Publications by authors named "Katsuyoshi Koh"

169 Publications

[Chronic-phase chronic myeloid leukemia with intracranial hemorrhage complicated with tumor lysis syndrome].

Rinsho Ketsueki 2021 ;62(5):346-351

Department of Hematology/Oncology, Saitama Children's Medical Center.

A 14-year-old male with autism was admitted to our hospital owing to altered consciousness and gait disturbance. Blood tests showed a white blood cell (WBC) count of 728,600/µl, and brain computed tomography revealed intracranial hemorrhage and a midline shift of the brain. The chronic phase of chronic myeloid leukemia (CML) was confirmed as per bone marrow aspiration findings. The patient underwent emergency craniotomy for hematoma removal, and he subsequently received hydroxyurea and rasburicase combination therapy. However, he developed tumor lysis syndrome (TLS) and died on the second day of hospitalization. Histopathological examination of autopsy specimens did not reveal any condition that could account for his death other than CML. Several reports have described intracranial hemorrhage during the accelerated phase or blast crisis of CML, but few have described this complication during the chronic phase. TLS concomitant with CML in the chronic phase or following hydroxyurea (an inhibitor of DNA synthesis) administration is rare. It is essential for clinicians to be aware that patients with chronic phase CML and high WBC counts may develop TLS, following the administration of hydroxyurea alone. In addition, extreme caution is warranted in severe cases accompanied by intracranial hemorrhage.
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http://dx.doi.org/10.11406/rinketsu.62.346DOI Listing
June 2021

Phase III study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients.

Jpn J Clin Oncol 2021 May 21. Epub 2021 May 21.

Department of Pediatrics, Kyushu University, Fukuoka, Japan.

Background: Palonosetron has demonstrated non-inferiority to ondansetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients in the United States and Europe. We conducted a single-arm registration study to evaluate the efficacy, safety and pharmacokinetics of palonosetron in pediatric patients in Japan.

Methods: Key inclusion criteria were age of 28 days to 18 years and malignant disease for which initial highly emetogenic chemotherapy or moderately emetogenic chemotherapy was planned. Patients received palonosetron at 20 μg/kg over at least 30 s intravenously before the start of highly emetogenic chemotherapy or moderately emetogenic chemotherapy and received dexamethasone on Days 1-3. The primary endpoint was the proportion of patients achieving a complete response in the overall phase (0-120 h) in Course 1, and its threshold was set at 30%.

Results: From December 2016 to June 2019, 60 patients were enrolled, and 58 received at least one dose of palonosetron. The proportion of patients achieving a complete response during the overall phase was 58.6% (95% confidence interval, 44.9%-71.4%), showing the primary endpoint was met (P < 0.0001). Treatment-related adverse events occurred in two patients (3.4%). Regarding the pharmacokinetics of palonosetron, neither the plasma concentration immediately after administration nor the area under the plasma concentration-time curve from time 0 to infinity differed significantly among the age groups.

Conclusion: We demonstrated the efficacy of palonosetron in pediatric patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy and confirmed the appropriateness of the 20 μg/kg dose, regardless of age, considering the safety and pharmacokinetic profiles.

Trial Registration: JapicCTI-163305, registered 6 June 2016.
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http://dx.doi.org/10.1093/jjco/hyab079DOI Listing
May 2021

Asian population may have a lower incidence of hip osteonecrosis in childhood acute lymphoblastic leukemia.

Int J Hematol 2021 Aug 18;114(2):271-279. Epub 2021 May 18.

Department of Hematology/Oncology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuou-ku, Saitama, 330-8777, Japan.

Osteonecrosis (ON), a long-term complication of acute lymphoblastic leukemia (ALL) treatment affects patients' quality of life. Although the incidence of any ON, including asymptomatic, was 21.7% among children with ALL in the U.S., the actual incidence and risk factors in Asia remain unknown. For over 11 years, we performed hip magnetic resonance imaging (MRI) screening to detect asymptomatic ON while initiating maintenance chemotherapy in newly diagnosed children with ALL. Overall, 164 of 175 patients underwent hip MRI screening. The incidence of symptomatic or any ON was 3.0% and 11.6%, respectively. Asymptomatic ON in patients < 10 and ≥ 10 years old was 4.0% and 35.9%, respectively (P < 0.001). In multivariate analysis, age ≥ 10 years was the only significant risk factor. Asymptomatic ON with necrosis of > 30% of the epiphyseal surface of the femoral head was detected in four patients (2.4%). All were ≥ 10 years. Three of them progressed to severe symptomatic ON. The incidence of any ON in Asia may be lower than that seen in the only screening study in the U.S. Future studies should clarify factors affecting such regional differences and develop an effective approach to avoid the progression of ON in children with ALL.
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http://dx.doi.org/10.1007/s12185-021-03163-1DOI Listing
August 2021

Application of Genome-Wide DNA Methylation Analysis to Differentiate a Case of Radiation-Induced Glioblastoma From Late-Relapsed Medulloblastoma.

