Pediatric Acute Lymphoblastic Leukemia Research Articles

The Effects of Pediatric Acute Lymphoblastic Leukemia Treatment on Cardiac Repolarization.

Background: In recent years, cardiac dysfunction in childhood cancer survivors has become an important issue. Studies are focusing on identifying means for the early identification of patients at risk. Considering this, our study aims to investigate 24-hour Holter electrocardiogram (ECG) repolarization changes throughout doxorubicin (DOX) and cyclophosphamide (CPM) administration in pediatric patients treated for acute lymphoblastic leukemia (ALL). Methods: This was an investigator-driven, single-center, prospective, observational study. Enrolled children had a baseline bedside ECG examination performed before starting chemotherapy (T0). Serial Holter ECG examinations were conducted at three moments during their treatment protocol: day 8 (T1), day 29 (T2), and day 36 (T3). This study evaluated several ECG repolarization parameters, such as the QT interval, corrected QT interval (QTc), and QTc dispersion, as well as ST segment variations. Results: We evaluated 37 children diagnosed with ALL. The T0 examination revealed that over a third of patients had a resting heart rate (HR) outside the normal range for their age and sex. During chemotherapy, statistically significant increases in both HR as well as QT and QTc dispersion values were noticed, especially during the first DOX administration. What is more, a significant increase in the percentage of patients with ST segment depression from T1 to T2 and T3 was noticed. Rhythm disturbances were rare in the study population, with only a few patients presenting ventricular or supraventricular extrasystoles. Conclusions: This study reveals silent repolarization changes occurring early during anticancer treatment in children treated for ALL. These findings could aid in a better understanding of the cardiac toxicity mechanism, and they could potentially improve cardiac risk stratification for oncologic patients. Because of the small number of patients, our results need to be validated by larger studies.

Machine learning-based evaluation of prognostic factors for mortality and relapse in patients with acute lymphoblastic leukemia: a comparative simulation study

BackgroundPredicting mortality and relapse in children with acute lymphoblastic leukemia (ALL) is crucial for effective treatment and follow-up management. ALL is a common and deadly childhood cancer that often relapses after remission. In this study, we aimed to apply and evaluate machine learning-based models for predicting mortality and relapse in pediatric ALL patients.MethodsThis retrospective cohort study was conducted on 161 children aged less than 16 years with ALL. Survival status (dead/alive) and patient experience of relapse (yes/no) were considered as the outcome variables. Ten machine learning (ML) algorithms were used to predict mortality and relapse. The performance of the algorithms was evaluated by cross-validation and reported as mean sensitivity, specificity, accuracy and area under the curve (AUC). Finally, prognostic factors were identified based on the best algorithms.ResultsThe mean accuracy of the ML algorithms for prediction of patient mortality ranged from 64 to 74% and for prediction of relapse, it varied from 64 to 84% on test data sets. The mean AUC of the ML algorithms for mortality and relapse was above 64%. The most important prognostic factors for predicting both mortality and relapse were identified as age at diagnosis, hemoglobin and platelets. In addition, significant prognostic factors for predicting mortality included clinical side effects such as splenomegaly, hepatomegaly and lymphadenopathy.ConclusionsOur results showed that artificial neural networks and bagging algorithms outperformed other algorithms in predicting mortality, while boosting and random forest algorithms excelled in predicting relapse in ALL patients across all criteria. These results offer significant clinical insights into the prognostic factors for children with ALL, which can inform treatment decisions and improve patient outcomes.

Developmental and epileptic encephalopathies after successful treatment of pediatric ALL: A case series and review of literature.

