Jude Total XV Research Articles

Outcome of the Modified St. Jude Total XV Protocol in Turkish Children with Newly Diagnosed Acute Lymphoblastic Leukemia: A Single-Center Retrospective Analysis

The prognostic factors and outcomes of Turkish children with newly diagnosed acute lymphoblastic leukemia (ALL), treated with the Modified St. Jude Total XV Protocol, which was adjusted by adding high-dose methylprednisolone (HDMP) before induction in the original protocol, were assessed in this study. The Modified St. Jude Total XV Protocol was administered to 183 newly diagnosed ALL patients, aged 1-18 years, between 1 January 2008 and 30 January 2016. HDMP was applied at doses of either 10 mg/kg/day (Group A) or 20 mg/kg/day (Group B) for 7 days before induction and then tapered over the next 7 days to 5 or 10 mg/kg/day, and continued at 2 mg/kg/day for 2 weeks during the induction phase. Absolute blast count (ABC) in peripheral blood and minimal residual disease (MRD) in bone marrow were assessed at the end of the initial 7-day HDMP treatment. MRD in the bone marrow was evaluated on day 15 and at the end of the induction period. The follow-up for these patients ended on 15 July 2019. The 5-year event-free (EFS) and overall survival (OS) rates for all patients were 85.6±2.6% and 89.2±2.3%, respectively. The rate of good response to steroids (defined as ABC in peripheral blood of less than 1000/mm3 on day 7) was 88% and 97% of children achieved complete remission after induction. The survival rate and infection frequency did not show statistically significant differences between Group A and B. EFS and OS correlated with initial leukocyte count, age of 10-18 years at diagnosis, CD20 positivity at diagnosis, and gram-negative bacterial infection during remission induction. The remarkable response rates on days 7 and 15, along with the promising EFS and OS results in childhood ALL patients treated with the Modified St. Jude Total XV Protocol, highlight the early and substantial response effect of HDMP. At the onset of induction, short-term HDMP can be initiated, preferably at 10 mg/kg/day for the first 7 days, to minimize potential side effects.

Patterns and Outcomes of Acute Central Nervous System Complications During Treatment of Childhood Acute Lymphoblastic Leukemia: A Single-center Experience.

Central nervous system (CNS) complications are considered adverse events during the treatment of pediatric acute lymphoblastic leukemia (ALL). This study aimed to assess the incidence, types, clinical and radiologic patterns, risk factors, and the fate of different CNS complications during the treatment of pediatric ALL. A retrospective study included 390 patients with pediatric ALL, treated according to St. Jude total XV protocol at the National Cancer Institute, Cairo University, from January 2012 to December 2017. Thirty-nine (10%) patients developed different types of CNS complications. Nineteen (4.9%) patients had cerebrovascular complications, 12 (3.1%) patients had posterior reversible encephalopathy syndrome (PRES), and 6 (1.5%) patients had leukoencephalopathy; both CNS infections and leukemic infiltrates were diagnosed in one patient each. CNS complications were significantly higher in patients older than 10 years old, patients with high-risk disease, and patients who were classified as CNS III status with a statistically significant P value of 0.040, 0.020, and 0.002, respectively. There were 31 (79.5%) cases that achieved complete recovery, 6 (15.4%) patients who died, and 2 (5.1%) patients who developed residual neurological deficits. In conclusion, pediatric patients with ALL, who presented with older age, high-risk disease initially, and had initial CNS III status, were at higher risk of developing acute CNS complications during their treatment period. Patients who developed visual disturbances were associated with unfavorable outcomes. Despite that, around 80% of patients showed complete recovery, but still, 15% of them died from these complications.

The Different Impacts of an MRD-Guided Protocol on Relapse of Childhood Acute Lymphoblastic Leukemia: The Report of Taiwan Pediatric Oncology Group (TPOG)-ALL-2013

Taiwan Pediatric Oncology Group (TPOG)-ALL-2013 protocol (TPOG-2013), modifying from St. Jude Total Therapy XV Study and Total Therapy XVI Study, was launched since January 2013. This is the first nationwide minimal residual disease (MRD)-directed protocol for treatment of childhood acute lymphoblastic leukemia (ALL) in Taiwan. According to TPOG-2013, two MRD measurements were scheduled on days 15-19 of induction (MRD1 time point, TP1) and days 35-42, end of induction (MRD2 time point, TP2) to make the definitive risk stratification to guide subsequent therapy. As of April 30, 2023, 814 newly diagnosed ALLs treated with TPOG-2013 and followed up ≥3 years were enrolled in the study. The outcomes were compared with those of TPOG-ALL-2002 protocol (TPOG-2002) (N=1350, between January 2002 and December 2012), which did not integrate the MRD monitoring. The 5-year event-free survival and overall survival were significantly improved from 76% (95% CI, 74-78) and 81% (80-84) of TPOG-2002 to 86% (83-88) and 89% (87-92) of TPOG-2013, respectively ( P< 0.0001). For further analysis of TPOG-2013, 585 (72%) patients with exact adherence (EA) to both TPs were assigned as MRD EA group; 225 patients who were non-adherence (NA) to either one of TPs as MRD NA group; and four patients were excluded for the comparative outcome analysis. For B-cell precursor (BCP) ALL, the 5-year cumulative incidence of relapse (CIR) significantly decreased from TPOG-2002 (N=1194) to TPOG-2013 MRD EA (N=527) ( P <0.0001). However, there was no significant improvement of CIR between TPOG-2002 and MRD NA (N=202) ( P= 0.21) (Figure 1). In MRD EA of BCP-ALL, compared with TPOG-2002, patients with ETV6::RUNX1 or BCR::ABL1 appeared to have significantly lower CIR. Patients without the common genetic subtypes , denoted as “negative” group, also had significant inferior CIR. And the trend of CIR decrease did not attain significant difference in high hyperdiploidy. In contrast, patients with T CF3::PBX1 or infant with KMT2A-rearrangement did not show CIR improvement (Table 1). In T-ALL, compared with TPOG-2002 (N=156), there was a significant decrease of CIR in TPOG-2013 MRD EA (N=58)( P= 0.01)(Table 1), but not in MRD NA (N=23)( P= 0.86). There was a longer duration to relapse in MRD EA of BCP-ALL. However, a delay of relapse was only demonstrated in patients with BCR::ABL1, which could be addressed by the introduction of MRD-monitoring and TKI inhibitor in TPOG-2013 (Table 1). Further, in term of early relapse before 1.5 year of remission, there was no significant difference in MRD EA of BCP-ALL, compared with TPOG-2002. In conclusion, this study demonstrated diffident impacts on relapse according to genetic subtypes and MRD adherence. In the negative group of BCP-ALL without the discovery of novel genetic alternations, the relapse could be much decreased with the MRD-directed treatment protocol.