J Neuropathol Exp Neurol 2021 Jun;80(6):552-557

From Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Recurrent medulloblastoma can be difficult to diagnose with conventional diagnostic methods because other lesions mimic tumor relapse, particularly at later stages. We report 2 cases of medulloblastoma, both of which seemed to develop late recurrences. Case 1 was a 6-year-old girl who had a medulloblastoma with focal desmoplasia. She was in complete remission for 9 years after treatment but developed an intradural lesion in her thoracic spine, which was pathologically confirmed as tumor recurrence by biopsy. Case 2 was a 10-year-old girl who had a nonmetastatic medulloblastoma. She developed a left cerebellar mass 5 years after the initial diagnosis; the pathological diagnosis was tumor relapse. We performed t-distributed stochastic neighbor embedding of the methylation data from these cases and reference data. In contrast to the consistency of methylation profiling and copy number abnormalities between primary and recurrent tumors of Case 1, the analysis of the recurrent tumor in Case 2 was distinct from medulloblastomas and clustered with "IDH-wild type glioblastomas," suggesting that the recurrent tumor was a radiation-induced glioblastoma. This report highlights the clinical utility of molecular genetic/epigenetic analysis combined with a standard diagnostic approach to confirm the diagnosis of brain tumor recurrence.
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http://dx.doi.org/10.1093/jnen/nlab043DOI Listing
June 2021

Effect of high-dose chemotherapy plus stem cell rescue on the survival of patients with neuroblastoma modified by MYCN gene gain/amplification and remission status: a nationwide registration study in Japan.

Bone Marrow Transplant 2021 Apr 28. Epub 2021 Apr 28.

Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [≤PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation's national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and ≤PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/ ≤ PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91-4.09; P < 0.001). The interaction between MYCN-GA and ≤PR was significant (p = 0.006). Hence, the patients with MYCN-GA with non-remission status at HDC-autoSCR had a significantly poorer prognosis than the other subgroups, suggesting that HDC-autoSCR may be effective in patients with CR/VGPR regardless of MYCN gene status and in patients with MYCN-NGA regardless of remission status.
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http://dx.doi.org/10.1038/s41409-021-01303-zDOI Listing
April 2021

A case of KMT2A-MLLT3 fusion-positive mature B-cell acute lymphoblastic leukemia.

Pediatr Int 2021 Jun 19;63(6):719-722. Epub 2021 Apr 19.

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

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http://dx.doi.org/10.1111/ped.14477DOI Listing
June 2021

Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia.

Nat Cancer 2020 Nov 19;1(11):1113-1127. Epub 2020 Oct 19.

Institute for Cancer Genetics, Columbia University, New York, NY, USA.

Multi-agent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene-drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identifies common and drug-specific pathways modulating chemotherapy response and underscores the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open novel therapeutic opportunities for the treatment of relapse and refractory disease.
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http://dx.doi.org/10.1038/s43018-020-00124-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011577PMC
November 2020

Effect of extramedullary disease on allogeneic hematopoietic cell transplantation for pediatric acute myeloid leukemia: a nationwide retrospective study.

Bone Marrow Transplant 2021 Mar 10. Epub 2021 Mar 10.

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.

Children with acute myeloid leukemia (AML) commonly develop extramedullary disease (EMD), which comprises central nervous system (CNS) lesions and myeloid sarcoma (MS). In this retrospective analysis, we aimed to determine the effect of EMD on the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 678 pediatric patients with de novo AML (median age, 7 years; range, 0.3-15 years) between 2006 and 2016. We compared the outcomes between patients with (EMD group, n = 158; CNS lesion, n = 47, CNS lesion + MS, n = 9, and MS, n = 102) and without EMD at diagnosis (non-EMD group, n = 520). Survivors were followed for a median of 4.5 years, and the 4-year overall survival (OS) rates were 60.6% and 56.4% in the EMD and non-EMD groups, respectively (P = 0.60). No significant differences in OS were observed with respect to the EMD site, except bone lesions, which were associated with poor OS after HCT in a non-remission status. A multivariate analysis revealed that EMD did not affect the outcomes of HCT. In conclusion, the study findings suggest that EMD should not be considered a poor prognostic factor in HCT for children with AML.
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http://dx.doi.org/10.1038/s41409-021-01250-9DOI Listing
March 2021

Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome.

Leukemia 2021 Feb 15. Epub 2021 Feb 15.

Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 93.3% and 95.0% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 96.2% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD or GATA1-MRD with EFS were 10.98 (p = 0.01) and 27.68 (p < 0.01), respectively. Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.
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http://dx.doi.org/10.1038/s41375-021-01157-wDOI Listing
February 2021

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.