Successful treatment of acute lymphoblastic leukemia (ALL) requires multiagent chemotherapy regimens and central nervous system prophylaxis, including intrathecal methotrexate. Although acute symptomatic seizures can occur during ALL treatment, epilepsy is less common. Furthermore, drug resistant epilepsy (DRE) is rare, presenting with two phenotypes: focal epilepsy, such as temporal lobe, or epileptic encephalopathies (EE), such as Lennox-Gastaut syndrome (LGS). For ALL survivors, the development of DRE has significant impact on morbidity, mortality, and quality of life. We describe four patients with ALL remission, who developed EEs, of which 3 had LGS. Mean age at ALL diagnosis was 1.9 years; range 1.1-2.5 years. All, but one, had normal development prior to ALL. No patient had CNS leukemic involvement. All patients received CNS prophylaxis with intrathecal methotrexate, without cranial radiotherapy. Three had symptomatic methotrexate neurotoxicity during treatment. The mean age at first seizure was 5.6 years; range 3.9-7.5 years, with a mean latency of 3.7 years from ALL diagnosis. All patients developed drug resistant EEs, moderate intellectual disability, and neuropsychiatric co-morbidities. Two patients had a minimal response to corpus callosotomy (CC), and one did not respond the ketogenic diet. Successful treatment of childhood ALL is rarely associated with the development of DRE and EEs. Young age at ALL diagnosis (<3 years) may be a predisposing factor. Palliative treatments, including ketogenic diet and CC have limited benefit in these patients. Individual genetic susceptibility to MTX toxicity is likely related to epileptogenesis, and further research is required for epilepsy biomarkers.

The significance of CD49f expression in pediatric B-cell acute lymphoblastic leukemia.

CD49f is an adhesion molecule present on malignant lymphoblasts in B-cell acute lymphoblastic leukemia; it is associated with a poor prognosis. CD49f expression has been proposed as a marker for measurable residual disease (MRD) marker, but this marker has yet to be implemented in clinical practice. In this study, we used flow cytometry to detect CD49f expression by leukemic blasts in paired bone marrow and cerebrospinal fluid samples at diagnosis and bone marrow at day 15 of treatment. At diagnosis, 93% of bone marrow and 100% of cerebrospinal fluid lymphoblasts expressed CD49f. The intensity of CD49f expression statisticallysignificantly increased during treatment (P < .001). In MRD-negative end-of-treatment samples, only a small population of hematogones expressed CD49f. Interestingly, the intensity of CD49f expression varied among the different groups of recurrent genetic abnormalities. The ETV6::RUNX1 fusion and ETV6::RUNX1 combined with the high hyperdiploid group were associated with increased expression, whereas the Philadelphia-like group showed low CD49f expression. The lower CD49f expression at diagnosis predicted a lower MRD rate at day 15 of treatment. We concluded that CD49f can be used as an MRD marker and possible prognostic factor in B-cell acute lymphoblastic leukemia.

Minimal Residual Disease in Pediatric Acute Lymphoblastic Leukemia

Background and ObjectiveThe detection of minimal residual disease at the end of initial therapy in Acute Lymphoblastic Leukemia to assess risk stratification is gaining clinical significance. While minimal residual disease assesses the extent of remission, remission is still defined by bone marrow morphology. The aim of this study is to determine the significance of minimal residual disease. Methods: In this cross-sectional study conducted at Zheen Oncology Center and Azadi hospital in Duhok, Iraq, data was collected from 46 patients’ records. Residual disease was detected by flow cytometry. On day 29 of induction therapy, a bone marrow sample was obtained for morphology and flow cytometry. The presence or absence of MRD was determined by using 8-color flow cytometry. Results: The median age of the study was 7 years and the male to female ratio was 1.7:1. B-cell lymphoblastic leukemia accounted for 80.43% and T-cell was 19.57%. Bloodounts at diagnosis revealed a mean white blood cell count of 74.32 x /L, mean hemoglobin level of 8.75, g/dL, and a mean platelet count of 97.84 x L. Minimal residual diease positive results were seen in 29 cases; 21 cases were of B-cell leukemia (56.75) and 8 (88.88) cases were T-cell leukemia. Minimal residual disease negative results were achieved in 17 cases; 43.24% were of B-cell origin (p value &lt;0.001), 11.11% were of T-cell origin (p value 0.008). Remission was achieved in 81.08 cases of B-cell (p value 0.103), and 66.66 of T-cell (p value 0.403). 16.21% of B-cell leukemia passed away (p value &lt;0.001) and 33.33% of T-cell leukemia (p value 0.065). Conclusion: Flow cytometry should be done in addition to bone marrow morphology.

Uncovering possible silent acquired long QT syndrome using exercise stress testing in long-term pediatric acute lymphoblastic leukemia survivors.