The results of the modified St Jude Total Therapy XV Protocol in the treatment of low- and middle-income children with acute lymphoblastic leukemia

The St Jude Total Therapy Study XV was the first clinical trial to prospectively use minimal residual disease levels during and after remission induction therapy to guide risk-directed treatment. We used the Total Therapy XV protocol with minimal modification in treating 115 newly diagnosed pediatric acute lymphoblastic leukemia patients from low- and middle-income groups from January 2011 to December 2017. The mean age at diagnosis was 5.97 ± 3.96 years. The median follow-up period was 88 months. Three (2.6%) patients had bone marrow relapse, and one (0.87%) had an isolated central nervous system relapse. Nineteen of the patients (16.52%) died due to infection-related complications, three (2.61%) died due to progressive disease, and one (0.87%) died due to hematopoietic stem cell transplant complications. Five-year overall survival was 80%, and event-free survival was 78.3%. Our results showed that the Total XV treatment protocol could be used successfully in patients with ALL from low- and middle-income populations. However, infection-related deaths remain a significant problem.

IKZF1plus Confers a Strong Adverse Prognostic Effect in Total Therapy Studies (XV/XVI)

Introduction Alterations in IKZF1, including the IKZF1plusgenetic profile, have been associated with poor prognosis in patients with B-acute lymphoblastic leukemia (B-ALL). Although the types and frequencies of IKZF1 alterations vary by leukemia subtype, the effects of IKZF1 alteration status and leukemia subtypes on clinical outcome are not fully understood. We have assessed the spectrum of IKZF1 alterations, including IKZF1plus, IKZF1 deletions only, the IKZF1 IK6 dominant negative mutant, sequence mutations, and their associations with clinical outcome, in the context of genomic subtypes of B-ALL. Patients and Methods We analyzed single nucleotide polymorphism 6.0 microarrays, whole genome sequencing, and whole exome sequencing data to detect genetic alterations in a cohort of 688 pediatric patients with B-ALL enrolled into St. Jude Total Therapy XV and XVI studies. The IKZF1plus genetic profile was denoted by the presence of IKZF1 deletions together with one or more of the following alterations: deletion in PAX5, CDKN2A, or both CDKN2B loci, or CRLF2-rearrangement, in the absence of copy number alterations in ERG or DUX4-rearrangement. Results Alterations in IKZF1 were detected in 11.8% of patients (81 out of 688), with IKZF1 deletions, sequence mutations, and concurrent deletion and sequence mutations present in 8.1%, 3.2%, and 0.4% of patients, respectively. The IKZF1plus profile was detected in 4.2% of patients and IKZF1 deletions only detected in 3.9% of patients. Of 29 patients with IKZF1plus, 51.7% had unfavorable subtypes of leukemia (including Ph and Ph-like-CRLF2), 27.6% had intermediate subtypes of leukemia, and 12.8% had favorable subtypes (DUX4, ETV6-RUNX1, and Hyperdiploid) of leukemia compared to patients with IKZF1 deletions only, sequence mutations only, or no IKZF1 alterations in whom favorable subtypes were enriched at 67.4%, 45%, and 59.3%, respectively (P<0.001). IK6 was observed in 16 patients, 11 of whom (68.8%) had the IKZF1plus profile. Patients with IKZF1 alterations had poorer responses to induction therapy with EOI MRD ≥ 0.01% detected in 51.7% of patients with IKZF1plus, 22.2% of patients with IKZF1 deletions only, and 18.2% of patients with IKZF1 sequence mutations, compared to 12.5% of patients without IKZF1 alterations (P < 0.0001). EOI MRD ≥ 0.01% was observed in 56.3% of patients with IK6 and 32.6% of patients with non-IK6 deletions (P<0.0001). Patients with IKZF1plus had the poorest 5-year event free survival (EFS), overall survival (OS) and cumulative incidence of relapse (CIR) of 65.5 ± 8.8%, 82.8 ± 7.0%, and 20.7 ± 7.7%, respectively. IKZF1 deletions only were associated with EFS of 81.5 ± 7.5%, OS of 88.9 ± 6.1%, and CIR of 11.1 ± 6.2%. IKZF1 sequence mutations were associated with better outcomes than other IKZF1 alterations (EFS of 86.1 ± 7.4%, OS 95.5 ± 4.4% and CIR 9.1 ± 6.3). Patients without any IKZF1 alterations had the best clinical outcomes with EFS of 92.6 ± 1.1%, OS 96.3 ± 0.8%, and CIR 5.7 ± 1% (P<0.001 for comparison of all groups). Compared to patients with non-IK6 deletions, mutations only, or no deletions, the IK6 deletion conferred increased risk of relapse with EFS of 68.8 ± 12% and CIR 25 ± 11% (P<0.0001 for EFS and 0.03 for CIR). Multivariable analyses, which included variables of genomic subtypes and final risk status, demonstrated an independent prognostic effect of both IKZF1plus and IKZF1 deletions only with the highest hazard ratio (HR) in EFS and CIR associated with IKZF1plus (EFS HR 7.77; 95% CI 2.41-25.03; P<0.001 and CIR HR 8.27; 95% CI 3.41-20.05); P<0.001). IKZF1 deletions only were associated with EFS HR 4.64; 95% CI 1.48 - 14.56; P<0.05 and CIR HR 4.77; 95% CI 1.30 - 17.58; P<0.05). IKZF1 sequence mutations were not associated with adverse outcomes. Unfavorable subtypes, including Ph and Ph-like-CRLF2 subtypes, had a significantly adverse prognostic effect. Conclusions We show adverse independent prognostic effects of IKZF1plus and non-IKZF1plusIKZF1 deletions in patients treated in Total XV and XVI studies, adding to the importance of these genetic profiles in identifying patients at risk of relapse. Identification of genomic subtypes associated with IKZF1plus together with incorporation of sequence analysis to reveal the full spectrum of IKZF1 alterations further informs prognostication of B-ALL and reveals subgroups of patients who remain at risk of poor outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rare Deleterious TCF3 Germline Variants and Predisposition to Acute Lymphoblastic Leukemia in Children

