Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

Association of Insulin-like Growth Factor-1 with Bone Mineral Density in Survivors of Childhood Acute Leukemia.

In this study, we investigated bone mineral deficits in children who survived childhood acute leukemia and explored the association between the insulin-like growth factor-1 (IGF-1) level and bone mineral density (BMD). This retrospective analysis enrolled 214 patients treated for acute leukemia, measuring various factors including height, weight, body mass index (BMI), and lumbar spine BMD after the end of treatment. The study found an overall prevalence of low BMD in 15% of participants. Notably, IGF-1 levels were significantly different between patients with low BMD and those with normal BMD, and correlation analyses revealed associations of the IGF-1 level and BMI with lumbar spine BMD. Regression analyses further supported this relationship, suggesting that higher IGF-1 levels were associated with a decreased risk of low BMD. The study findings suggest that IGF-1 may serve as a valuable tool for evaluating and predicting osteoporosis in survivors of childhood acute leukemia.

A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real-World Data: A Retrospective Observational Study.

Background: Rapid reduction of leukemic cells in the bone marrow during remission induction chemotherapy (RIC) can lead to significant complications such as tumor lysis syndrome (TLS). We investigated whether prephase steroid treatment before RIC could decrease TLS incidence and improve overall survival in pediatric patients with acute lymphoblastic leukemia (ALL). Methods: Data were extracted from the Common Data Model databases in two tertiary-care hospitals in Seoul, South Korea. Patients were classified into the treated or untreated group if they had received RIC with prephase steroid treatment ≥7 days before RIC in 2012-2021 or not, respectively. Stabilized Inverse Probability of Treatment Weighting (sIPTW) was applied to ensure compatibility between the treated and untreated groups. The incidence of TLS within 14 days of starting RIC, overall survival (OS), and the incidence of adverse events of special interest were the primary endpoints. Multiple sensitivity analyses were performed. Results: Baseline characteristics were effectively balanced between the treated (n=308.4) and untreated (n=246.6) groups after sIPTW. Prephase steroid treatment was associated with a significant 88% reduction in the risk of TLS (OR 0.12, 95% CI: 0.03-0.41). OS was numerically greater in the treated group than in the untreated group although the difference was not statistically significant (HR 0.64, 95% CI 0.25-1.64). The treated group experienced significantly elevated risks for hyperbilirubinemia and hyperglycemia. The reduction in TLS risk by prephase steroid treatment was maintained in all of the sensitivity analyses. Conclusion: Prephase steroid treatment for ≥7 days before RIC in pediatric patients with ALL reduces the risk of TLS, while careful monitoring for toxicities is necessary. If adequately analyzed, real-world data can provide crucial effectiveness and safety information for proper management of pediatric patients with ALL, for whom prospective randomized studies may be difficult to perform for ethical and practical reasons.

Front-Line Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia: A Study on Efficacy and Safety.

We conducted a retrospective study on 51 pediatric patients with newly diagnosed chronic myeloid leukemia chronic phase or accelerated phase. The patients were classified into the IMA group (N = 33), treated with imatinib, and the DSA group (N = 18), treated with dasatinib, as front-line tyrosine kinase inhibitors (TKIs). At 12 months, the rates of complete cytogenetic response were similar between the IMA group (92.3%) and DSA group (100%) (p = 0.305). However, the rate of early molecular response was higher in the DSA group than in the IMA group (100.0% vs. 80.0%, p = 0.043). By 12 and 24 months, the DSA group showed faster and higher cumulative rates of both major (DSA group: 72.2% and 100%, respectively; IMA group: 41.2% and 68.7%, respectively; p = 0.002) and deep molecular responses (DSA group: 26.0% and 43.6%, respectively; IMA group: 13.8% and 17.5%, respectively; p = 0.004). Both TKIs were well tolerated. Although the height standard deviation scores decreased in both groups, the height decline was greater in the DSA group between one and two years from the start of TKI therapy. In this study, dasatinib achieved faster and higher molecular responses with an acceptable safety profile. Further follow-up is necessary to assess the long-term outcomes of TKI treatment in children.

