Monitoring measurable residual disease in paediatric acute lymphoblastic leukaemia using immunoglobulin gene clonality based on next-generation sequencing.

BACKGROUND: Assessment of measurable residual disease (MRD) is an essential prognostic tool for B-lymphoblastic leukaemia (B-ALL). In this study, we evaluated the utility of next-generation sequencing (NGS)-based MRD assessment in real-world clinical practice. METHOD: The study included 93 paediatric patients with B-ALL treated at our institution between January 2017 and June 2022. Clonality for IGH or IGK rearrangements was identified in most bone marrow samples (91/93, 97.8%) obtained at diagnosis. RESULTS: In 421 monitoring samples, concordance was 74.8% between NGS and multiparameter flow cytometry and 70.7% between NGS and reverse transcription-PCR. Elevated quantities of clones of IGH alone (P < 0.001; hazard ratio [HR], 22.2; 95% confidence interval [CI], 7.1-69.1), IGK alone (P = 0.011; HR, 5.8; 95% CI, 1.5-22.5), and IGH or IGK (P < 0.001; HR, 7.2; 95% CI, 2.6-20.0) were associated with an increased risk of relapse. Detection of new clone(s) in NGS was also associated with inferior relapse-free survival (P < 0.001; HR, 18.1; 95% CI, 3.0-108.6). Multivariable analysis confirmed age at diagnosis, BCR::ABL1-like mutation, TCF3::PBX1 mutation, and increased quantity of IGH or IGK clones during monitoring as unfavourable factors. CONCLUSION: In conclusion, this study highlights the usefulness of NGS-based MRD as a routine assessment tool for prognostication of paediatric patients with B-ALL.

Poor Mobilization-Associated Factors in Autologous Hematopoietic Stem Cell Harvest.

Peripheral blood stem cell transplantation (PBSCT) is an important therapeutic measure for both hematologic and non-hematologic diseases. For PBSCT to be successful, sufficient CD34+ cells need to be mobilized and harvested. Although risk factors associated with poor mobilization in patients with hematologic diseases have been reported, studies of patients with non-hematologic diseases and those receiving plerixafor are rare. To identify factors associated with poor mobilization, data from autologous PBSC harvest (PBSCH) in 491 patients were retrospectively collected and analyzed. A multivariate analysis revealed that in patients with a hematologic disease, an age older than 60 years (odds ratio [OR] 1.655, 95% confidence interval [CI] 1.049-2.611, p = 0.008), the use of myelotoxic agents (OR 4.384, 95% CI 2.681-7.168, p < 0.001), and a low platelet count (OR 2.106, 95% CI 1.205-3.682, p = 0.009) were associated with poor mobilization. In patients with non-hematologic diseases, a history of radiation on the pelvis/spine was the sole associated factor (OR 12.200, 95% CI 1.934-76.956, p = 0.008). Among the group of patients who received plerixafor, poor mobilization was observed in 19 patients (19/134, 14.2%) and a difference in the mobilization regimen was noted among the good mobilization group. These results show that the risk factors for poor mobilization in patients with non-hematologic diseases and those receiving plerixafor differ from those in patients with hematologic diseases; as such, non-hematologic patients require special consideration to enable successful PBSCH.

Long-term Outcomes of Protocol-Based Treatment for Newly Diagnosed Medulloblastoma.

PURPOSE: The Korean Society of Pediatric Neuro-Oncology (KSPNO) conducted treatment strategies for children with medulloblastoma (MB) by using alkylating agents for maintenance chemotherapy or tandem high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) according to the risk stratification. The purpose of the study was to assess treatment outcomes and complications based on risk-adapted treatment and HDC. MATERIALS AND METHODS: Fifty-nine patients diagnosed with MB were enrolled in this study. Patients in the standard-risk (SR) group received radiotherapy (RT) after surgery and chemotherapy using the KSPNO M051 regimen. Patients in the high-risk (HR) group received two and four chemotherapy cycles according to the KSPNO S081 protocol before and after reduced RT for age following surgery and two cycles of tandem HDC with ASCR consolidation treatment. RESULTS: In the SR group, 24 patients showed 5-year event-free survival (EFS) and overall survival (OS) estimates of 86.7% (95% confidence interval [CI], 73.6 to 100) and 95.8% (95% CI, 88.2 to 100), respectively. In the HR group, more infectious complications and mortality occurred during the second HDC than during the first. In the HR group, the 5-year EFS and OS estimates were 65.5% (95% CI, 51.4 to 83.4) and 72.3% (95% CI, 58.4 to 89.6), respectively. CONCLUSION: High intensity of alkylating agents for SR resulted in similar outcomes but with a high incidence of hematologic toxicity. Tandem HDC with ASCR for HR induced favorable EFS and OS estimates compared to those reported previously. However, infectious complications and treatment-related mortalities suggest that a reduced chemotherapy dose is necessary, especially for the second HDC.

Diagnostic yield of targeted next-generation sequencing for pediatric hereditary hemolytic anemia.