Introduction TCF3 is a hematopoietic transcription factor essential for lymphoid differentiation. The role of TCF3 in the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL) is well documented because of recurrent chromosomal rearrangements leading to TCF3 fusion with PBX1 or HLF1. In contrast, less is known about the occurrence and significance of germline TCF3 variants in this blood cancer. Here we present a comprehensive screen and characterization of TCF3 germline variants in children with B-ALL. Methods First, we performed targeted sequencing of TCF3 coding regions in 4,183 children with newly diagnosed B-ALL enrolled in Children's Oncology Group (COG) clinical trials AALL0232, P9904/5/6, and AALL0331 as well as St. Jude Total Therapy XIII and XV clinical trials. Rare variant analysis was performed using the CoCoRV pipeline (Chen W et al., Nat Commun. 2022, PMID: 35545612), where the GnomAD v2 genome-based summary counts (n=15,708) were used as the non-ALL control cohort. Rare deleterious TCF3 variants were defined as follows: allele frequency ≤5x10-4 in GnomAD, protein-truncating variants (frameshift and nonsense) or missense variants with a REVEL score ≥0.65. For transcription factor activity measurement, we used a dual-luciferase reporter assay in HEK 293T cells. Finally, we compared the clinical characteristics of B-ALL patients with rare deleterious TCF3 germline variants to B-ALL patients without these variants enrolled in COG AALL0232 (n=2,180) and COG P9904/5/6 (n=1,619) clinical trials. Results TCF3 alternative splicing gives rise to two distinct isoforms, E47 and E12, of which we found TCF3-E12 to be the predominant transcript expressed in B-ALL. Focusing our analysis on the E12 isoform (NM_003200), we identified 12 rare deleterious TCF3 variants in 12 B-ALL patients, significantly and strikingly more frequent than what is seen in non-ALL controls (p=1.24×10-5, OR=19.9) (Figure 1A). Nine TCF3 variants lead to protein truncation with the loss of the basic helix-loop-helix (b-HLH) domain and three missense variants cluster within TCF3 exon 18a, which encodes the b-HLH domain that is responsible for TCF3 dimerization and DNA binding. Functional characterization by luciferase reporter assay revealed a severe reduction of TCF3 transcriptional activity for two B-ALL-related missense variants. TCF3 E12-p.N554S and E12-p.A568D showed a 6.2- (p<0.0001) and 6.9-fold (p<0.0001) reduction in transcription factor activity compared to wildtype TCF3 E12 (Figure 1B). TCF3 E47-p.E555K is a known loss of function variant and therefore was included as a positive control. As expected, its transcription factor activity was reduced by 11.8-fold compared to wildtype TCF3 E47 (p<0.0001). These results are consistent with the notion that single nucleotide variations within the b-HLH domain impair TCF3 dimerization and DNA binding. Nonsense and frameshift variants result in the loss of the b-HLH domain and were presumed to be deleterious. Finally, we compared clinical features of 10 TCF3 germline variant carriers to 3,799 B-ALL patients without TCF3 variation enrolled in COG clinical trials. We did not observe any difference in age, sex, ancestry, or white blood count at diagnosis. Further, none of the 10 patients with TCF3 germline variant had somatic fusion genes involving TCF3 (i.e., TCF3-PBX1 or TCF3-HLF1). Conclusion We systematically examined germline genetic variants in the TCF3 gene in B-ALL patients, reporting 12 rare deleterious TCF3 variants with a cumulative frequency of 0.29%. These variants directly affect the TCF3 b-HLH domain, which is critical for TCF3 transcription factor activity. Taken together, our findings provide new insights into genetic predisposition to pediatric B-ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ALL-204 Barriers to Improving Outcomes of Children With Acute Lymphoblastic Leukemia in Low- to Middle-Income Countries

Despite recent improvements in supportive care services, treatment deaths remain one of the major problems that affect the outcome of pediatric acute lymphoblastic leukemia (ALL), especially in middle-income countries. The study aimed to assess the incidence, risk factors, and outcomes of treatment-related complications during therapy of pediatric ALL. A retrospective study included patients ≤18 years old with pediatric ALL, treated according to St. Jude Total XV protocol at the National Cancer Institute, Cairo University from January 2012 to December 2017. All patients were reviewed and analyzed for treatment-related toxicities and overall and attributable mortality rates. The study included 434 patients with a median age of 5 years and an M/F ratio of 1.3:1. Out of the total group, 367 patients (84.5%) developed documented infectious complications, 58 (13%) had cerebrovascular complications, and 18 (4%) had organ damage. Bacterial infection was most frequent throughout all treatment phases, diagnosed in 74.2% of patients, followed by invasive fungal infection in 17.7% and viral infections in 8.0% of the patients. Gram-negative infections were more predominant during all treatment phases (65% compared to 35% gram-positive). The most frequent gram-negative bacteria were E. coli (37.7%), Klebsiella (25.4%), and Acinetobacter (16.4%). Multidrug resistance (MDR) was more frequently found among E. coli infections (52.2%). With a median follow-up of 101 months, the 5-year overall survival (OS) and event-free survival (EFS) for the whole group were 67.3% and 58.8%, respectively. The overall mortality rate was 32.6%; infection-related mortality constitutes 91.0% of overall mortality, and the remainder was due to either organ damage or disease. The attributable mortality rate was highest among E. coli patients (65.2%) followed by Klebsiella and Acinetobacter patients (42.0% and 20.0%, respectively). The 5-year OS and EFS were significantly worse in those with infection complications (OS 37.7% vs. 61.4%, P< 0.001; EFS 57% vs. 84%, P=0.006). Infectious complications are a major obstacle to reaching desirable outcomes for pediatric patients with ALL in developing countries. Gram-negative infection, especially with MDR, remains a major challenge that warrants more attention and prompt intervention during treatment of those patients.

Early post-induction augmented therapy improves outcome in children and adolescents with T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all newly diagnosed ALL in children and adolescents and is associated with worse outcomes compared to pre-B ALL. We aimed to decrease T-ALL relapses by intensifying our regimen. Patients with T-ALL were treated using two different regimens; before September 2014, patients were treated per St. Jude Total XV protocol; subsequently, a major change was adopted by adding two intensive blocks: FLAG and Reintensification. Cranial radiation was limited to patients with WBC≥ 100 k/μl at diagnosis and/or patients with CNS2/CNS3 status. Between June 2005 and April 2020, a total of 100 patients (76 males) were treated and followed up for a median of 70 months (range 14-181). Median age at diagnosis was 9 years (range 0.5-17.8). Forty-eight patients were diagnosed after September 2014 and received the augmented regimen; their median follow up was 46 months (range 14-74). The 5-year-EFS estimates for patients who received the augmented regimen versus standard regimen were 87% ± 4.9% versus 67% ± 6.8% (p=.03); and the 5-year-OS estimates were 87% ± 5.1% versus 71% ± 6.3% (p=.06), respectively. Treatment related mortality (TRM) was reported in two patients treated per standard regimen but none for patients who received the augmented regimen. We implemented a novel approach with early intensification added to a backbone of modified St. Jude Total-XV regimen for patients with T-ALL that resulted in improved outcome with no treatment related mortality.

Sex-Based Differences in Functional Brain Activity During Working Memory in Survivors of Pediatric Acute Lymphoblastic Leukemia.

