Standard-risk Acute Lymphoblastic Leukemia Research Articles

Outcomes of allogeneic stem cell transplantation in acute leukemias – single centre study

Aim: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended in first complete remission (CR) for adverse and intermediate-risk acute myeloid leukemia (AML) and not recommended for AML patients with favourable disease. Allo-HSCT is standard of care in high-risk acute lymphoblastic leukaemia (ALL) and relapsed ALL but is not indicated for standard-risk ALL. Even though in many studies benefit for survival was proven for these patients, relapse rates (RR) at one year (32.9% for LAM and 34% for LAL) remains problematic. We want to report the outcomes of patients treated for acute leukaemia in our centre. Materials and methods: We conducted a retrospective descriptive analysis of 215 patients with acute leukaemia treated with allo-HSCT between 2017 and 2022 in Fundeni Clinical Institute. Data analysis aimed the overall survival (OS) rate, progression free survival (PFS) and RR at one year based on genetic risk, number of CR, minimal residual disease (MRD) status and conditioning regimen used. Results: At one year evaluation we observed OS rate of 64% and a 34% RR for ALL patients, while AML patients had a 74% OS rate and 13% RR. Conclusions: The results obtained in our centre are similar to the ones reported in literature. The highest risk of relapse and smallest rate of survival are registered for patients who present with negative risk factors. The multifactorial influence over OS and RR impose the need for future studies in which different patient categories can benefit from an optimal therapeutic management.

24 Adaptive Functioning and Academic Achievement in Survivors of Childhood Acute Lymphoblastic Leukemia

Objective:Executive functioning (EF) and socioeconomic status (SES) are associated with functional outcomes (adaptive functioning and academic achievement) in healthy controls and pediatric populations with executive dysfunction. However, these relationships have yet to be investigated in survivors of childhood acute lymphoblastic leukemia (ALL), a population with EF impairment resulting from disease and treatment characteristics. The objective of this study was to examine the associations of functional outcomes with EF and SES (neighborhood-specific variables and academic support) in survivors of childhood ALL.Participants and Methods:Forty-four participants (38.6% female, 72.7% non-Hispanic White, ages 6-17) previously diagnosed with low-risk or standard-risk pre-B cell ALL and treated with chemotherapy-only were included. Participants were evaluated on performance-based measures of EF (cognitive flexibility, verbal fluency, working memory, and processing speed) and academic achievement (word reading and math calculation), and parent-ratings of EF and adaptive functioning. All measures were expressed as T-scores with lower scores indicating better performance. Neighborhood-specific variables were based on participants’ zip codes and census block group, and included area deprivation index (ADI) and child opportunity index (COI). Lower ADI and COI indicate lesser deprivation and greater opportunity. Individualized education plan (IEP) status was used as a proxy of academic support, coded dichotomously as with or without IEP. Percentages of participants showing impairments in functional outcomes were calculated using a cutoff of > 1 SD above the normative mean. Partial correlations were conducted while controlling for age at evaluation, age at diagnosis, sex, and verbal IQ, to examine whether participants with poorer performance-based and parent-rated EF would show reduced functional outcomes. Multiple regression analyses were conducted to evaluate whether neighborhood-specific variables and IEP status would predict functional outcomes while controlling for covariates.Results:Compared to population norms, survivors of childhood ALL showed worse functional outcomes. Within adaptive functioning, 45.5% of participants showed impairment in activities of daily living and leadership. Adaptive functioning was significantly positively correlated with parent-rated, but not performance-based, EF (r=0.694, p<0.001). Compared to female survivors, male survivors were at increased risk for adaptive functioning difficulties (r=-0.401, p<0.05). Impairments for word reading and math calculation were 25% and 41.7%, respectively. Greater math calculation was associated with better verbal fluency (r=0.378, p<0.05) and processing speed (r=0.439, p<0.05). Older participants at evaluation (/3=-0.580, p<0.001) and those without IEP support (ß=0.465, p<0.05) showed better word reading. Lower ADI predicted better verbal fluency (ß=0.282, p=0.041), however, neighborhood-specific variables were not associated with functional outcomes.Conclusions:Prior findings indicate that performance-based measures and parent-ratings assess different constructs of EF. Thus, adaptive functioning may relate more to the behavioral construct of EF than its cognitive construct. Current findings also suggest that male survivors are at increased risk for reduced adaptive functioning, consistent with recent reports that male survivors of ALL are at greater risk for specific neurocognitive outcomes. Overall, functional outcomes may be more strongly related to EF than neighborhood-specific variables. Long-term goals include early screening of adaptive and academic difficulties, targeted intervention, and neuropsychological monitoring to support pediatric survivors’ neurocognitive and psychosocial development.

Health-related quality of life and its determinants during and after treatment for paediatric acute lymphoblastic leukaemia: a national, prospective, longitudinal study in the Netherlands

ObjectivesHealth-related quality of life (HRQoL) is impaired in paediatric patients with acute lymphoblastic leukaemia (ALL). Over the past decades, ALL treatment has successfully been adjusted to the risk of relapse,...

Genomic determinants of outcome in acute lymphoblastic leukemia: A Children’s Oncology Group study.