BACKGROUND: Hereditary hemolytic anemia (HHA) refers to a heterogeneous group of genetic disorders that share one common feature: destruction of circulating red blood cells (RBCs). The destruction of RBCs may be due to membranopathies, enzymopathies, or hemoglobinopathies. Because these are genetic disorders, incorporation of next-generation sequencing (NGS) has facilitated the diagnostic process of HHA. METHOD: Genetic data from 29 patients with suspected hereditary anemia in a tertiary hospital were retrospectively reviewed to evaluate the efficacy of NGS on hereditary anemia diagnosis. Targeted NGS was performed with custom probes for 497 genes associated with hematologic disorders. After genomic DNA was extracted from peripheral blood, prepared libraries were hybridized with capture probes and sequenced using NextSeq 550Dx (Illumina, San Diego, CA, USA). RESULT: Among the 29 patients, ANK1 variants were detected in five, four of which were pathogenic or likely pathogenic variants. SPTB variants were detected in six patients, five of which were classified as pathogenic or likely pathogenic variants. We detected g6pd pathogenic and spta1 likely pathogenic variants in two patients and one patient, respectively. Whole-gene deletions in both HBA1 and HBA2 were detected in two patients, while only HBA2 deletion was detected in one patient. One likely pathogenic variant in PLKR was detected in one patient, and one likely pathogenic variant in ALAS2 was detected in another. CONCLUSION: Here, NGS played a critical role in definitive diagnosis in 18 out of 29 patients (62.07%) with suspected HHA. Thus, its incorporation into the diagnostic workflow is crucial.

Response to chemotherapy in juvenile myelomonocytic leukemia and its clinical implications for survival: A retrospective registry-based study of the Korean Pediatric Hematology-Oncology Group.

Juvenile myelomonocytic leukemia (JMML) is a life-threatening myeloproliferative neoplasm. The chemotherapeutic effect on survival remains unclear, and feasible standardized response criteria are yet to be established. We aimed to evaluate the chemotherapeutic response and its effect on survival in patients with JMML. A retrospective registry was reviewed for children diagnosed with JMML between 2000 and 2019. Response was assessed according to the criteria proposed by the International JMML Symposium in 2007 (criteria I) and the updated version in 2013 with its modifications (criteria II). A total of 73 patients were included in this study. Complete response (CR) rates were 46.6% and 28.8% using the criteria I and criteria II, respectively. A platelet count ≥ 40 × 109/L at diagnosis was associated with higher CR rates using the criteria II. Patients with criteria I-based CR had a better overall survival (OS) than those without CR (81.1% vs. 49.1% at 5 years). Patients with criteria II-based CR showed better OS (85.7% vs. 55.5% at 5 years) and event-free survival (EFS) (71.1% vs. 44.7% at 5 years) than those without CR. Additionally, a trend toward better EFS was observed in patients with criteria II-based CR than in those with criteria I-based CR but without criteria II-based CR (71.1% vs. 53.8% at 5 years). Chemotherapeutic response is associated with better survival outcomes. Along with splenomegaly, the addition of platelet count recovery, existence of extramedullary leukemic infiltration, and more stringent leukocyte counts to the response criteria allows for a more sensitive prediction of survival outcomes.

The Efficacy of Alternate Systemic Intravenous Chemotherapy and Intra-arterial Chemotherapy Approach for Eye Globe Salvage in Retinoblastoma.

PURPOSE: The advances in the treatment of retinoblastoma have enabled salvaging the globe in advanced stages with intra-arterial chemotherapy (IAC). We developed a strategy of alternate application of systemic intravenous chemotherapy (IVC) and IAC (referred to as alternate systemic IVC and IAC; ASIAC) to reduce central nervous metastases during IAC and examined its efficacy and safety in eye globe salvage in this study. MATERIALS AND METHODS: Between January 2010 and February 2021, 43 eyes of 40 patients received ASIAC treatment for retinoblastoma at the Yonsei Cancer Center, Yonsei University Health System. Their medical records were reviewed retrospectively to evaluate the eye salvage rate (ESR), defined from diagnosis to enucleation. High-risk retinoblastoma was defined as group D or E by the International Classification of Retinoblastoma. RESULTS: The study enrolled 38 and five cases of high-risk and low-risk retinoblastoma, respectively. In total, 178 IAC and 410 IVC courses were administered, with a median of 4 (interquartile range [IQR], 3.0 to 5.0) IAC and 9 (IQR, 6.0 to 11) IVC courses per eye, respectively. The 5-year ESR was 60.4%±8.7% for the whole cohort, 100% for low-risk retinoblastoma, and 53.6%±9.8% for high-risk retinoblastoma. Among those diagnosed since 2015, the 5-year ESR for high-risk retinoblastoma was 63.5%±14.0%. Fifteen eyes underwent enucleation; no viable tumor was found in three enucleated eyes. There were no deaths in this cohort. CONCLUSION: Primary IAC-IVC (i.e., ASIAC) for patients with retinoblastoma was tolerable and effective in salvaging the eye and maintaining survival.

Allogeneic hematopoietic cell transplantation in patients with juvenile myelomonocytic leukemia in Korea: a report of the Korean Pediatric Hematology-Oncology Group.