Proven Cytomegalovirus Colitis Associated with Dasatinib Administration in Two Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Gastrointestinal (GI) bleeding is a rare adverse event of dasatinib, which is known to be caused by dasatinib-induced colitis, severe thrombocytopenia, and platelet dysfunction. We present two cases of pediatric patients who developed hematochezia during treatment with dasatinib after hematopoietic stem cell transplantation (HSCT). A colonic tissue biopsy was performed to differentiate the cause of GI bleeding. Both patients were diagnosed with proven cytomegalovirus (CMV) colitis, but only one was treated with ganciclovir. The patient who did not receive antiviral therapy experienced recurrent GI bleeding during dasatinib administration, leading to multiple treatment interruptions. During dasatinib therapy after HSCT, patients with GI bleeding and confirmed CMV colitis may benefit from antiviral therapy to reduce interruptions in dasatinib therapy.

Current Status and Physicians' Perspectives of Childhood Cancer Survivorship in Korea: A Nationwide Survey of Pediatric Hematologists/Oncologists.

BACKGROUND: Data on the status of long-term follow-up (LTFU) care for childhood cancer survivors (CCSs) in Korea is lacking. This study was conducted to evaluate the current status of LTFU care for CCSs and relevant physicians' perspectives. METHODS: A nationwide online survey of pediatric hematologists/oncologists in the Republic of Korea was undertaken. RESULTS: Overall, 47 of the 74 board-certified Korean pediatric hematologists/oncologists currently providing pediatric hematology/oncology care participated in the survey (response rate = 63.5%). Forty-five of the 47 respondents provided LTFU care for CCSs five years after the completion of primary cancer treatment. However, some of the 45 respondents provided LTFU care only for CCS with late complications or CCSs who requested LTFU care. Twenty of the 45 respondents oversaw LTFU care for adult CCSs, although pediatric hematologists/oncologists experienced more difficulties managing adult CCSs. Many pediatric hematologists/oncologists did not perform the necessary screening test, although CCSs had risk factors for late complications, mostly because of insurance coverage issues and the lack of Korean LTFU guidelines. Regarding a desirable LTFU care system for CCSs in Korea, 27 of the 46 respondents (58.7%) answered that it is desirable to establish a multidisciplinary CCSs care system in which pediatric hematologists/oncologists and adult physicians cooperate. CONCLUSION: The LTFU care system for CCS is underdeveloped in the Republic of Korea. It is urgent to establish an LTFU care system to meet the growing needs of Korean CCSs, which should include Korean CCSs care guidelines, provider education plans, the establishment of multidisciplinary care systems, and a supportive national healthcare policy.

Case report: First report of isolated central nervous system lymphoblastic crisis in a child with chronic myeloid leukemia on dasatinib therapy.

Most children with chronic myeloid leukemia (CML) present with the chronic phase (CML-CP) at diagnosis, exhibiting an excellent treatment response to contemporary tyrosine kinase inhibitors (TKIs). However, despite TKI therapy, patients with CML-CP may progress to blastic crisis (BC). CML-BC rarely occurs in extramedullary sites, and isolated central nervous system (CNS) BC is an extremely rare condition. It may with present various neurologic symptoms that necessitates differential diagnosis from other causes such as TKI toxicity. Information on the diagnosis and treatment of this condition is lacking, as are well-established diagnostic criteria. Here, we report a case of isolated CNS lymphoblastic crisis in a child with CML-CP who was treated with dasatinib. The patient, an 8-year-old girl, was admitted owing to visual disturbance and severe headache. We highlight the importance of a CSF study for the differential diagnosis of CNS BC in patients with CML-CP who present with common neurologic symptoms during TKI therapy.

Self-reported physical activity behaviors of childhood cancer survivors: comparison to a general adolescent population in Korea.