10015 Background: While cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, half of relapses arise in those originally classified with standard risk (SR) disease. Methods: We performed genome/transcriptome sequencing of diagnostic and germline samples of children with SR (n=1381) B-ALL or high-risk (HR) B-ALL with favorable cytogenetics ( ETV6: RUNX1 or double trisomy (DT) of chromosomes (chr) 4+10; n=115) to identify predictors of relapse. We used a case-control study to analyze 439 patients who relapsed and 1057 who remained in complete remission for > 5 years. Results: Genomic subtype was associated with relapse. Unbalanced ETV6:RUNX1 translocations were more common than balanced in relapse patients (OR=2.01, CI=1.25-3.20, P=0.002). Conversely, balanced TCF3:PBX1 translocations were more often associated with relapse than unbalanced in TCF3:PBX1 ALL (OR=0.11, CI=0.01-0.50, P=0.003). A striking finding was the high relapse rate in PAX5 altered ALL (57 of 116 cases (49%); OR=3.29, CI=2.16-5.01, P=3.49x10-8). The nature of the heterogeneous PAX5 driver alterations of this subtype influenced relapse risk, with internal PAX5 amplifications and biallelic PAX5 alterations associated with the highest risk. Specific chr gains influenced outcome in hyperdiploid ALL, with gain of chr 10 and disomy of chr 7 associated with favorable outcome (OR=0.27, CI=0.17-0.42, P=8.02x10-10, St Jude Children’s Research Hospital (SJCRH) validation cohort: OR=0.22, CI=0.05-0.80, P=0.009), while disomy of chr 10 and 17 and gain of chr 6 were enriched in patients that relapsed (OR=7.16, CI=2.63-21.51, P=2.19x10-5; SJCRH cohort: OR=21.32, CI=3.62-119.30, P=0.0004). Genomic alterations were also associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6:RUNX1, IKZF1 and CREBBP in hyperdiploid, and FHIT in Ph-like ALL. Conclusions: Genetic subtype, aneuploidy patterns, and secondary genomic alterations influence risk of relapse in children otherwise classified with SR ALL, or HR ALL with favorable genetics. Comprehensive genomic analysis is required for optimal risk stratification and treatment allocation, and particularly to study reduction of therapy in the lowest risk patients. [Table: see text]

Childhood Leukemia Survival in the US-Mexico Border: Building Sustainable Leukemia Care Using Health Systems Strengthening Models.

Pediatric leukemia outcomes are poor in most low- and middle-income countries (LMICs) and exacerbated by health care systems ill equipped to manage cancer. Effective leukemia management in LMICs involves curating epidemiologic data; providing health care workforce specialty training; developing evidence-based treatments and supportive care programs; safeguarding access to medications and equipment; providing patient and family psychosocial, financial, and nutritional support; partnering with nongovernmental organizations, and ensuring treatment adherence. In 2013, through a partnership between North-American and Mexican institutions, we used the WHO Framework for Action, a health systems strengthening model to implement a leukemia care sustainable program aimed at improving acute lymphoblastic leukemia (ALL) outcomes at a public hospital in Mexico. We prospectively assessed clinical features, risk classification, and survival outcomes in children with ALL at Hospital General-Tijuana from 2008 to 2012 (preimplementation) and from 2013 to 2017 (postimplementation). We also evaluated program sustainability indicators. Our approach led to a fully-staffed leukemia service, sustainable training programs, evidence-based and data-driven projects to improve clinical outcomes, and funding for medications, supplies, and personnel through local partnerships. Preimplementation and postimplementation 5-year overall survival for the entire cohort of children with ALL, children with standard-risk ALL, and children with high-risk ALL improved from 59% to 65% (P = .023), 73% to 100% (P < .001), and 48% to 55% (P = .031), respectively. All sustainability indicators improved between 2013 and 2017. Using the health systems strengthening WHO Framework for Action model, we improved leukemia care and survival in a public hospital in Mexico across the US-Mexico border. We provide a model for the development of similar programs in LMICs to sustainably improve leukemia and other cancer outcomes.

Childhood leukemia survival in the US-Mexico border: Building sustainable leukemia care using health systems strengthening models.

1502 Background: Pediatric leukemia outcomes are poor in most low-and middle-income countries (LMIC) and exacerbated by healthcare systems ill-equipped to manage cancer. Effective leukemia management in LMIC involves curating epidemiologic data; providing healthcare workforce specialty training; developing evidence-based treatments and supportive care; safeguarding access to medications and equipment; providing patient and family psychosocial and financial support; partnering with non-governmental organizations, and ensuring treatment adherence. Methods: We describe the implementation of a collaborative program to achieve sustainable high-quality care for children with leukemia in a unique border health setting. In 2013, in a partnership between North-American and Mexican institutions, we used the health systems strengthening model developed by the World Health Organization (WHO) Framework for Action with domains in Services delivery, Workforce, Information systems, Access to essential medicines, Financing, and Leadership and Governance to implement a sustainable program aimed at improving acute lymphoblastic leukemia (ALL) outcomes at a public, referral hospital in the US-Mexico border region. We evaluated program sustainability indicators, and prospectively assessed clinical features, risk classification, and survival outcomes in children with ALL at Hospital General in Tijuana, Mexico from 2008-2012 (pre-implementation) and from 2013-2017 (post-implementation). Results: Our approach led to a fully-staffed leukemia service, sustainable training programs, evidence-based, data-driven projects to improve clinical outcomes, and funding for medications, supplies and personnel through local partnerships. Pre-implementation and post-implementation 5-year overall survival for children with standard-risk and high-risk ALL improved from 52% to 82% (P = 0 ×023) and from 46% to 76% ( P = 0 ×031), respectively. All sustainability indicators significantly improved between 2013 and 2017. Conclusions: By using a health systems strengthening approach, we improved leukemia care and survival in a public Mexican hospital in the US-Mexico border region. The demonstrated increase in overall survival across a decade after the implementation of our program validates the use of the health systems strengthening models, as they are not only efficacious in improving clinical outcomes, but also serve as financially and organizationally means of building sustainable capacity. Our model serves as an example for future international partnerships aimed at sustainably improving cancer outcomes in LMIC. Future research should evaluate best practices in establishing global health collaborations with particular attention paid towards the individual circumstances that impact healthcare delivery locally in each unique community.