An example of chemotherapy-induced cardiotoxicity in cancer survivors is acquired long QT syndrome (aLQTS), which may cause serious yet preventable life-threatening consequences. Our objective was to identify and characterize childhood acute lymphoblastic leukemia (ALL) survivors with possible aLQTS using maximal exercise testing. In this cross-sectional study with exploratory analysis, a total of 250 childhood ALL survivors were evaluated for abnormal QT interval prolongation using the McMaster cycle exercise test. A total of 198 survivors (102 males; 96 females), having reached their peak (mean 32.1 ± 8.4 mL/kg/min; range 15.5-57.8 mL/kg/min), were included in our analyses. Two survivors were excluded for possible congenital LQTS. QT intervals were corrected for heart rate using the Bazett, Fridericia, and Rautaharju formulas at rest (supine, sitting, and standing positions), at the end of each stage of the CPET, and at 1, 3, and 5 minutes into the recovery period. The corrected QT (QTc) of borderline (n = 37) and long QT survivors (n = 20) was significantly longer than normal survivors (n = 141) at rest, exercise, and recovery. Out of 57 survivors presenting an abnormal QTc prolongation, 40 survivors (70%) showed no QT interval anomalies at rest but developed various anomalies during exercise. No significant differences were found between the groups for any of the measured clinical characteristics or cardiac parameters. The standardization of exercise testing in the regular follow-up of oncology patients is necessary for appropriate cardiac prevention and surveillance to enhance the health and quality of life of the ever-increasing number of cancer survivors.

Upregulation of Insulin-like Growth Factor-I in Response to Chemotherapy in Children with Acute Lymphoblastic Leukemia.

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1-17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): -1.2 SDS (-1.9 to -0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from -0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = -0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.

Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia

Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Thiopurine exposure was the most prominent source of new mutations in relapse, affecting over half of the studied patients in first and/or later relapse and causing potential relapse-driving mutations in multiple patients. Our data demonstrate that multiple mutational processes frequently act in parallel as prominent secondary drivers with dynamic activity during ALL development and progression.

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.

Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.

QRICH1 suppresses pediatric T-cell acute lymphoblastic leukemia by inhibiting GRP78

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that commonly affects children and adolescents with a poor prognosis. The terminal unfolded protein response (UPR) is an emerging anti-cancer approach, although its role in pediatric T-ALL remains unclear. In our pediatric T-ALL cohort from different centers, a lower QRICH1 expression was found associated with a worse prognosis of pediatric T-ALL. Overexpression of QRICH1 significantly inhibited cell proliferation and stimulated apoptosis of T-ALL both in vitro and in vivo. Upregulation of QRICH1 significantly downregulated 78 KDa glucose-regulated protein (GRP78) and upregulated CHOP, thus activating the terminal UPR. Co-overexpression of GRP78 in T-ALL cells overexpressing QRICH1 partially reverted the inhibited proliferation and stimulated apoptosis. QRICH1 bound to the residues Asp212 and Glu155 of the nucleotide-binding domain (NBD) of GRP78, thereby inhibiting its ATP hydrolysis activity. In addition, QRICH1 was associated with endoplasmic reticulum (ER) stress in T-ALL, and overexpression of QRICH1 reversed drug resistance. Overall, low QRICH1 expression is an independent risk factor for a poor prognosis of pediatric T-ALL. By inhibiting GRP78, QRICH1 suppresses pediatric T-ALL.

832P CLOMB: A validated scoring model to predict the relapse in the central nervous system of pediatric acute B-cell lymphoblastic leukemia

832P CLOMB: A validated scoring model to predict the relapse in the central nervous system of pediatric acute B-cell lymphoblastic leukemia

Episodes of acute methotrexate-related neurotoxicity linked to compromised long-term neurocognitive function.

Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12months post diagnosis (mean=4years) between ALL patients with (n=25) and without (n=146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p=.02) and attention (p=.02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention.

Prognostic significance and treatment strategies for IKZF1 deletion in pediatric B-cell precursor acute lymphoblastic leukemia