PURPOSE: Adequate physical activity (PA) can significantly contribute to the prevention of undesirable health outcomes in childhood cancer survivors (CCS). This study aimed to identify the patterns of PA and related factors in Korean CCS. METHODS: Study subjects were 184 adolescents selected from an ongoing cohort study of Korean CCS and 1,840 sex- and school grade-matched controls randomly selected from the participants of the 2019 Korea Youth Risk Behavior Web-based Survey. Information on PA and sedentary behaviors was collected by self-administered questionnaire. We estimated body mass index (BMI)-adjusted odds ratio (OR) and 95% confidence interval (CI) for the advisable healthy behaviors of CCS compared with healthy controls using conditional logistic regression analysis. In addition, the associations of advisable healthy behaviors of CCS with sociodemographic and clinical factors were estimated using multiple logistic regression analysis. RESULTS: CCS were less likely to be physically active than controls, but this finding was evident only in males. The ORs (95% CIs) for regular exercise, moderate intensity PA, vigorous intensity PA, and walking were 0.42 (0.27-0.65), 0.39 (0.24-0.63), 0.53 (0.33-0.84), and 0.64 (0.42-0.98), respectively, in male CCS compared with same-sex controls. Compared with same-sex controls, male CCS were 4.60 times and female survivors were 15.19 times more likely to sleep longer than 8 h a day. Among CCS, males were 2.92 times and 3.07 times more likely to perform moderate intensity PA and muscle-strengthening exercise, respectively, than female. Higher BMI (OR: 1.16), highest family income (OR: 3.98), and a caregiver who performed regular exercise (OR: 2.08) were positively associated with vigorous intensity PA of CCS. With increasing time after treatment completion, the probability of engaging in sedentary activity for less than 6 h per day decreased (OR = 0.89, 95% CI 0.79-1.00). CONCLUSION: Korean adolescent CCS were physically inactive compared with control adolescents. Several sociodemographic factors such as sex, family income, caregiver PA, and obesity level were associated with PA behaviors of CCS. IMPLICATIONS: Strategic effort would be needed to increase physical activity of childhood cancer survivors in adolescent period with consideration of various sociodemographic factors found in this study.

Epidemiologic and Clinical Outcomes of Pediatric Renal Tumors in Korea: A Retrospective Analysis of The Korean Pediatric Hematology and Oncology Group (KPHOG) Data.

PURPOSE: Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea. MATERIALS AND METHODS: From January 2001 to December 2015, data of pediatric patients (0-18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed. RESULTS: Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001). CONCLUSION: The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.

Short-term effect of growth hormone treatment in childhood leukemia survivors with growth hormone deficiency.

PURPOSE: Survivors of childhood leukemia are at risk of growth impairment due to intensive chemotherapy and radiation treatments. This study investigated the auxological and biochemical characteristics of childhood leukemia survivors diagnosed with growth hormone deficiency (GHD) and the changes in these parameters after 1 year of growth hormone (GH) treatment. METHODS: A total of 24 children diagnosed with GHD after leukemia treatment was analyzed. Clinical and biochemical data were collected retrospectively at leukemia diagnosis, GHD diagnosis, and 1 year after GH treatment. Standard deviation score (SDS) was calculated based on the age- and gender-adjusted population. RESULTS: Of the 24 children included in this study, 19 received GH treatment. The median age at GHD diagnosis was 12.3 years, and the median delay in bone age was 1.46 years. Height SDS decreased from -0.69 at leukemia diagnosis to -2.58 at GHD diagnosis (P<0.001). The change in height SDS with and without GH for 1 year was 0.35 and -0.21, respectively (P=0.044). In regression analyses, higher height SDS at GHD diagnosis and a smaller decrease of the height SDS between leukemia and GHD diagnoses were positively correlated with height SDS after GH treatment. CONCLUSION: GH treatment could be beneficial and safe for improving height in childhood leukemia survivors with GHD. Height SDS at GHD diagnosis and reduction of height SDS between leukemia and GHD diagnosis could be potential factors in predicting the therapeutic effects. Close auxological monitoring is recommended for any childhood leukemia survivors who experience posttreatment height decline.

Factors affecting bone mineral density in children and adolescents with secondary osteoporosis.

