effects on cortical bone. Dexamethasone treatment increased trabecular bone separation, cortical marrow area, and cortical bone periosteal perimeter. Mice treated with l-asparaginase did not have any bone phenotypes. In conclusion, these data indicate that the majority of the chemotherapy agents used in induction therapy for pediatric ALL have long-term effects on bone in mice. A single dose of doxorubicin in juvenile mice was sufficient to cause the majority of the bone phenotypes, with combination therapy intensifying these effects.

Expression Pattern of Long Non-coding RNA Growth Arrest-specific 5 in the Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia.

SummaryBackgroundLong non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing GAS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response.MethodsGAS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology.ResultsOur results have shown interindividual differences in GAS5 expression at all time points. For each ALL patient, GAS5 expression was higher on day 15 in comparison to its level at diagnosis (p<0.0005). On day 33, the level of GAS5 expression decreased in comparison with day 15 (p<0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per μL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009).ConclusionsOur results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.

Bovine Colostrum Against Chemotherapy-Induced Gastrointestinal Toxicity in Children With Acute Lymphoblastic Leukemia: A Randomized, Double-Blind, Placebo-Controlled Trial.

The toxic effect of chemotherapy on the gastrointestinal tract may lead to mucositis and is associated with the pathogenesis of other treatment-related complications. We hypothesized that nutrition supplementation with bovine colostrum, rich in bioactive factors, would ameliorate gastrointestinal toxicity and reduce the incidence of fever and infectious complications during induction treatment for childhood acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were included in a 2-center, randomized, double-blind, placebo-controlled clinical trial. Patients were randomized to receive a daily colostrum or placebo supplement during 4 weeks of induction treatment. Data on fever, bacteremia, need for antibiotics, and mucosal toxicity were prospectively collected. (Trial registration: www.clinicaltrials.gov NCT01766804). Sixty-two patients were included. No differences were found for the primary outcome (number of days with fever). No difference was observed for neutropenic fever, intravenous antibiotics, or incidence of bacteremia. Peak severity of oral mucositis was significantly reduced by colostrum (7/29 patients, 24% mild; 6/29, 21% moderate; 1/29, 3% severe) compared with placebo (12/31, 39% mild; 1/31, 3% moderate; 7/31, 23% severe) (P = 0.02). Among patients receiving at least 1 dose of supplement (colostrum: n = 22; placebo: n = 30), the peak weekly self-reported oral mucositis score was overall significantly less severe in the colostrum group (P = 0.009). The use of prophylactic bovine colostrum showed no effect on fever, infectious morbidity, or inflammatory responses. Nevertheless, these data may suggest protective effects on the oral mucosa during induction therapy in childhood ALL, encouraging additional studies confirming these findings.

No evidence that G6PD deficiency affects the efficacy or safety of daunorubicin in acute lymphoblastic leukemia induction therapy.

Anthracyclines are used in induction therapy of pediatric acute lymphoblastic leukemia (ALL) and are known to generate oxidative stress; whether this translates into enhanced antileukemic activity or hemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency is unknown. Among 726 pediatric patients with newly diagnosed ALL treated at St. Jude Children's Research Hospital, 22 had deficient G6PD activity. We compared the prevalence of positive minimal residual disease (MRD) ≥1% at Day 15/Day 19 of induction or ≥0.01% at Day 42/Day 46 (end of induction) and the number of red blood cell (RBC) transfusions after daunorubicin in induction between patients with or without G6PD deficiency, adjusting for ALL risk group, treatment protocol, age, and gender. There was no difference in Day 15/19 (P=1) or end of induction MRD (P=0.76) nor in the number of RBC transfusions (P=0.73); the lack of association with MRD was confirmed in a dataset of 1192 newly diagnosed male patients enrolled in a Children's Oncology Group trial (P=0.78). We found no evidence that G6PD deficiency affects daunorubicin activity during induction treatment for ALL.