BackgroundThe predictive importance of IKZF1del in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown variability across different studies. Thus, the optimal treatment approach for children with IKZF1del BCP-ALL remains contentious, with the ongoing debate surrounding the use of IKZF1del-based high-risk stratification versus a minimal residual disease (MRD)-guided protocol.MethodsIKZF1 status was reliably determined in 804 patients using multiplex ligation-dependent probe amplification (MLPA) data obtained from four hospitals in Fujian, a province of China. In the Chinese Children Leukemia Group (CCLG)-ALL 2008 cohort, IKZF1 status was included in the risk assignment, with all IKZF1del patients receiving a high-risk regimen. Conversely, in the Chinese Children’s Cancer Group (CCCG)-ALL 2015 cohort, IKZF1del was not incorporated into the risk assignment, and patients were treated based on an MRD-guided risk stratification protocol.ResultsIKZF1del was found in 86 patients (86/804, 10.7%) overall and in 30 (30/46, 65.2%) BCR::ABL1-positive patients. Overall, IKZF1del was a poor prognostic predictor for patients, though the significance diminished upon age adjustment, white blood cell (WBC) count at diagnosis, treatment group, and MRD status. In the CCLG-ALL 2008 cohort, IKZF1del conferred a notably lower 5-year overall survival (OS) and event-free survival (EFS) and a significantly higher 5-year cumulative incidence of relapse (CIR) than IKZF1wt. In the CCLG-ALL 2015 cohort, IKZF1del conferred a lower 5-year OS and EFS and a higher 5-year CIR than IKZF1wt, but the differences were insignificant. The IKZF1del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) had a markedly lower 5-year OS and EFS compared with those treated with the MRD-guided protocol (CCCG-ALL 2015 protocol). Furthermore, patients treated with the CCLG-ALL 2008 high-risk regimen experienced a higher frequency of serious adverse events (SAEs), especially infection-related SAEs, compared with those treated with the CCCG-ALL 2015 MRD-guided protocol.ConclusionsThe prognostic effect of IKZF1del may vary in different protocols. Compared with higher intensity chemotherapy, the MRD-guided protocol may be a more effective approach to treating BCP-ALL with IKZF1del in children.

Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia

Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions.

Asparaginase-Associated Pancreatitis in Pediatric Acute Lymphoblastic Leukemia

Asparaginase-Associated Pancreatitis in Pediatric Acute Lymphoblastic Leukemia

Predictive Value of CTLA-4/PD-1 Gene Polymorphisms and Susceptibility to Pediatric Acute Lymphoblastic Leukemia

Predictive Value of CTLA-4/PD-1 Gene Polymorphisms and Susceptibility to Pediatric Acute Lymphoblastic Leukemia

Prognostic significance of CRLF2 in patients with acute lymphoblastic leukemia: a meta-analysis and systematic review.

The association between cytokine receptor-like factor 2 (CRLF2) and clinical outcomes in acute lymphoblastic leukemia (ALL) has been a topic of ongoing debate, with divergent findings. This article intended to investigate the influence of CRLF2 alterations on ALL prognosis. Following the PRISMA 2020 guidelines, this meta-analysis was conducted. Hazard ratio (HR) values and confidence intervals (CIs) were the primary statistical measures used. Data heterogeneity was judged using the chi-square test and I2 statistic. Publication bias was appraised with funnel plots, Begg's test, and Egger's test. 16 studies with 6771 patients were finally screened out. CRLF2 over-expression (CRLF2 OE) was associated with poorer event-free survival (EFS) (HR = 1.70, 95% CI = 1.18-2.44, P = 0.004) and relapse-free survival (RFS) (HR = 1.70, 95% CI = 1.28-2.24, P = 0.000) in pediatric ALL. Patients with CRLF2-deregulation (CRLF2-d), also known as CRLF2 rearrangement, exhibited shorter overall survival (OS) (HR = 2.22, 95% CI = 1.49-3.32, P = 0.000), EFS (HR = 1.93, 95% CI = 1.43-2.60, P = 0.000), and RFS (HR = 2.2, 95% CI = 1.53-3.18, P = 0.000) compared to those without CRLF2-d. Subgroup analysis of multivariate HRs and corresponding CIs indicated that childhood with CRLF2 OE had a shorter RFS (HR = 1.70, 95% CI = 1.28-2.24, P = 0.006), and CRLF2-d was identified as an independent prognostic biomarker for OS (HR = 2.22, 95% CI = 1.49-3.32, P = 0.000), EFS (HR = 1.95, 95% CI = 1.44-2.64, P = 0.000), and RFS (HR = 2.2, 95% CI = 1.53-3.18, P = 0.000) in pediatric ALL patients. Both CRLF2 OE and CRLF2-d are associated with poor prognosis in ALL patients.

TP53 variants underlying pediatric low-hypodiploidy B-cell acute lymphoblastic leukemia demonstrate diverse origins and may persist as a hematopoietic clone in remission.