ALL-REZ BFM 2002 Is Associated with Improved Outcome as Compared to ALL-R3 Strategy in Children with Standard Risk Isolated CNS Relapse of Acute Lymphoblastic Leukemia, while Maintaining Comparable Efficacy in Patients with Bone Marrow Relapse. Results of the Multi-National, Multi-Center Trial IntReALL SR 2010

Background: Around 15% of children with acute lymphoblastic leukemia (ALL) experience disease relapse. The prognosis of these patients largely depends on the site of recurrence, time to relapse and leukemia immunophenotype. The ALL-REZ BFM 2002 and the ALL R3 trials have proved to be effective in previous trials. The IntReALL SR 2010 trial, conducted under the umbrella of the I-BFM SG, aimed at investigating feasibility, toxicity and efficacy of both treatment strategies in a large multi-national, multi-center prospective randomized trial. Methods: Patients with a first standard-risk (SR) ALL relapse aged 1 - 17 years were recruited to the trial from 23/Oct/2014 to 31/Jul/2020 in 17 countries (210 centers). SR relapse criteria were: late (≥ 6 months after end of initial therapy) isolated bone marrow (BM) relapse, late or early (< 6 months after end of initial therapy and ≥ 18 months after initial diagnosis) combined BCP-ALL BM relapse, any late/early isolated extramedullary (IEM) relapse. They were randomized at a 1:1 rate to receive either arm A (ALL-REZ BFM 2002) or B (ALL R3). During consolidation, patients were randomized to receive the CD22-directed monoclonal antibody epratuzumab in addition to backbone chemotherapy. Results of this 2nd randomization will be communicated separately. Patients with late BM relapse were allocated to consolidation and maintenance chemotherapy or to allogeneic hematopoietic stem-cell transplantation (HSCT), depending on their minimal residual disease (MRD, cut-off arm A 10e-3 and arm B 10e-4) assessed after induction therapy. Patients with early either combined BM or IEM relapse were allocated to receive allogeneic HSCT. Results: Overall, 620 patients were randomized to receive arm A (n=304) or Arm B (n=316). Patient's characteristics were equally distributed among both groups (table 1). Induction death, 2nd remission rate, death in remission (5-years cumulative incidence (CI) 4.1 vs 7.4%, p=0.10), and subsequent relapse rates by arm A and B (CI 23.8 vs 22.8, p=0.80) did not differ between both groups. The MRD response rate with < 10e-4 post induction was significantly higher in Arm B (p=0.015), but not significantly different based on the arm specific cut-off, leading to comparable rates of allogeneic HSCT. The probability of 5-years event-free survival (pEFS) with arm A versus arm B was 70.2±3.1 SE versus 68.5±3.1 (p=0.61, figure 1) and that of overall survival (pOS) was 86.7±2.3 versus 87.1±2.0 (p=0.8). Subgroup analyses revealed a significantly higher pEFS in patients with isolated CNS relapse when treated with arm A (81.6±6.3, n=40) compared to arm B (43.3±8.3, n=45, p=0.001), whereas in patients with BM involvement or those with non-CNS IEM relapse, no significant difference was found (p=0.41). However, patients with isolated BM relapse experienced a higher CI of subsequent relapse with arm A (12.5±2.1, n=146) as compared to arm B (6.5±1.6, n=153, p=0.008). Patients with late BM relapse and MRD poor response after induction had comparable pDFS (arm A 65.8±6.4, n=74; arm B 68.8±6.2, n=75; p=0.71), which also did not differ from that of patients with MRD good response (arm A 67.7±5.6, n=100; arm B 68.9±5.6, n=113; p=0.77). Patients with late IEM relapse achieved a pEFS of 86.7±4.6 whereas those with early relapse and HSCT indication achieved a pEFS 61.8±5.4 (p=0.0004). Rates of reported severe adverse events (SAEs) per treatment phase did not differ between arms except nervous system disorders occurring more frequently in arm A (p=0.03, table 1). Conclusion: Both arm A and B were effective in this large multi-national trial. EFS and OS probabilities compare favorably to results recently published by other cooperative groups. In particular, the outcome of patients with early IEM relapse or with late BM relapse and MRD poor response is encouraging confirming the benefit of allo HSCT in these subgroups. Due to superior outcome of isolated CNS relapse with arm A, patients without BM involvement will receive that arm as backbone in future trials. Since arm B showed a better MRD response rate after induction and a lower relapse rate in patients with BM relapse, it will be implemented as backbone for future trials in patients with BM involvement. Toxicity (TRM and SAE rates) is substantial in both arms demonstrating the urgent medical need of replacing toxic chemotherapy elements with equally effective, but less toxic targeted immunotherapy strategies in future trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The impact of early PEG-asparaginase discontinuation in young adults with ALL: a post hoc analysis of the CALGB 10403 study

AbstractAsparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, a similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup Cancer and Leukemia Group B (CALGB) 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as <4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range, 1-6), with 57 (32%) patients with ED. The ED patients were older (median, 26 vs 23 years; P = .023). Survival was apparently lower for ED patients compared with those receiving ≥4 doses, but this finding was not statistically significant (hazard ratio [HR], 1.82; 95% confidence interval [CI], 0.97-3.43; P = .06), with corresponding 5-year overall survival (OS) rates of 66% and 80%, respectively. In patients with standard-risk ALL, the ED of PEG-asparaginase adversely influenced OS (HR, 2.3; 95% CI, 1.02-5.22; P = .04) with a trend toward inferior event-free survival (EFS) (HR, 1.84; 95% CI, 0.92-3.67; P = .08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P = .64) or EFS (P = .32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, and/or high white blood cell count at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL.

Evaluation of Interleukin-6 Level Before Chemotherapy in Acute Lymphoblastic Leukemia L1 Standard-Risk and High-risk Patients

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignancy originating from the clonal expansion of lymphoid progenitors that have undergone neoplastic transformation at various stages of differentiation. Interleukin-6 (IL-6) is a pleiotropic inflammatory cytokine produced by various cell types, including T-cells, macrophages, and stromal cells in response to tumor necrosis factor-alpha and interleukin-1. AIM: This study aims to evaluate serum levels of IL-6 before chemotherapy in standard-risk (SR) and high-risk (HR) ALL patients. METHODS: The research method was a cross-sectional study conducted on ALL patients who were treated at Dr. Wahidin Sudirohusodo hospital from April 2021 to June 2021. A total of 60 ALL patients were included in the study. Serum IL-6 specimens were examined before the patient received chemotherapy. RESULTS: The results showed that from 60 samples of ALL patients, 30 were SR and 30 were HR. Elevated levels of IL-6 before chemotherapy were found in both SR and HR ALL but were significantly higher in the HR group compared to the SR group with p value = 0.022. The cutoff point of 64.23 ng/mL for HRALL patients was obtained through ROC with a sensitivity of 63.3%, specificity of 63.3%, a positive predictive value of 63.3%, and a negative predictive value of 63.3%. Adjusted odds ratio are 2,983 with 95% confidence interval of 1.044–8.527. CONCLUSION: IL-6 levels among HR ALL were higher than SR. Elevated levels of IL-6 were found in both SR and HR ALL.

Thrombosis Prophylaxis with Apixaban in Patients Treated with Asparaginase

Thrombosis Prophylaxis with Apixaban in Patients Treated with Asparaginase

Bone health in long-term survivors of pediatric acute lymphoblastic leukemia. An assessment by peripheral quantitative computed tomography.

Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may be encountered long into survivorship. Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. A sample of 74 subjects, ages 13.5-38.3years more than 10years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density, and architecture. Average values in multiple metrics were similar to those in healthy individuals, but deficits in both trabecular and cortical bones were revealed by lower Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard-risk ALL had greater connectivity in and more compact trabecular bone than high-risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation, or use of a bisphosphonate. These long-term survivors of ALL have somewhat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.

Results of the Full Pediatric, Minimal Residual Disease (MRD)-Oriented Trial LAL-RI/2008 for Adolescents and Young Adults (AYA) with Standard Risk (SR), Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL)