PURPOSE: This study aimed to investigate the clinical factors associated with bone mineral density (BMD) among children and adolescents with osteoporosis secondary to treatment for underlying clinical conditions. METHODS: We retrospectively reviewed the medical records of patients aged 10-18 years and evaluated them for lumbar spine BMD (LSBMD) after treatment for underlying diseases, including hemato-oncologic, rheumatologic system, and inflammator y bowel diseases. LSBMD measured by dual-energy x-ray absorptiometry (DXA) performed from March 2019 to March 2021 was evaluated. We analyzed 117 patients who underwent initial DXA after treatment for underlying diseases. RESULTS: Subjects in this study had multiple underlying diseases: hemato-oncologic (78.6%), rheumatologic (11.1%), and inflammatory bowel diseases (10.3%). There was no significant association between the z-score and bone metabolic markers (P>0.05). However, higher cumulative glucocorticoid (GC) dose significantly reduced LSBMD z-score (P=0.029). Moreover, the association between cumulative dose of GC and initial z-score of LSBMD was significant in logarithmic regression analysis (P=0.003, R2=0.149). GC accumulation was a significant risk factor for vertebral fracture when the initial BMD was evaluated after treatment (P=0.043). Bone metabolic markers did not significantly influence the risk of vertebral fracture. CONCLUSION: Initial bone mass density of the lumbar spine evaluated after long-term GC use for underlying diseases is a predictor of further vertebral fractures.

Serologic status and vaccine response against hepatitis B virus after allogeneic hematopoietic cell transplantation in pediatric patients.

BACKGROUND: Although vaccination against hepatitis B virus (HBV) is recommended for hematopoietic cell transplantation (HCT) recipients, previous studies evaluating serologic status and immunologic response to HBV vaccination in pediatric allogeneic HCT recipients are not enough. OBJECTIVE: This study aimed to evaluate serologic status against HBV and immunologic responses to HBV vaccination in children and adolescents receiving allogeneic HCTs. METHODS: Medical records of the enrolled 61 pediatric patients < 19 years of age who received their first allogeneic HCTs were retrospectively reviewed. RESULTS: Twenty-two (36.1%) of the enrolled patients were positive for hepatitis B surface antibody (HBsAb) after HCT. Chronic graft-versus-host disease was significantly associated with negative HBsAb status after HCT (p = 0.01). With one dose of HBV vaccination after HCT, 40.5% of the vaccinated patients became positive for HBsAb. No clinical factor was associated with the positive conversion of HBsAb after vaccination. CONCLUSIONS: Considering the unsatisfactory seropositive rate and vaccine response against HBV and the lack of significant clinical and laboratory factors predicting serostatus in HCT recipients, universal three doses of HBV vaccination should be necessary after allogeneic HCT.

High-Dose Busulfan-Fludarabine Conditioning and Low Alveolar Volume as Predictors of Pulmonary Complications after Allogeneic Peripheral Blood Stem Cell Transplantation in Children.

This study was conducted to investigate risk factors and predictors of infectious and noninfectious pulmonary complications (PCs) after allogeneic hematopoietic stem cell transplantation in children. We conducted a retrospective analysis of the post-transplantation PCs of 240 patients who underwent allogeneic peripheral blood stem cell transplantation (allo-PBSCT) between 2009 and 2018. Transplantation-related variables, pretransplantation baseline spirometry, body plethysmography, and CO diffusing capacity were analyzed for association with the development of infectious PCs (IPCs) and noninfectious PCs (NIPCs). Compared with the control group, the PC group had statistically significantly lower overall survival (50.6% versus 77.8%; P < .001), higher disease-related mortality (26.6% versus 54.4%; P < .001), and higher nonrelapse mortality (31.6% versus 5.9%; P < .001). A greater number of patients received pretransplantation conditioning with high-dose busulfan (520 mg/m2; Bu 520) and fludarabine (160 mg/m2; Flu 160) in both the IPC and NIPC groups. In the multivariate Cox hazard regression analysis, Bu 520 significantly increased the risk of NIPCs (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.13 to 3.49; P = .016), and Flu 160 was a predictor of IPCs (HR, 1.99; 95% CI, 1.13 to 3.49; P = .016). The Bu 520 + Flu 160 regimen was associated with a statistically significant increase in the risk of NIPC (HR, 1.92; 95% CI, 1.09 to 3.37; P = .023). In a multivariate analysis using pretransplantation baseline lung function, alveolar volume (VA) grades 3 and 4 and lung function score (LFS) VA categories III and IV were associated with increased risk for both IPCs and NIPCs. Our data identify receipt of the high-dose Bu-Flu conditioning regimen as an independent risk factor for NIPCs after allo-PBSCT. Impaired CO diffusing capacity before transplantation, especially VA reduction, contributes to the risk of post-transplantation pulmonary complications, and pretransplantation risk can be estimated by grading the degree of insufficiency of VA and LFS VA.