Juvenile myelomonocytic leukemia (JMML) is a life-threatening myeloproliferative neoplasm. This multicenter study evaluated the characteristics, outcomes, and prognostic factors of allogeneic hematopoietic cell transplantation (HCT) in recipients with JMML who were diagnosed between 2000 and 2019 in Korea. Sixty-eight patients were retrospectively enrolled-28 patients (41.2%) received HCT during 2000-2010 and 40 patients (58.8%) during 2011-2020. The proportion of familial mismatched donors increased from 3.6 to 37.5%. The most common conditioning therapy was changed from Busulfan/Cyclophosphamide-based to Busulfan/Fludarabine-based therapy. The 5-year probabilities of event-free survival (EFS) and overall survival (OS) were 52.6% and 62.3%, respectively. The 5-year incidence of transplant-related mortality was 30.1%. Multivariate analysis revealed that the proportion of hemoglobin F ≥ 40%, abnormal cytogenetics, and matched sibling donors were independent risk factors for a higher relapse rate. Patients whose donor chimerism was below 99% had a significantly higher relapse rate. Better OS and lower treatment-related mortality were observed in patients with chronic graft-versus-host disease (GVHD), whereas grade III or IV acute GVHD was associated with worse EFS. In conclusion, the number of transplant increased along with the increase in alternative donor transplants, nevertheless, similar results were maintained. Alternative donor transplantation should be encouraged.

Factors influencing perceived communication quality for successful fertility preservation counseling for adolescent and young adult cancer patients and their caregivers in Korea.

PURPOSE: Although relatively new in Asian countries, fertility preservation (FP) discussions are crucial for adolescent and young adult (AYA) cancer patients. This study highlights patients' and their caregivers' perceptions of communications quality during FP discussions in Korea. METHODS: Participants were AYA patients and their caregivers (each: n = 34). The study examined the clinical pathways for FP and used surveys to collect details on discussion characteristics and satisfaction levels during FP discussions at the Yonsei Cancer Center, Seoul, Korea. Quality and degree of satisfaction with FP discussions were measured on a scale ranging from 1 to 7. RESULTS: Two caregivers did not complete the survey. All respondents reported high overall satisfaction; however, several factors were related to low satisfaction with information quality. Caregivers who received both verbal communication and nonverbal communication tools (e.g., pamphlets, Internet resources) were more satisfied with the information quality than those who only received verbal communication. Regarding provider type, both respondent groups reported high overall satisfaction with physicians, rather than other types of care providers. Regarding the number of discussion sessions, respondents reported an improved understanding of FP and better communication and information quality if they participated in more than one discussion session. CONCLUSION: The FP process for AYA cancer patients can be improved by adjusting the type of provider, number of discussion sessions, and types of information. This will form the cornerstone of effective FP communication in Korea.

Efficacy of low dose and short duration defibrotide prophylaxis for hepatic veno-occlusive disease after autologous haematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a serious systemic endothelial complication after stem cell transplantation. Defibrotide is under investigation as a prophylactic agent for VOD; however, high costs limit its utility. We evaluated the prophylactic efficacy of a low-dose defibrotide regimen for VOD. We retrospectively enrolled 147 paediatric patients who underwent autologous haematopoietic stem cell transplantation (HSCT; 69 with defibrotide prophylaxis and 78 historical controls) at the Yonsei Cancer Center in Seoul, Korea, between March 2013 and Feb 2020. Low-dose defibrotide (12.5 mg/kg/day) was administered from D-3 to D+10 after HSCT. The most common diagnosis in the cohort was brain tumour (N = 86). VOD developed in 10 (12.8%) and 3 (4.3%) patients in the control and prophylaxis groups, respectively (P = 0.071). In the second HSCT group, VOD incidence was significantly lower in the prophylaxis group [2.9% (1/35)] than in the control group (28.6%, 6/21, P = 0.005). VOD severity was significantly higher in the control group than in the prophylaxis group (P = 0.006). Three VOD-related mortalities occurred in the control group, whereas no VOD-related mortality occurred in the prophylaxis group. In conclusion, low-dose defibrotide prophylaxis is a promising and economical strategy for preventing VOD, especially in second-round HSCT.

Protein-Losing Enteropathy as a Complication of the Ketogenic Diet.

The ketogenic diet is an effective treatment for the patients with intractable epilepsy, however, the diet therapy can sometimes be discontinued by complications. Protein-losing enteropathy is a rarely reported serious complication of the ketogenic diet. We present a 16-month-old Down syndrome baby with protein-losing enteropathy during the ketogenic diet as a treatment for West syndrome. He suffered from diarrhea, general edema and hypoalbuminemia which were not controlled by conservative care for over 1 month. Esophagogastroduodenoscopy and stool alpha-1 antitrypsin indicated protein-losing enteropathy. Related symptoms were relieved after cessation of the ketogenic diet. Unexplained hypoalbuminemia combined with edema and diarrhea during ketogenic suggests the possibility of protein-losing enteropathy, and proper evaluation is recommended in order to expeditiously detect it and to act accordingly.