Pediatric low-hypodiploidy B-cell acute lymphoblastic leukemia (LH-ALL) with TP53 variants has been proposed to be considered a manifestation of Li-Fraumeni syndrome (LFS). However, our study demonstrates that of the majority the pathogenic variants in the TP53 gene are somatic (70.5%), and only 12.5% of patients with germline fulfilled the criteria of LFS. We also describe the first case of hypodiploid BCP-ALL with a mosaic pathogenic mutation in TP53 and the first case of the persistence of clonal hematopoiesis with the TР53 gene mutation in the child during 3-year minimal residual disease-negative remission, similar to what has been described in adults.

Symptomatic osteonecrosis in children treated for Hodgkin lymphoma: A population-based study in Sweden, Finland, and Denmark.

Osteonecrosis (ON) is a potentially disabling skeletal complication of cancer treatment. Although symptomatic osteonecrosis (sON) is well-known in acute lymphoblastic leukemia (ALL), with an incidence around 6%, studies on sON in pediatric Hodgkin lymphoma (HL) are scarce. The aim of this study was to examine the incidence, risk factors, and outcome of sON in children treated for HL. A total of 490 children under 18, diagnosed with HL between 2005 and 2019 in Sweden, Finland, and Denmark were eligible for the study. Data on patient characteristics, HL treatment, and development of sON were collected from patients' medical records. Magnetic resonance imaging scans were used to establish ON diagnosis and grade ON according to the Niinimäki grading system. Cumulative 2-year incidence of sON among the 489 included patients was 5.5% (n=30). The risk for developing sON was higher for those with older age (odds ratio [OR] 1.25, 95% confidence interval [CI]: 1.05-1.49, p<.010), female sex (OR 4.45, CI 1.87-10.58, p<.001), high total cumulative glucocorticoid (GC) doses (OR 1.76, 95% CI: 1.21-2.56, p=0.003), and advanced HL (OR 2.19, 95% CI: 1.03-4.65, p=.042). Four (13.3%) patients underwent major surgical procedures and 13 (43.3%) had persistent symptoms due to ON at follow-up. This study shows that sON is as common in pediatric HL as in pediatric ALL, with risk factors such as older age, female sex, high cumulative GC doses, and advanced HL. Future HL protocol development should aim to reduce the burden of ON by modifying GC treatment.

Delineation of features, responses, outcomes, and prognostic factors in pediatric PDGFRB-positive acute lymphoblastic leukemia patients: A retrospective multicenter study.

PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. The authors identified 28 pediatric PDGFRB-positive ALL. They analyzed the features, outcomes, and prognostic factors of this disease. This multicenter, retrospective study included 6457 pediatric patients with newly diagnosed PDGFRB fusion ALL according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 20 hospitals in China. Of these patients, 3451 were screened for PDGFRB fusions. Pediatric PDGFRB-positive ALL accounted for only 0.8% of the 3451 cases tested for PDGFRB. These patients included 21 males and seven females and 24 B-ALL and 4 T-ALL; the median age was 10 years; and the median leukocyte count was 29.8 × 109/L at baseline. Only one patient had eosinophilia. Three patients had an IKZF1 deletion, three had chromosome 5q31-33 abnormalities, and one suffered from a complex karyotype. The 3-year event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were 33.1%, 65.5%, and 32.1%, respectively, with a median follow-up of 25.5 months. Twenty patients were treated with chemotherapy plus tyrosine-kinase inhibitors (TKIs) and eight were treated without TKI. Complete remission (CR) rates of them were 90.0% and 63.6%, respectively, but no differences in EFS, OS, or CIR. Univariate analyses showed patients with IKZF1 deletion or measurable residual disease (MRD) ≥0.01% after induction had inferior outcomes (p<.05). Pediatric PDGFRB-positive ALL has a poor outcome associated with high-risk features. Chemotherapy plus TKIs can improve the CR rate, providing an opportunity for lower MRD levels and transplantation. MRD ≥0.01% was a powerful adverse prognostic factor, and stratified treatment based on MRD may improve survival for these patients. Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high-risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse. Chemotherapy plus tyrosine-kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB-positive acute lymphoblastic leukemia (ALL) patients. The MRD level was also a powerful prognostic factor for pediatric PDGFRB-positive ALL patients.