BackgroundLong-term survivors of pediatric acute lymphoblastic leukemia are at elevated risk for neurocognitive deficits and corresponding brain dysfunction. This study examined sex-based differences in functional neuroimaging outcomes in acute lymphoblastic leukemia survivors treated with chemotherapy alone.MethodsFunctional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors (46% male; median [min-max] age = 14.2 years [8.3-26.5 years]; time since diagnosis = 7.7 years [5.1-12.5 years]) treated on the St. Jude Total XV treatment protocol. Participants performed the n-back working memory task in a 3 T scanner. Functional neuroimaging data were processed (realigned, slice time corrected, normalized, smoothed) and analyzed using statistical parametric mapping with contrasts for 1-back and 2-back conditions, which reflect varying degrees of working memory and task load. Group-level fMRI contrasts were stratified by sex and adjusted for age and methotrexate exposure. Statistical tests were 2-sided (P < .05 statistical significance threshold).ResultsRelative to males, female survivors exhibited less activation (ie, reduced blood oxygen dependent–level signals) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and bilateral superior frontal medial gyrus during increased working memory load (family-wise error–corrected P = .004 to .008, adjusting for age and methotrexate dose). Female survivors were slower to correctly respond to the 2-back condition than males (P < .05), though there were no differences in overall accuracy. Performance accuracy was negatively correlated with fMRI activity in female survivors (Pearson’s r = −0.39 to −0.29, P = .001 to .02), but not in males.ConclusionsThese results suggest the working memory network is more impaired in female survivors than male survivors, which may contribute to ongoing functional deficits.

Clinicopathologic and prognostic features of TdT-negative pediatric B-lymphoblastic leukemia

Little is known about B-lymphoblastic leukemia (B-ALL) that lacks expression of terminal deoxynucleotidyl transferase (TdT). To address this, we performed the largest study to date of TdT-negative B-ALL using data from St. Jude Total XV and XVI clinical trials. Compared to TdT-positive B-ALL (n = 896), TdT-negative B-ALL (n = 21) was associated with younger age (median, 1.4 versus 6.8 years, P < 0.001), higher white blood cell count (median, 52.8 versus 9.9 × 109/L, P < 0.001), absence of hyperdiploidy (0 versus 27.8%, P = 0.002), KMT2A rearrangement (100 versus 1.9%, P < 0.001), and inferior 5-year event-free survival (EFS) (76.2 versus 90.3%, P = 0.047). In the context of KMT2A-rearranged B-ALL (n = 38), TdT-negativity was significantly associated with the MLLT1 rearrangement partner (P = 0.026) but was not independently predictive of survival, suggesting that the high-risk features of TdT-negative B-ALL are secondary to underlying KMT2A rearrangements. Finally, we compared the sensitivity of TdT-negativity to neuron-glial antigen 2 (NG.2) expression for the detection of KMT2A rearrangements and found that 63% of KMT2A-rearranged B-ALL cases not identified by NG.2 were TdT-negative. The results of this study expand the spectrum of immunophenotypic features that are specific for high-risk KMT2A rearrangements in pediatric B-ALL and can be readily implemented using existing standard acute leukemia flow cytometry panels.

Decreasing Dose and Duration of Dexamethasone Therapy for Low-Risk Childhood Acute Lymphoblastic Leukemia Aiming to Avoid Serious Viral Infections Results in Significant Increase in Isolated CNS Relapse: A Prospective Study

Background: In the era of treating childhood acute lymphoblastic leukemia (ALL) without cranial irradiation, optimization of central nervous system (CNS) active therapeutic agents is needed to prevent CNS relapse. Dexamethasone is an essential part of maintenance therapy in most current protocols for its excellent CNS penetration and anti-leukemic effect. The dose and duration of dexamethasone treatment for low-risk patients vary across trials. In our institution, we adopted the St Jude Total XV protocol with minor modifications since 2002. This treatment has resulted in 5-year OS and EFS rates of 96.4% and 94% respectively for low-risk patients. However, around 11% of patients developed serious viral infections, mainly disseminated varicella (6%), CMV retinitis (3.6%) and progressive multifocal encephalopathy (1.1%). The aim of this trial was to decrease the incidence of serious viral infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy.Patients and Methods: This is a prospective, non-randomized trial of all consecutive low-risk ALL patients aged 1-18 years treated at the Children's Cancer Center of Lebanon that included patients diagnosed after June 2013 as well as patients diagnosed earlier who had not reached week 100 of maintenance therapy by June 2013. Low-risk patients were defined elsewhere [Muwakkit et al, Am J Hematol. 2012 Jul;87(7):678-83].For patients diagnosed after June 2013; dexamethasone dose was decreased by 25% (from 8 to 6 mg/m2/day for 5 days/week every 4 weeks) and dexamethasone pulses were stopped at week 69 instead of week 100 from start of maintenance therapy. For patients on therapy who had not reached week 69 of maintenance; dexamethasone pulses were stopped at week 69, and dexamethasone dose was decreased by 25% (from 8 to 6 mg/m2/day for 5 days/week every 4 weeks) starting June 2013. For patients who had completed 69 weeks but did not reach week 100 of maintenance by June 2013, dexamethasone pulses were stopped. The interval between dexamethasone pulses was 4 weeks for all patients, before and after the change.The number of intrathecal chemotherapy injections was not changed.For analysis, historical control patients who completed therapy before June 2013 and patients on therapy who completed more than half of their planned dexamethasone pulses (week 50) by June 2013 were assigned to group 1. Patients who were diagnosed after June 2013 and those who had received less than half of their planned dexamethasone pulses (week 50) by June 2013 were assigned to group 2.The trial was stopped in May 2017 due to the observed increased incidence of isolated CNS relapse in group 2.Results: The total number of patients was 84 in group 1 and 33 in group 2. There was no significant difference in patient characteristics between the two groups. After a median follow-up of 88 months (range: 24-177), the 4-year cumulative incidence of isolated CNS relapse increased from 0% in group 1 to 9.5% (n=3) (95% CI: 0-19.2%) in group 2 (P : 0.005). The mean cumulative dose of dexamethasone was 1129 mg/m2 (SD 49 mg/m2) for group 1 and 838 mg/m2 (SD 31 mg/m2) for group 2 (P : <0.001). The mean total duration of dexamethasone pulses from start of maintenance treatment was 97 weeks (SD 8 weeks) for group 1 and 69 weeks (SD 0 weeks) for group 2 (P <0.001). The cumulative dose of dexamethasone received by patients with isolated CNS relapse was 824, 876 and 930 mg/m2. The isolated CNS relapses occurred at weeks 74, 95 and 116 of maintenance therapy. None of the patients with isolated CNS relapse had an initial traumatic lumbar puncture. None of group 2 patients developed disseminated varicella, CMV retinitis, or progressive multifocal encephalopathy. None of the patients in both groups developed bone marrow relapse within 4 years of diagnosis. The 4-year cumulative incidence of infection-related mortality was 3.5% (95% CI: 0-7.4%) for group 1 and 0% for group 2 (P : 0.27). The 4-year OS rate was 96.4% (95% CI: 89.3-98.8%) for group 1 and 100% for group 2 (P : 0.27). The 4-year EFS rate was 96.4% (95% CI: 89.3-98.8%) for group 1 and 90.5% (95% CI: 73.2-96.8%) for group 2 (P : 0.24).Conclusions: Decreasing dose and duration of dexamethasone therapy for low-risk childhood ALL patients aiming to avoid serious viral infections led to significant increase in isolated CNS relapse. Further studies are needed to identify the optimal dose and duration of dexamethasone therapy for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Response Adapted Therapy in ETV6/RUNX1-Positive Childhood Acute Lymphoblastic Leukemia Treated per Modified St Jude Total XV Study