Prognostic impact of total body irradiation dose in pediatric acute lymphoblastic leukemia patients treated with allogeneic hematopoietic stem cell transplantation in second complete remission.

Background: Allogeneic HSCT may improve survival in pediatric ALL patients who relapse. In this study, we analyzed the outcome and prognostic factors of 62 ALL patients (35 male, 56.5%) who received allogeneic HSCT in second complete remission (CR) at our institution between April 1st 2009 and December 31st 2019. Methods: The median time from diagnosis to relapse was 35.1 months (range, 6.0‒113.6 mo). Fifty-three patients (85.5%) experienced bone marrow relapse only. The number of patients who received transplant according to each donor type was as follows: HLA matched family donor 17 (27.4%), matched unrelated donor (UD) 22 (35.5%), mismatched donor 23 (37.1%). All patients received HSCT with a myeloablative conditioning, 58 patients (93.5%) with the incorporation of TBI [31 patients 12 Gray (Gy), 24 patients 13.2 Gy, 3 patients 8 Gy]. Results: The 5-year event-free survival (EFS), and overall survival of the study group was 41.3±6.3% (26/62), and 42.3±6.6% (27/62), respectively. The cumulative incidence of relapse and transplant-related mortality was 57.1±6.4% and 1.6±1.6%, respectively. Infant ALL, shorter time from diagnosis to relapse, and TBI dose of 12 Gy, rather than 13.2 Gy, resulted in significantly worse EFS. In multivariate analysis, infant ALL and TBI dose of 12 Gy during conditioning predicted significantly lower EFS. Conclusion: In our study group, treatment with a higher dose of TBI during conditioning resulted in better EFS for ALL patients who underwent HSCT in second CR. Further study is needed to determine potential long-term complications associated with a higher TBI dose.

Dental developmental complications in pediatric hematopoietic stem cell transplantation patients: A study using CMC clinical data warehouse.

OBJECTIVE: This study aimed to investigate the prevalence and extent of dental developmental complications in patients who have undergone pediatric hematopoietic stem cell transplantation (SCT) and identify the risk factors. MATERIALS AND METHODS: We retrospectively investigated the clinical data warehouse of the Catholic Medical Center information system for identifying patients who: 1) visited the Department of Pediatrics between 2009 and 2019, 2) underwent SCT under the age of 10, and 3) had panoramic radiographs. Thus 153 patients were included in this study. The prevalence and extent of tooth agenesis, microdontia, and root malformation were assessed using panoramic radiographs obtained after SCT, and the risk factors were analyzed using regression analysis. RESULTS: All 153 patients had at least one dental anomaly. When grouped according to the age at initial chemotherapy (≤ 2.5; 2.6-5.0; 5.1-7.5; > 7.5 years), the prevalence of agenesis showed statistically significant differences among the different age groups (P < 0.001). The prevalence of agenesis was highest in the youngest age group. As the initial age at chemotherapy increased, the number of affected teeth per patient decreased for all three anomalies. The location of the affected tooth was also influenced by the age at initial chemotherapy. Regression analysis demonstrated that young age at initial chemotherapy was a risk-increasing factor for tooth agenesis and microdontia. CONCLUSIONS: The age at initial chemotherapy may be a critical factor in determining the type, extent, and location of dental complications after SCT. These results suggest that careful dental follow-up and timely treatment are recommended for pediatric patients undergoing SCT.