Background and objective. Full pediatric or pediatric-derived trials constitute the treatment of choice for AYA with SR-ALL. In the MRD era, patients (pts) with SR factors at baseline with poor MRD clearance should be considered as HR patients. The objectives of the full pediatric LAL-RI/2008 trial (NCT02036489) from the Spanish PETHEMA group were to assess the proportion of AYA with SR-ALL at baseline who have HR features based on poor early cytological response and/or poor MRD clearance, and to compare their prognosis with that from those pts who achieve good early cytological response and good MRD clearance.Patients and methods. SR ALL was defined in adolescents (age 15 to 18 years) and young adults (age 19 to 29 years) fulfilling all the following criteria: WBC count ≤30 × 109/L, and absence of t(9;22), t(1;19), t(4;11) or any other 11q23 rearrangements. Induction therapy included vincristine (VCR), prednisone (PDN), daunorubicin (DNR) and native E. coli asparaginase (ASP) for 4 weeks. Pts who achieved complete remission (CR) and MRD<0.1% proceeded to consolidation-1 (high-dose methotrexate [MTX], intermediate-dose ARA-C, etoposide and mercaptopurine [MP]), consolidation-2/reinduction (VCR, dexamethasone, DNR, cyclophosphamide and ASP), maintenance-1 (MP and MTX with monthly reinductions with VCR, PDN and ASP until the end of the 1st year) and maintenance-2 (MP and MTX without reinductions until the end of the 2nd year). CNS prophylaxis consisted of triple intrathecal therapy (MTX, ARA-C and hydrocortisone, 16 doses throughout the treatment). Pts with poor early cytological response (BM blast cells >10% on day 14 of induction), MRD level >0.1% (assessed by flow cytometry) at CR or MRD level >0.05% at any time after CR were considered as high risk (HR) pts and received the ALL-HR trial consisting of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) (Ribera JM et al. J Clin Oncol 2014; 32:1595-604).Results. Between 2008 and 2017, 79 eligible pts were treated according to the ALL-RI-08 protocol. Median age (range) was 20 years (15-29), 34 (43%) were adolescents and 45 (57%) YA. The mean (SD) WBC count was 10 (9) x109/L, and 73 patients (94%) had B-cell precursor ALL. Two patients are on treatment and 74 out of the remaining 77 (96%) achieved the CR. From the 77 pts, 15 had poor early cytological response, 3 had MRD >0.1% at the time of CR and 1 pt showed reappearance of MRD level >0.05% during maintenance. In all, 19 patients were considered as HR. Of the 58 patients who remained SR and followed the LAL-RI/2008 protocol, 14 relapsed (7 during treatment and 7 off therapy), whereas in the HR group, 3 were resistant, 4 relapsed and 2 died by toxicity (transplant-related in 1 out of 4 pts submitted to alloHSCT). Table 1 shows the DFS, OS and cumulative incidence of relapse (CIR) at 5-yrs for the whole series, the patients remaining SR and those who turned HR. Of note, OS was lower in the HR pts (Figure 1). On comparison with the results of the ALL-RI-96 trial (same inclusion criteria, same treatment but no follow-up by MRD, Ribera JM et al. J Clin Oncol 2008; 26:1843-9), no differences were observed in DFS, OS and CIR (Table 1).ConclusionsTwenty-five percent of AYA pts with SR ALL at baseline are in fact HR based on slow early cytological response to therapy and/or poor MRD clearance. High-risk pts showed lower OS despite being moved to a HR protocol.Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain. [Display omitted] DisclosuresRibera:Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; ARIAD: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Amgen Inc.: Research Funding, Speakers Bureau. Montesinos:Celgene Corporation: Honoraria, Research Funding.

High Serum Level of Interleukin-15 Predicts Poor Prognosis in Adult Standard-Risk Acute Lymphoblastic Leukaemia

BackgroundInterleukin-15 (IL-15) is a proinflammatory cytokine involved in the proliferation, survival and activation of acute lymphoblastic leukaemia (ALL). However, the prognostic significance of serum IL-15 level in adult patients with standard-risk ALL has not been well established.MethodsSerum IL-15 level was measured using enzyme-linked immunosorbent assay in 130 adult patients diagnosed with standard-risk ALL.ResultsThe optimal cut-off value for IL-15 in predicting patient survival is 4.82 pg/mL, with an area under the curve value of 0.808 (P < 0.001). The early complete response (CR) on day 14 in in low IL-15 group is 65.3%, which is significantly higher than that in high IL-15 group (39.7%, P= 0.003). Patients in the low IL-15 group exhibited significantly higher survival rate compared with those in the high IL-15 group [5-year event-free survival (EFS) rate: 62.2% vs. 23.3%, P < 0.001; 5-year overall survival (OS) rate: 64.1% vs. 27.7 %, P= 0.001]. Multivariate analysis revealed that serum IL-15 level > 4.82 pg/mL, late CR and older age are adverse factors for EFS and OS.ConclusionsSerum IL-15 level at diagnosis is a novel, effective predictor of prognosis in adults with standard-risk ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Upregulated Cholesterol Biosynthesis Is a Biomarker for Isolated Central Nervous System Relapse in Acute Lymphoblastic Leukaemia