Introduction: ETV6-RUNX1 is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a precursor-B phenotype. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies. Relapses tend to occur late and have a better salvage rate than other ALL subtypes. Moreover, conflicting data in literature regarding the prognostic significance of ETV6-RUNX1 after accounting for age, initial count and treatment intensity. We sought to study the clinical features, therapy response in newly diagnosed ETV6-RUNX1-positive treated at King Hussein Cancer Center. Methods: Patients were treated per modified St Jude Total (XV) study, risk stratification was further refined by including minimal residual disease (MRD)measurements on day 15 and day 46 of remission induction therapy. Patients with the ETV6- RUNX1 fusion or hyperdiploidy without CNS or testicular disease and a satisfactory early MRD decline (&amp;lt;1% on day 15 and &amp;lt;0.01% on day 46) were classified as being low-risk for relapse and were treated on lower -risk arm regardless of age and leukocyte count. Results: Seventy patients (n=70) with ETV6-RUNX1-positive treated at our institution between May 2006 to October 2017. The median age at diagnosis, 5.8 years (range, 1.5-10.8). ETV6-RUNX1 was associated with favorable age between 1- and 6-years in 55 patients (79%), male gender in 41 patients (59%), initial leukocyte count &amp;lt;10 in 39 patients (56%), CNS status 1 in 100% of patients. The majority, n= 58 (83%) of patients had NCI standard risk (SR) and n=12 (17%) had NCI high risk (HR). Sixty-six patients (94%) had MRD &amp;lt;1% at day 15 and all patients achieved remission with MRD&amp;lt;0.01% at day 46 of remission induction. All patients were treated as LR ALL per modified St Jude total XV protocol. At median follow up of (36 months; range, 26 to 154), in the subgroups of ETV6-RUNX1-positive patients classified as NCI standard risk (SR)and NCI high risk (HR) the 5-year EFS estimates were 94.1% ± 3.2 and 82%±1(P=.13), 5-year OS estimates were 100% and 92% ± 8 (p=0.31) respectively. Conclusion: MRD treatment schema in ETV6/RUNX1 -positive patients have excellent outcomes if they achieved favorable response at day 15 and end of remission induction regardless of the age and Initial leukocyte count. Treatment reduction is feasible and declared safe for children with NCI-HR who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD post remission induction therapy. Disclosures No relevant conflicts of interest to declare.

Successful Therapy Reduction in NCI Standard Risk (SR) Highly Favorable Subgroup of Childhood Acute Lymphoblastic Leukemia

Background: Acute Lymphoblastic Leukemia (ALL) is the most common cancer in childhood; it is curable in 80-90% of patients. Current efforts focus on therapy guided by sensitive and specific methods of minimal residual disease (MRD) monitoring, tailoring the type and intensity of chemotherapeutic agents to improve cure rates, quality of life and decrease morbidity. We sought to study the outcome of low risk (LR) ALL treated per modified St Jude total XV Study. Methods: We adopted the modified St Jude total XV study ,B-cell precursor patients with age between 1 and 10 years and presenting leukocyte count &amp;lt;50×10^9/L, leukemic cell DNA index ≥1.16, or TEL-AML1 fusion are classified to have low-risk ALL, provided that they do not have testicular or central-nervous-system (CNS-3) leukemia, hypodiploidy (&amp;lt;45 chromosomes), E2A-PBX1 fusion, or MLL rearrangement, and have a treatment response at day 15 by minimal residual disease (MRD) of &amp;lt;5% and at day 46 of remission-induction &amp;lt;0.01%. We further identified a subgroup of (LR) ALL; defined by presenting age between 2 and 6 years, leukocyte count of &amp;lt;10x 10^9/L and MRD of &amp;lt;0.01% at day 15 of remission induction as Very Low Risk ALL (VLR). Patients with St Jude Low Risk (LR) ALL were treated per St Jude total XV study with several modifications: On 2007; doxorubicin was omitted from reinduction II to lower the total cumulative dose of anthracycline to 80 mg/m2, pulses of dexamethasone and vincristine were stopped at week 72 of maintenance instead of 100. On 2012; for patients identified as VLR; pulses of vincristine /dexamethasone were stopped at week 52 and HDMTX given at week 10 and 12 of maintenance therapy was omitted, frequency of triple Intrathecal chemotherapy remained unchanged (13-18) for LR ALL based on CNS status. Results: We reviewed 184 patients with (LR) between May 2006 to Feb 2018, (the median age at diagnosis, 7.3 years; range, 1.5-9.8). Eighty-two patients (45%) and 102 patients (55%) were treated as VLR and LR ALL respectively. The only significant difference in patients of two groups were age at diagnosis 2-6 years(VLR, 100%; LR, 46%; p&amp;lt;0.001), initial count &amp;lt;10x 10^9/L (VLR, 100%; LR, 65%; p&amp;lt;0.001) and MRD at day 15&amp;lt;0.01%(VLR, 100%; LR, 61%; p&amp;lt;0.001). At median follow up of (48 months; range, 17 to 157), in the subgroups of NCI standard risk defined above; as very low risk(VLR) ALL and low risk (LR) ALL, the 5-year EFS were 92%±3.4; 85%±4 (p=0.12), and the 5-year OS were 98%±1.7; 93%±3.3 (p=0.2) respectively. Conclusion: Chemotherapy was substantially reduced safely in subgroup of children with low risk ALL who were selected on the basis of presenting age, leukocyte count and undetectable MRD levels early at day 15 and at day 46 of remission induction without jeopardizing the survival rate. Patients with St Jude LR ALL maintained outstanding outcomes despite reduction of chemotherapy. Disclosures No relevant conflicts of interest to declare.