Parent caregivers' preferences and satisfaction with currently provided childhood cancer survivorship care.

PURPOSE: The aim of this study was to investigate the level of satisfaction of parent caregivers of childhood cancer survivors (CCSs) with currently provided survivorship care and their preferences for survivorship care provider. METHODS: Study subjects were parent caregivers recruited at three hospitals in Korea. Study data were collected from self-administered questionnaires and medical records. We assessed parent caregivers' levels of satisfaction with specific survivorship care contents and preferred types of survivorship care provider among oncologists, primary care physicians (PCPs), and institutional general physicians (IGPs). Factors associated with parent caregivers' preferences for survivorship care provider were evaluated by multiple logistic regression analysis. RESULTS: 680 parent caregivers (mother 62.1% and father 37.9%) of 487 CCSs (mean age at diagnosis: 6.9 ± 5.1 years; mean time since treatment completion 5.4 ± 4.4 years) were included. Parent caregivers' dissatisfaction was the highest with screening for second primary cancer, followed by psychosocial problem management. Higher educational level of parent caregiver, parent caregiver's higher level of dissatisfaction with currently provided care, higher age of CCSs at cancer diagnosis, history of receiving hematopoietic stem cell transplant, and longer time lapse after cancer treatment were significantly associated with parent caregivers' higher preference for PCPs or IGPs than oncologists. Parent caregiver's multiple comorbidities and higher fear of cancer recurrence were associated with parent caregivers' higher preference for oncologists than PCPs or IGPs. Around 80% of parent caregivers recognized that a shared care system was helpful for promoting the health of CCSs. CONCLUSION: Parent caregivers were substantially dissatisfied with currently provided care, especially regarding the health issues not directly associated with the primary cancer. Parent caregivers' preferences for survivorship care provider is influenced by multiple factors, including age and survival time of CCSs, characteristics of parent caregivers, satisfaction level with care, and specific survivorship care contents. IMPLICATIONS FOR CANCER SURVIVORS: The findings of our study suggest that shared survivorship care for CCSs with consideration of specific care contents can complement the current oncologist-led survivorship care system.

Spectrum of Genetic Mutations in Korean Pediatric Acute Lymphoblastic Leukemia.

The wide application of next-generation sequencing (NGS) technologies has led to the discovery of multiple genetic alterations in pediatric acute lymphoblastic leukemia (ALL). In this work, we aimed to investigate the mutational spectrum in pediatric ALL. We employed a St. Mary's customized NGS panel comprising 67 leukemia-related genes. Samples were collected from 139 pediatric ALL patients. Eighty-five patients (61.2%) harbored at least one mutation. In B-cell ALL, the RAS pathway is the most involved pathway, and the three most frequently mutated genes were NRAS (22.4%), KRAS (19.6%), and PTPN11 (8.4%). NRAS and PTPN11 were significantly associated with a high hyperdiploidy karyotype (p = 0.018 and p < 0.001, respectively). In T-cell ALL, the three most frequently mutated genes were NOTCH1 (37.5%), FBXW7 (16.6%), and PTEN (6.2%). Several pairs of co-occurring mutations were found: NRAS with SETD, NRAS with PTPN11 in B-cell ALL (p = 0.024 and p = 0.020, respectively), and NOTCH1 with FBXW7 in T-cell ALL (p < 0.001). The most frequent newly emerged mutation in relapsed ALL was NT5C2. We procured comprehensive genetic information regarding Korean pediatric ALL using NGS technology. Our findings strengthen the current knowledge of recurrent somatic mutations in pediatric ALL.

Clinical implication of minimal residual disease assessment by next-generation sequencing-based immunoglobulin clonality assay in pediatric B-acute lymphoblastic leukemia.