Background:Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer. In early trials CNS relapse was a common occurrence, and the introduction of CNS-directed therapy in the 1960s-70s resulted in the largest single improvement in outcome for childhood ALL. Today, despite universal intensive CNS-directed therapy - with significant associated toxicity - the CNS is involved in around 50% of ALL relapses, with 50% of these being isolated CNS (iCNS) relapse. Whilst many factors appear to increase risk of CNS relapse, few are specific for CNS relapse. Discovery of biomarkers for CNS relapse would allow increased therapy for children at high risk, and potentially less CNS-directed therapy for those at low risk.Despite the clinical significance of CNS infiltration, relatively little is known about the biological differences between systemic and CNS ALL. In the CNS, leukaemic cells form plaques adherent to the leptomeninges, bathed in low-nutrient, low-oxygen CSF. It was hypothesised that leukaemic cells adapt metabolically to this nutritionally poor CNS microenvironment, and these adaptations may be targetable as specific biomarkers for CNS relapse.Findings:Human precursor-B ALL cell lines (SEM (t(4;11) and REH (t(12;21)) were purified from the CNS and spleen after xenotransplantation into immunodeficient (NSG) mice, and transcriptomic analysis was carried out using RNASeq. Gene Set Enrichment Analysis (GSEA), showed upregulation of the cholesterol biosynthesis pathway in the CNS compared with systemic ALL (adj. p<0.0001). This finding was confirmed in publicly available microarray data of human ALL cells retrieved from CNS and bone marrow samples (GEO dataset GSE60926; p=006). To further validate this finding, metabolic analysis of xenografted SEM cells was performed using HPLC-mass spectrometry, showing an increase in intracellular abundance of cholesterol-precursor mevalonate (p=0.003) in SEM cells in the CNS compared with spleen.To confirm lack of cholesterol as a key metabolic challenge for ALL cells in the CNS, total cholesterol was quantified in CSF and plasma from normal human controls and NSG mice, with and without leukaemia. To investigate the effect of leukaemia on CSF cholesterol abundance in humans, CSF from patients at diagnosis (i.e. with untreated ALL) and during maintenance therapy was analysed. In control samples from humans, there was approximately 1000-fold lower total cholesterol in CSF compared to plasma (in murine CSF there was approx. 500-fold lower cholesterol). In addition, plasma cholesterol was around 33% lower in mice xenografted with SEM cells (p=0.02), with a trend towards a similar reduction in CSF cholesterol (p=0.08). In humans there was an approx. 2-fold increase in CSF cholesterol between samples taken at diagnosis compared with samples taken during maintenance chemotherapy (i.e. CSF cholesterol was lower in children with untreated ALL, p=0.03).Having shown upregulated cholesterol biosynthesis to be an adaptation to the CNS microenvironment, the utility of finding this signature in the bone marrow of children at diagnosis as a biomarker of CNS relapse was assessed. Publicly available data from GEO dataset GSE11877/NCI TARGET program was analysed for association between upregulated cholesterol biosynthesis and CNS relapse. Upregulation of 2 or more genes in the cholesterol biosynthetic pathway, determined using a z-score approach, (n=44 upregulated, n=163 not upregulated) was associated with a 3-fold increased risk of isolated CNS but not bone marrow relapse (28.5% absolute risk of iCNS relapse compared with 9.5% after 14 years follow up, p=0.0007). This increase in CNS relapse risk remained after multivariate analysis. Early validation using data from the NOPHO ALL2008 trial of all risk groups (n=163) showed that both children with iCNS relapse had upregulation of cholesterol synthesis by these criteria. Further validation in additional independent cohorts is ongoing.Conclusions:These findings suggest that cholesterol biosynthesis is a key metabolic pathway for childhood ALL cells infiltrating the CNS. This is in keeping with very low levels of cholesterol detected in the CSF, particularly in the presence of leukaemia. Upregulated cholesterol synthesis genes in diagnostic bone marrow are associated with increased risk of CNS relapse in high risk ALL, with supporting evidence of a similar association in standard-risk ALL. DisclosuresHalsey:Jazz Pharmaceuticals: Consultancy, Other: Support to attend educational meetings.

Practice Patterns of Allogeneic Hematopoietic Cell Transplantation (HCT) for Adults with Acute Lymphoblastic Leukemia (ALL)

Introduction:HCT is a valuable therapeutic modality in ALL. Though controversial in standard-risk ALL, particularly those who are treated with pediatric chemotherapy regimen, HCT is still considered to be the standard of care in high-risk patients such as Philadelphia chromosome positive ALL. Variations exist in the utilization of HCT across the centers. In this context, we sought to evaluate practice patterns of HCT in ALL patients using a large national database.Methods:We utilized the National Cancer Database (NCDB) Participant User File to extract patient-level data of adult patients (aged 18-80 years) diagnosed with ALL between 2003-2012. Patients with unknown HCT or chemotherapy status and those who did not receive chemotherapy were excluded. Only patients treated in the reporting facility were included. Data abstracted include age, sex, race, income, insurance, educational status, and HCT. Specific chemotherapy regimen, molecular data and data regarding minimal residual disease were not available in NCDB. Multivariate logistic regression analysis was performed to determine variables associated with the use of HCT.Results:Of 11,871 patients included in the study, 1502 patients (12.7%) received HCT. Patients who did versus did not receive HCT were more likely to be younger (median age 42 vs. 47 years; p <0.001), female (p<0.01), Caucasian (p<0.0001), treated at an academic facility (p <0.001), have higher educational status (p=0.001), higher income status (p <0.001), private insurance (p<0.0001) and lower Charlson comorbidity scores (p=0.001). In a multivariate analysis, age >60 years, male sex, higher Charlson comorbidity score, treatment at a non-academic center, poor educational status and Medicare/Medicaid insurance or uninsured status were associated with a significantly lower likelihood of receiving HCT (Table 1). Race and income status did not influence receipt of HCT.Conclusion:Our large study demonstrates variations in the HCT practices in ALL patients based on biological and non-biological factors. While a lower use of HCT in older patients or those with higher comorbidities is expected, variations based on facility type, insurance, educational status, and to some extent, gender may indicate a possibility of health care disparity based on socioeconomic and health system factors. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Peg-Asparaginase Administration on Day 3 of Remission Induction Accelerates MRD Response in Children with B-Cell Precursor Acute Lymphoblastic Leukemia