The Outcome of Modified St. Jude Total XV Protocol in Turkish Children with Newly Diagnosed Acute Lymphoblastic Leukemia

Introduction: Childhood acute lymphoblastic leukemia (ALL) treatment with St. Jude Total therapies showed superior outcome with event-free and overall survival rates 85.6 ± 2.9% and 93.5 ± 1.9%, respectively. Here, we studied prognostic features and the outcome of Turkish children with newly diagnosed ALL treated with modified St. Jude Total Therapy XV Protocol. Patients and methods: There were 182 newly diagnosed ALL patients aged 1-18 years old and treated with modified Total Therapy XV between 1 January 2008 and 30 January 2016. According to our previous successful results with high dose methylprednisolone (HDMP), each patient received 7 days of HDMP as an initial treatment and randomized at doses of 20 mg/kg/d or 10mg/kg/d HDMP, not exceeding at maximum 1000 mg MP. After the first 7-day steroid treatment, concomitant chemotherapy was given and the steroid doses were tapered to 10mg/kg/d and 5mg/kg/d during the next week in each group, respectively. Afterwards, the whole group received 2 mg/kg/d MP for the following two weeks. Also, there were a third group received lower doses (&lt;10 mg/kg/d) of MP because of the hyperleukocytosis for the first 7 days. Results: Out of 182 patients, 174 completed the treatment and 1 patient experienced induction failure, 4 patients died during remission induction, 3 patients abandoned treatment during maintenance. 97.2% of the children entered complete remission after remission induction. 16 patients (8.9%) had relapses during follow-up, 9 isolated bone marrow, 7 isolated CNS and 3 of 7 patients who had CNS relapse experienced a second relapse (bone marrow) afterwards. The five-year event-free survival (EFS) and overall survival (OS) were 85.6±2.6 % and 89.2±2.3%, respectively. There was no significant difference according to the survival rates between different MP doses (10 and 20mg/kg/d) which were given before induction. Moreover, difference in frequency of infection between patient groups treated with different steroid doses during induction period was not found statistically significant. Univarite analysis showed that age ≥ 10 years at the time of diagnosis, initial leukocyte count ≥50x109/L, low MP doses (&lt;10mg/kg/d) and infection with gram negative bacteria during remission induction were associated with inferior EFS. Multivariate analysis revealed lower EFS rates with an initial leukocyte count ≥50x109/L [HR=5.58, 95% CI: 1.99-15.64, p&lt;0.001], age ≥ 10 years at the time of diagnosis [HR=3.81, 95% CI: 1.65-8.81, p=0.002], infection with gram negative bacteria during remission induction [HR=3.71, 95% CI: 1.55-8.88, p=0.003] and CD20 positivity (&gt;20%) at diagnosis [HR=2.49, 95% CI: 1.08-5.73, p=0.031]. Response to MP measured as &lt;1000/mm3absolute blast count in peripheral blood sample after first 7 days did not have statistically significant influence on survival in comparison with poor MP response (&lt;1000/mm3absolute blast count in peripheral blood). Conclusion: Our encouraging EFS result with modified St. Jude Total XV in childhood ALL patients is comparable with the one in original protocol. Favorable effect of higher doses of MP (20 mg/kg/d) on survival could not be demonstrated when compared with 10mg/kg/d. Disclosures No relevant conflicts of interest to declare.

The Adherence to MRD Time Points Is a Significantly Prognostic Predictor in an MRD-Directed Therapy for Childhood Acute Lymphoblastic Leukemia in Taiwan

Backgrounds and Purposes Minimal residual disease (MRD) monitoring has been proved to be the most important prognostic predictor in childhood acute lymphoblastic leukemia (ALL). The nationwide TPOG-ALL-2013 protocol (TPOG-2013), adapted from the St. Jude Total Therapy XV Study and Total Therapy XVI Study, was launched since January 2013. This is the first MRD-directed protocol for treatment of childhood ALL in Taiwan. Here, we report the improved treatment outcomes and the impacts of adherence to MRD time points. Patients and Methods Totally, 402 patients aged between 1-18 years and diagnosed before December 31, 2018, who had MRD monitoring at the major central laboratory (Chang Gung Memorial Hospital-Linkou), were enrolled with the last follow-up on June 30, 2019. According to TPOG-2013, two MRD measurements were scheduled on days 15-19 of induction (MRD1 time point, TP1) and days 35-42, end of induction (MRD2 time point, TP2) to make the definitive risk stratification to guide subsequent therapy. The methodologies of MRD measurement included multicolor flow cytometry for leukemia-associated immunophenotypes (LAIP) (82.3% of TPOG-2013 cohort), qPCR assay for clonally rearranged antigen-receptor genes (Ig/TCR) if no LAIP (12.5%). Since January 2018, reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) was applied to patients carrying fusion transcripts (5.2%) of TCF3-PBX1, ETV6-RUNX1, BCR-ABL1, KMT2A-AFF1 (AF4) and KMT2A-MLLT3. The clinical features and outcomes of patients treated with TPOG-2013 were compared with those of 1,300 patients treated with the previous TPOG-ALL-2002 protocol (TPOG-2002), which did not integrate the MRD monitoring. Results The median follow-up time of the 402 patients of TPOG-2013 cohort was 32.5 months (range, 1.0-79.2 months). There were no significant differences in gender, age, WBC counts, and lineage at diagnosis between the patients treated with TPOG-2002 and TPOG-2013. However, based on the MRD data, the percentages of patients assigned to each risk group of TPOG-2013 was statistically differed from those of TPOG-2002 (P&lt; 0.0001). The 5-year event-free survival (EFS) (% ± SE) was significantly improved from 78.1 ± 1.2 of TPOG-2002 to 85.4 ± 2.5 of TPOG-2013 (P&lt; 0.0001). Further, the cumulative incidences (% ± SE) of isolated CNS relapse and any CNS relapse significantly decreased from 4.0 ± 0.5 to 0.3 ± 0.3 (P= 0.001) and from 5.8 ± 0.7 to 1.2 ± 0.9 (P= 0.001), respectively. The issue of non-adherence to MRD monitoring emerged since the implementation of MRD-directed TPOG-2013. For further analysis, 321 (80%) patients with exact adherence (EA) to both TPs were assigned as MRD EA group; 80 (20%) patients who were non-adherence (NA) to either one of TPs as MRD NA group; and one patient died between the two TPs was excluded for the comparative outcome analysis. The rate of non-adherence decreased significantly from 26.5% in 2013 to 2.4% in 2018. The major causes of non-adherence for both TPs were delaying MRD monitoring due to neutropenic fever and documented infections. In MRD EA group, 12.5% of patients were upgraded to higher-risk treatment groups based on their MRD results. The MRD NA group had older age (≥ 10 years), lower standard-risk and lower incidence of ETV6-RUNX1 compared with MRD EA group. There were significant differences in outcomes between MRD EA and MRD NA groups: the 5-year EFS were 89.4 ± 2.4 and 71.9 ± 7.4, respectively (P= 0.0005), overall survival (OS) were 90.9 ± 2.1 and 75.6 ± 5.8, respectively (P= 0.0003), and the cumulative incidence of isolated CNS relapse were 0 and 1.4 ± 1.3, respectively (P= 0.048) (Figure 1). In multivariate analysis, older age (≥ 10 years), higher WBC count (≥ 50 × 109/L) at diagnosis and MRD non-adherence were independent predictors for inferior EFS. In addition to these three factors, a higher-risk classification also predicted an inferior OS (Figure 2). Conclusions Contemporary MRD-directed therapy has improved the treatment outcomes of childhood ALL in Taiwan. The adherence to MRD time points remains a significantly prognostic predictor in the era of MRD-guided treatment. Disclosures No relevant conflicts of interest to declare.

Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated. Patients with ALL on St. Jude Total Therapy XV (n=365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy. We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P=0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P=0.00086) and arteriopathy (P=0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P=0.00045) and arteriopathy (P=0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS. These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.

Traumatic and Bloody Lumbar Puncture at Diagnosis in Children with Acute Lymphoblastic Leukemia: A St. Jude Total XV and Total XVI Cohort Study

Background: Traumatic and bloody lumbar punctures (TLPs and BLPs, respectively) at the diagnosis of pediatric acute lymphoblastic leukemia (ALL) impair the interpretation of central nervous system status and are associated with worse outcomes. We previously analyzed risk factors for TLP and BLP in 958 patients with ALL treated at St. Jude Children's Research Hospital (St. Jude) between 1984 and 1998. With an incidence of 19% and 5% at diagnosis, respectively, TLPs and BLPs were associated with unmodifiable and modifiable risk factors (URFs and MRFs, respectively). URFs included age less than 1 year and black race. MRFs included a platelet count (PLT) of <100 × 109/L, a less experienced practitioner, a non-dedicated procedural setting, and no sedation. Since then, preventive measures have been adopted for the first lumbar puncture (LP) at St. Jude: patients undergoing an LP ideally have a PLT of ≥100 × 109/L; the procedure is performed by the most experienced practitioner available; and we use a dedicated procedure area and general anesthesia.Objectives: To determine the incidence and risk factors of TLPs and BLPs, defined by the presence of at least 10 and 500 red blood cells per microliter of cerebrospinal fluid, respectively, at the diagnosis of pediatric ALL after the introduction of preventive measures.Patients and Methods: We performed a retrospective cohort study on children with newly diagnosed ALL who were consecutively enrolled on the Total XV and Total XVI protocols at St. Jude from October 2000 through March 2017. Patients who received their first LP at a center other than St. Jude or did not have a PLT within 24 hours of undergoing LP were excluded.Results: A total of 1006 patients (median age, 5.68 years at diagnosis; range, 0.12 to 18.89 years) were included in our study. Of the 1006 LPs at diagnosis, 80 (7.9%) were TLPs and 15 (1.5%) were BLPs. Of the 80 TLPs, 47 (58.7%) showed leukemia blasts (vs 30.9% [286/926] of non-TLPs; P < 0.001). Of the 15 BLPs, 13 (86.7%) showed leukemia blasts (vs 32.3% [320/991] of non-BLPs; P < 0.001). Regarding the adopted preventive measures, 561 patients received a platelet transfusion within 24 hours of LP because of a low PLT, but in 135 (13.4%) of these cases, a repeat PLT was not evaluated before the procedure (see Table). Therefore, of 871 available PLTs within 24 hours of LP, 638 (73.2%) were ≥100 × 109/L and 779 (89.4%) were ≥75 × 109/L. Experienced practitioners (defined as those having performed at least 200 procedures during the study period) performed 880 (89.2%) of the 986 LPs for which practitioner information was available. General anesthesia was used in 948 (96.7%) of 980 LPs for which anesthesia information was available. All the procedures were performed in a dedicated area. We saw no significant differences in the incidence of TLP with respect to these MRFs. TLP was associated with age less than 1 year, black race, T lineage, a white blood cell count (WBC) of ≥50 × 109/L both at diagnosis and within 24 hours of LP, and a higher international normalized ratio (INR) in univariate analysis (see Table). Multivariable analysis, performed on variables available for all patients and showing P < 0.1 in univariate analysis, confirmed the association between TLP and age less than 1 year, black race, and a WBC of ≥50 × 109/L at diagnosis (see Table). INR also remained significant when adjusted for age at diagnosis, race, and WBC at diagnosis. We found no significant association between BLPs and the analyzed variables.Conclusions: Best practices were used in almost all cases in our recent cohort, and the incidences of TLP and BLP at diagnosis decreased markedly (to 7.9% and 1.5%, respectively). This decrease can be ascribed to the adoption of preventive factors (requirements for a PLT of ≥100 × 109/L, if possible; the most experienced practitioner; general anesthesia; and a dedicated procedure area). The previous association of TLP with the URFs age less than 1 year and black race was confirmed by this study. Our analysis suggests that LPs must be performed carefully in infants and black patients, as well as in those with WBCs of ≥50 × 109/L, and that it may be preferable to delay the first LP until peripheral blood blasts disappear and the INR is normal. [Display omitted] DisclosuresHoward:BTG: Consultancy, Research Funding; Shire: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Inaba:Shire: Research Funding.

Bone mineral density in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) can develop reduced bone mineral density (BMD). However, data from patients who received treatment on a frontline regimen without cranial irradiation are limited, and no genome-wide analysis has been reported. Lumbar BMD was evaluated by quantitative computed tomography at diagnosis, after 120 weeks of continuation therapy, and after 2 years off therapy in pediatric patients with ALL (ages 2-18 years at diagnosis) who were treated on the St. Jude Total XV Protocol. Clinical, pharmacokinetic, and genetic risk factors associated with decreased BMD Z-scores were evaluated. The median BMD Z-score in 363 patients was 0.06 at diagnosis, declined to -1.08 at week 120, but partly recovered to -0.72 after 2 years off therapy; BMD in patients with low BMD Z-scores at diagnosis remained low after therapy. Older age (≥10 years vs 2-9.9 years at diagnosis; P < .001), a higher BMD Z-score at diagnosis (P = .001), and a greater area under the plasma drug concentration-time curve for dexamethasone in weeks 7 and 8 of continuation therapy (P = .001) were associated with a greater decrease in BMD Z-score from diagnosis to week 120. Single-nucleotide polymorphisms in 2 genes important in osteogenesis and bone mineralization (COL11A1 [reference single-nucleotide polymorphism rs2622849]; P = 2.39 × 10-7 ] and NELL1 [rs11025915]; P = 4.07 × 10-6 ]) were associated with a decreased BMD Z-score. NELL1 (P = .003) also was associated with a greater dexamethasone area under the plasma drug concentration-time curve. BMD Z-scores decreased during therapy, especially in patients who had clinical, pharmacokinetic, and genetic risk factors. Early recognition of BMD changes and strategies to optimize bone health are essential. Cancer 2018;124:1025-35. © 2017 American Cancer Society.