Measuring minimal residual disease (MRD) during treatment is valuable to identify acute lymphoblastic leukemia (ALL) patients who require intensified treatment to avert relapse. We performed the next-generation sequencing (NGS)-based immunoglobulin gene (Ig) clonality assay and evaluated its clinical implication in pediatric B-ALL patients to assess MRD. Fifty-five patients who were diagnosed and treated with de novo (n = 44) or relapsed/refractory B-ALL (n = 11) were enrolled. MRD assessment was performed using the LymphoTrack® Dx IGH and IGK assay panels. The percentage of the clonal sequences per total read count was calculated as MRD (% of B cells). The data were normalized as the proportion of total nucleated cells (TNC) by LymphoQuant™ Internal control or the B-cell proportion in each sample estimated by flow cytometry or immunohistochemistry. Clonal Ig rearrangement was identified in all patients. The normalized MRD value was significantly lower than the unnormalized MRD value (p < 0.001). When categorizing patients, 27 of 50 patients (54%) achieved normalized MRD <0.01%, while 6 of them did not achieve MRD <0.01% when applying the unnormalized value. The normalized post-induction MRD value of 0.01% proved to be a significant threshold value for both 3-year event-free survival (100% for MRD <0.01% vs. 60.9% ± 10.2% for MRD ≥0.01%, p = 0.007) and 3-year overall survival (100% for MRD <0.01% vs. 78.3% ± 8.6% for MRD ≥0.01%, p = 0.011). However, unnormalized MRD was not a significant factor for outcome in this cohort. Our study demonstrated that MRD assessment by NGS-based Ig clonality assay could be applied in most pediatric B-ALL patients. Normalized post-induction MRD <0.01% was a significant prognostic indicator.

Discontinuation of tyrosine kinase inhibitors based on BCR-ABL1 monitoring by digital droplet PCR in pediatric chronic myeloid leukemia.

Lifelong treatment of pediatric chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitors (TKIs) can affect their growth and development. For these reasons, clinical trials have explored the feasibility of TKI discontinuation in children with a sufficient TKI response. We evaluated the analytical performance of digital droplet PCR (ddPCR) to quantify BCR-ABL1 and compared the results with reverse transcription quantitative polymerase chain reaction (RT-qPCR). We further investigated whether ddPCR could be used to determine TKI discontinuation in a clinical setting. Performance of ddPCR was evaluated using standard materials for BCR-ABL1, and a total of 197 clinical samples from 45 pediatric CML patients was included for comparison with RT-qPCR. ddPCR showed excellent analytical sensitivity with 0.001% international scale (IS) and linearity with R 2 > 0.99 in log scale. BCR-ABL1 % IS results correlated well with those of RT-qPCR (R 2 = 0.9435), however, they showed a moderate strength for agreement with a Cohen's kappa of 0.41 due to higher sensitivity of ddPCR. Among 45 pediatric CML patients, 42 were treated with first-line TKIs including imatinib (n = 27, 64%) and dasatinib (n = 12, 29%), and three patients that were started with imatinib were switched to dasatinib. When we evaluated whether follow-up samples fulfilled ABL1 copies ≥ 10,000 required for deep molecular response (DMR), all samples were acceptable by ddPCR, whereas 18% by RT-qPCR did not reached acceptable ABL1 copies. Moreover, 52 and 13% reached ABL1 copies ≥ 32,000 required for MR4.5 by ddPCR and RT-qPCR, respectively. Seven patients discontinued TKI and the median TKI treatment duration was 73 months prior to discontinuation. Prior to discontinuation, the median duration of sustained undetected BCR-ABL1 was 60 months. Two patients experienced loss of major MR (MMR) during follow-up and restarted dasatinib 5 months after discontinuation. They achieved MMR again and maintained better than DMR afterward. Results from those patients demonstrated that RT-qPCR did not match the need for adequate ABL1 copies for MR4.5 while majority of ddPCR could. Therefore, ddPCR was technically more acceptable to decide and monitor pediatric CML patients before and after TKI discontinuation.