To improve the outcome of children with standard and intermediate risk acute lymphoblastic leukemia (ALL) by the addition of PEG-asparaginase (PEG) on day 3 of remission induction was one of the key aims of trial ALL MB-2008 (J. Roumjantseva et al, Pediatriya, 2009). Therapy was designed based on previous MB-group studies (A. Karachunsky et al, Leukemia, 2008). Aim of the present study was to evaluate the influence of day 3 PEG on the end-induction MRD-status which is one of the significant predictors of outcome in children with B-cell precursor ALL (BCP-ALL).Patients and methods. In total, 474 patients (242 boys and 232 girls aged 1 to 17 years (median 5 years 8 months) were studied. Inclusion criteria were: BCP-ALL, treatment according to protocol ALL MB-2008, compliance with standard risk group (SRG, n=266) and intermediate risk group (ImRG, n=208) criteria according to the protocol stratification system, and availability of end-induction (day 36) bone marrow (BM) samples. Remission induction of ALL MB-2008 consisted of oral dexamethasone (6mg/m2 daily), 5 injections of vincristine (1,5 mg/m2), 0-2 injections of daunorubicin (DNR, 45 mg/m2) and 6 triple intrathecal injections. Patients were randomized in respect to PEG administration on day 3. SRG patients were divided into three groups (PEG+DNR+, PEG+DNR- and PEG-DNR+); ImRG patients were split into two (PEG+DNR+ and PEG-DNR+). MRD detection was performed by multicolor flow cytometry (MFC) in three reference laboratories. Samples with a tumor cell level above 0.01% were considered MRD-positive. Outcome parameters were event-free survival (EFS) and cumulative incidence of relapse (CIR). Median of follow up was 5 years.Results. Outcome in 474 study group patients was not significantly different from outcome of 2310 children with BCP-ALL enrolled in SRG and ImRG of ALL MB-2008 trial in whom MRD was not studied: EFS was 0.86±0.02 and 0.84±0.01, respectively, p=0.14, and CIR was 0.12±0.02 and 0.09±0.01, p=0.38.MFC MRD data obtained at day 36 had a significant impact on prognosis in SRG patients. EFS as well as CIR were worse for patients with MRD >0.1% (n=26; EFS 0.47±0.15, CIR 0.49±0.17) compared with 248 patients with low/negative MRD (EFS 0.94±0.2, CIR 0.05±0.02, p<0.001). Nevertheless, the distribution of MRD levels was completely different dependent on randomization arms: in arm PEG-DNR+ (n=92) 18.5% of patients belonged to the group with unfavorable MRD compared with only 6.2% in arm PEG+DNR- (n=80, p=0.017) and 4.3% in arm PEG+DNR+ (n=94, p=0.002). Interestingly, in two PEG+ arms the number of patients with high MRD was not significantly different (p=0.558). Despite the lower proportion of high MRD levels in PEG+ arms MRD maintained its prognostic significance also in these patients. EFS was 0.65±0.16 and CIR 0.35±0.18 in 9 children with MRD ≥0.1 compared with EFS 0.94±0.02 and CIR 0.05±0.02 in 165 patients of the low MRD group (p<0.001 for both EFS and CIR).In ImRG, MFC MRD data disclosed a prognostic value, as well. EFS was 0.92±0.03 and CIR 0.06±0.02 for 143 patients with MRD-negativity on day 36; in contrast, outcome of 78 MRD-positive patients was significantly inferior (EFS 0.73±0.06, CIR 0.25±0.06, p<0.001 for both comparisons). Like in SRG, in ImRG the distribution of MRD levels was different between two randomization arms. In PEG-DNR+ group (n=93) only 54.8% of patients were MRD-negative at the end of remission induction. In contrast, in PEG+DNR+ group (n=115) the proportion of patients with favorable MRD results was significantly higher (76.5%, p=0.001). Again even with low number of MRD-positive cases in PEG+ arm, day 36 MRD disclosed a significant influence on outcome: In 88 MRD-negative patients EFS was 0.93±0.03 and CIR 0.05+0.03, significantly better than in 27 MRD-positive patients (EFS 0.80+0.08 and CIR 0.17+0.08, p=0.025 and p=0.019, respectively).Conclusions. Administration of PEG at day 3 of remission induction leads to a more rapid MRD response in children both with standard-risk and intermediate-risk BCP-ALL. In SRG, rapidity of MRD clearance in PEG+ arms was independent of the additional administration of daunorubicin. We conclude that end-induction MRD data are independent predictors of outcome despite the small proportion of MRD-positive patients after the implementation PEG during induction. DisclosuresNo relevant conflicts of interest to declare.

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.

Cerebral Thromboses during Treatment of Childhood Acute Lymphoblastic Leukaemia.