Infant Lymphoblastic Leukemia: A Single Center Experience

Infantacute lymphoblastic leukemia (ALL) is a rare disease and consist of 4-5% of all childhood ALL. Despite improved survival rates of childhood ALL, infants with ALL have a worse prognosis . There were 206 patients diagnosed with ALL at Hacettepe University, Pediatric Hematology Department between 1 January 2008 and 31 December 2016, 11 out of 206 (5.3%) were diagnosed as infant ALL. We aimed to evaluate clinical findings, laboratory results and treatment outcome of our infant ALL patients retrospectively. There were 9 boys and two girls with a median age of 8 months (range 1-12 months) and nine out of 11 (82%) were older than 6 months of age at the initial diagnosis. Interestingly 2 of 3 siblings born from spontaneous triplet pregnancy diagnosed at the same time when they were 7 months old while the other sibling diagnosed 4 months later when he was 11 months old. Physical examination revealed hepatosplenomegaly in 10 out of 11 patients and 1 patient had extramedullary involvement with subcutaneous nodules on the forehead. On admission median WBC count was found 202x10-9/L (range 37.4-739x10-9/L) with a median hemoglobin level 9 g/dL (range 2.6-12.9 g/dL) and median platelet count 81x10-9/L (range10- 314x10-9/L). Immunophenotyping revealed CALLA+ B cell leukemia in 3 patients, CALLA- B cell in 6 patients and T cell leukemia in 2 patients. Cytogenetic analysis showed t(4;11) positivity in 4 patients and 3 of them were spontaneous triplets. Initial CNS involvement were positive in 2 of the patients. Eight patients (73%) were treated with Interfant protocols (Interfant 99 (n=4), Interfant 06 (n=4)) and 3 patients received Modified St. Jude Total XV protocol. Relapse were observed in 2 patients (one had both CNS and bone marrow relapse one year after the completion of chemotherapy and the other experienced an early bone marrow relapse at the 7thmonth of the treatment). Hematopoetic stem cell transplantation (HSCT) was performed in five patients from matched related donor (n=2), unmatched related donor(n=1), and matched unrelated donor(n=2). Moreover, relapse after HSCT was observed in 2 patients 3 and 4 months later; one received second transplantation and survived while the other died because of progressive disease. Four of the five patients who had HSCT survived 74 months, 45, 18 and 13 months after the initial diagnosis, respectively. After a median of 18 months (range 4- 74 months ) follow-up period 6 patients are alive (45 %) and on remission 4 after HSCT and 2 with only chemotherapy. Infant leukemia usually presents with high hyperleucocytosis and extramedullary involvement. The prognosis is poor and international colloborative studies reprorted that 4 year -event free survival rates were between 28-54%. Our results suggest that bone marrow transplantation seems to be a good and efficient choice of treatment. However there is still a big issue to decide which patient should go under transplantation and more studies are needed to reevaluate the eligibility criteria for HSCT in this group of patients. Moreover to the best of our knowledge infant leukemia in triplets without monozygocity were first time reported. DisclosuresNo relevant conflicts of interest to declare.

Asparaginase May Affect Mercaptopurine Tolerability in the Context of Multi-Agent Therapy for Acute Lymphoblastic Leukemia

▪Background: Mercaptopurine (MP) and asparaginase (ASP) are critical components in the treatment of acute lymphoblastic leukemia (ALL). Dose-limiting toxicities of the two drugs are common, resulting in therapy interruption, which has been associated with inferior treatment outcome in some studies. However, the interaction between these drugs has not been clearly identified. Merryman et al (Pediatr Blood Cancer 2012) reported that in DFCI ALL 05-01, patients had lower blood counts and more dosage reductions of MP during consolidation therapy (with concomitant ASP treatment) than during continuation therapy (identical treatment without concomitant ASP). Among groups of homogeneously treated patients with ALL, variability in ASP exposure due to inactivating antibodies can affect ASP pharmacodynamics: we have reported that ASP antibodies were associated with lower plasma ASP activity and higher dexamethasone (DEX) clearance, leading to a lower risk of osteonecrosis and a higher risk of CNS relapse (Liu, Leukemia 2012; Kawedia, Blood 2012). Here we studied the possible effect of ASP antibodies on MP tolerability in St. Jude Children's Research Hospital Total XV, a clinical trial featured intensive ASP treatment.Methods: A total of 390 children with ALL treated on St. Jude Total XV protocol were evaluable. TPMT genotype was used to guide starting doses of MP. During maintenance treatment, planned MP doses were higher on the low-risk arm (LR; n = 202) than on the standard/high-risk arm (SHR; n = 188). MP dose intensity was estimated as (prescribed dose)/(protocol dose) for weeks 1-146 (boys) or 1-120 (girls) for patients on the LR and SHR arms of maintenance therapy.Native E.coli-ASP (Elspar) was administered intramuscularly at 10000 U/m2 thrice weekly for 6 or 9 doses during remission induction. During maintenance therapy, patients on the LR arm received ASP only during reinductions I (weeks 7-9) and II (weeks 17-19), whereas those on the SHR arm received 19 weekly doses at 25000 U/m2 during weeks 1-19. Patients were tested for serum anti-Elspar antibodies at days 5, 19, 34 of remission induction, day 1 of reinduction I and day 1 of reinduction II, and were grouped based on whether they were ever positive for antibodies at any time during therapy or not. The area under the antibody concentration-time curve (AUC) for the entire period up to week 19 was also estimated in 360 patients.Result: Overall MP dose intensity was higher in those with vs without ASP antibodies in patients on the LR (median 83 vs 75%, P = 0.003) and SHR arms (median 86 vs 76%, P = 3.3 × 10-5; Figure 1A), and MP dose intensity was correlated with ASP antibody AUC in patients on both treatment arms (LR, P = 7.7 × 10-3 and SHR, P = 2.4 × 10-4; Figure 1B). In a multivariate model including age, sex, risk arm, ancestry, TPMT status, NUDT15 genotype and ASP antibody status, TPMT genotype was the strongest determinant of MP dose intensity (-17% in heterozygotes, P = 1.9 × 10-8), followed by ASP antibody positivity (+8.9% dose intensity in those with antibodies, P = 5.8 × 10-6). The model also confirmed previously identified associations of higher MP dose intensity with higher African ancestry (Bhatia et al. Blood 2014) (P = 1.8 × 10-4) and lower Asian ancestry (P = 0.05) (Yang et al. J Clin Oncol 2015).Conclusion: Interindividual differences in ASP systemic exposure, as reflected by ASP antibodies, had a strong impact on MP tolerance, especially in patients on the SHR arm who received intensive ASP therapy. We have previously shown that patients who are positive for ASP antibodies not only have lower exposure to ASP but also to dexamethasone (Kawedia, Blood 2012; Liu, Leukemia 2012). These data further emphasize the capacity for variation in ASP exposure to impact yet another critical component of ALL therapy. [Display omitted] DisclosuresEvans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.