Thromboembolic events are currently among the most serious complications occurring during treatment of acute lymphoblastic leukaemia (ALL), and account for cases of morbidity and even mortality. The role of L-Asparaginase, particularly that of E. coli L-Asparaginase (L-ASPA) in association or not with corticotherapy has been demonstrated by several authors. Most of the time, these thromboses are located within the central nervous system. Our retrospective study was carried out from December 2000 to December 2004 within 18 French centres. 902 children were prospectively included in the FRALLE 2000 protocol and were assigned to two risk groups: the A group with standard risk ALL (n=502) received dexamethasone during induction and 9 infusions of 6000 U/m2 of L-ASPA, while the B group with high risk ALL (n=400) was to receive prednisone. Both groups received a delayed intensification with dex and L-ASPA. 27 thrombotic events were reported, 16 of which were cerebrovascular accidents. The thromboses lay in the superior sagittal sinus (n=14), in the lateral sinus (n=7) and in the sinus rectus (n=2) and were revealed by convulsions in 30,7% of the cases and by diffuse neurologic signs in 68,7% of the cases. The course turned out positively 15 times out of 16, but one child died of haemorrhage. Hereditary thrombophilic factors were evaluable in 15 patients out of 16. We found out a congenital Protein C deficiency in one patient, but no Protein S or anti-thrombin deficiencies. We found out two Factor V G1691A heterozygous mutations and two Factor II G20210A heterozygous mutations. Five patients out of 14 have a MTHFR C677T mutation: one is homozygous in combination with a Factor V G1691A mutation, and 4 are heterozygous, isolated in two cases, in combination with a Factor V G1691A mutation in one case, and in combination with a Factor II G20210A in the other. Hereditary thrombophilic factors (isolated heterozygous MTHFR C677T mutations excepted) were thus reported in 31,2% (n = 5) of the cases.Conclusion: even if the frequency of thrombophilia may be underestimated in this study due to its retrospective design and non exhaustivity (APL antibodies, lipoprotein A were not investigated), it nevertheless points out CNS thrombosis represents an important cause of morbidity in childhood ALL treated with high dose steroid and L-ASPA. A prospective analysis of all thrombophilic factors seems justified in this setting for prevention possibly based on LMWH.

Resolving driver events in MLL-r negative high-risk infant ALL.

10030 Background: Infant acute lymphoblastic leukemia (ALL) is the only subtype of childhood ALL whose outcome has not improved over the past two decades. The most important prognosticator is the presence of rearrangements in the Mixed Lineage Leukemia gene (MLL-r), however, many patients present with high-risk clinical features but without MLL-r. We recently identified two cases of infant ALL with high-risk clinical features resembling MLL-r, but were negative for MLL-r by conventional diagnostics. RNA sequencing revealed a partial tandem duplication in MLL (MLL-PTD). We thus aimed to determine if MLL-PTD, other MLL abnormalities, or other genetic or transcriptomic features were driving this subset of high-risk infant ALL without MLL-r. Methods: We obtained 19 banked patient samples from the Children’s Oncology Group (COG) infant ALL trial (AALL0631) from MLL wildtype patients as determined by FISH and cytogenetics. Utilizing deep RNA-sequencing, we manually inspected the MLL gene for MLL-PTD, while also performing automated fusion detection and gene expression profiling in search of defining features of these tumors. Results: 3 additional MLL-PTDs were identified, all in patients with infant T-cell ALL, whereas both index cases were in patients with infant B-cell ALL. Gene expression profiling analysis revealed that all five MLL-PTD infants clustered together. Eight infants (7 with B-cell ALL) were found to have Ph-like expression. Five of these 8 infants were also found to have an IKZF1/JAK2 expression profile; one of these five had a PAX5-JAK2 fusion detected. Two infants (including the one noted above) had novel PAX5 fusions, known drivers of B-cell leukemia. Additional detected fusions included TCF3-PBX1 and TCF4-ZNF384. Conclusions: MLL-PTDs were found in both B- and T-cell infant ALL. Though Ph-like ALL has been described in adolescents and young adults, we found a substantial frequency of Ph-like expression among MLL-WT infants. Further characterization of these infants is ongoing. If replicated in other infant cohorts, these two findings may help explain the poor prognosis of MLL-WT ALL when compared to children with standard risk ALL, and offer the possibility of targeted therapy for select infants.

Hyperglycemia in Childhood Acute Lymphoblastic Leukemia During Induction Chemotherapy

Introduction: Hyperglycemia is a well-known adverse effect of the corticosteroids and asparaginase given during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL). ALL is a type of hematologic malignancy with high incidence in the childhood. The aim of this study is to investigate the impact of hyperglycemia during induction chemotherapy in childhood ALL. &#x0D; Methods: This prospective study was done in Dr. Soetomo hospital from January to April 2018. The subject was newly diagnosed as ALL under the age of 18 years, treated with Indonesian childhood ALL 2013 protocol (standard risk (SR) group and high risk (HR) group). Hyperglycemia was defined as at least two separate random plasma glucose levels &gt;200 mg/dL, which was evaluated before and during induction chemotherapy. Statistical analysis using Paired T-test for parametric and Wilcoxon test for nonparametric. &#x0D; Results: Thirty-three children were enrolled, 18/33 boys with mean age 5.8 (SD 3.78) years, compromised as ALL-L1 30/33. They were treated with ALL-HR 19/33 and ALL-SR 14/33. In overall groups, the mean random blood glucose level significantly increased from 108 (SD 21.3) mg/dl to 147 (SD 48.1) mg/dl, (mean difference 38.67 mg/dl; 95% CI 18.08 to 59.26 mg/dl, p=0.008). In SR group, there was a significant increase of mean random blood glucose level from 102 (SD 13.5) mg/dl to 133 (SD 37.3) mg/dl, (mean difference 31.8 mg/dl; 95% CI 8.78 to 54.8 mg/dl; p=0.01). In HR group, the mean random blood glucose level increased from 113 (SD 51.9) mg/dl to 165 (SD 25.4) mg/dl, (mean difference 51.9 mg/dl; 95% CI 18.6 to 85.2 mg/dl, p=0.004). &#x0D; Conclusion: Blood glucose level is significantly increase during induction chemotherapy in both SR and HR Indonesian childhood ALL 2013 protocol.