EBioMedicine 2021 Feb 10;64:103235. Epub 2021 Feb 10.

Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Background: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL.

Methods: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia.

Findings: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo.

Interpretation: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL.

Funding: This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.
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http://dx.doi.org/10.1016/j.ebiom.2021.103235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878180PMC
February 2021

Clot waveform analysis for perioperative hemostatic monitoring of arthroscopic synovectomy in a pediatric patient with hemophilia A and inhibitor receiving emicizumab prophylaxis.

Int J Hematol 2021 Jun 10;113(6):930-935. Epub 2021 Feb 10.

Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Emicizumab reduces bleeding in patients with hemophilia A and inhibitors (PwHA-I). Coagulation potential during the perioperative period in emicizumab-treated PwHA-I undergoing surgery remains to be evaluated. We describe a 14-year-old boy with HA-I receiving emicizumab prophylaxis who experienced arthroscopic synovectomy. He was treated with a bolus infusion of recombinant factor VIIa (rFVIIa; 80 μg/kg) immediately before surgery, and treatment continued at the same dose every 3 h on day 1, every 4 h on day 2, and every 6 h on day 3. Treatment with rFVIIa was discontinued on day 4. No perioperative bleeding or thrombotic events were observed. Coagulation potential throughout the perioperative period was retrospectively assessed with an easy-to-use clot waveform analysis (CWA). Measurements from CWA returned to within or near the normal range, suggesting successful hemostatic management. Coagulation potentials assessed by CWA showed a significant correspondence with those from a thrombin generation assay (TGA) that is already in use. CWA and TGA could both provide useful data for assessing coagulation potential in the perioperative hemostatic management of emicizumab-treated PwHA-I.
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http://dx.doi.org/10.1007/s12185-021-03095-wDOI Listing
June 2021

An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia.

Haematologica 2021 Jul 1;106(7):2026-2029. Epub 2021 Jul 1.

Department of Transplantation and Cell Therapy, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatrics, the University of Tokyo, Tokyo.

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http://dx.doi.org/10.3324/haematol.2020.266320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252943PMC
July 2021

The outcomes of relapsed acute myeloid leukemia in children: Results from the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05R study.

Pediatr Blood Cancer 2021 01 29;68(1):e28736. Epub 2020 Sep 29.

Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

Background: The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory.

Procedure: In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study.

Results: The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P < .01). Moreover, achieving a second complete remission (CR2) prior to HCT was associated with a good prognosis (P < .01). Etoposide, cytarabine, and mitoxantrone (ECM)- or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (P < .01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (P = .04) and core binding factor-AML, t(8;21), and inv(16) as good prognostic markers (P < .01).

Conclusions: Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.
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http://dx.doi.org/10.1002/pbc.28736DOI Listing
January 2021

Long-term outcome in patients with Fanconi anemia who received hematopoietic stem cell transplantation: a retrospective nationwide analysis.

Int J Hematol 2021 Jan 19;113(1):134-144. Epub 2020 Sep 19.

Department of Innovative Medical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

We retrospectively analyzed nationwide records of 163 Fanconi anemia (FA) patients [aplastic anemia (AA), n = 118; myelodysplastic syndrome (MDS), n = 30; acute leukemia, n = 15] who underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 1987 and 2015 in Japan. An alternative donor was used in 119 (73%) patients, and 160 (98%) patients received a non-T-cell-depleted graft. With an 8.7-year median follow-up, 5-year overall survival (OS) was 81%. The 5-year OS was significantly higher in AA patients than in MDS and acute leukemia patients (89%, 71%, and 44%, respectively). In the MDS/leukemia group, factors associated with poor outcome in univariate analysis were older age at HSCT (≥ 18 years), conditioning regimen without anti-thymocyte or lymphocyte globulin, and grade II-IV acute graft-versus-host disease. After 1 year, of 137 survivors, 15 developed subsequent malignancies, of whom 12 were diagnosed with head and neck (HN)/esophageal cancer. An irradiation regimen and older age were associated with the risk of HN/esophageal cancer. Five of seven deaths were attributed to subsequent malignancies more than 5 years after HSCT. On the basis of the risk factors for HSCT in MDS/leukemia patients and subsequent malignancies, a more effective HSCT approach is required.
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http://dx.doi.org/10.1007/s12185-020-02991-xDOI Listing
January 2021

A Cry for the Development of Newborn Screening for Familial Hemophagocytic Lymphohistiocytosis.

J Clin Immunol 2020 11 10;40(8):1196-1198. Epub 2020 Sep 10.

Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

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http://dx.doi.org/10.1007/s10875-020-00863-xDOI Listing
November 2020

Attempts to optimize postinduction treatment in childhood acute myeloid leukemia without core-binding factors: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

Pediatr Blood Cancer 2020 12 4;67(12):e28692. Epub 2020 Sep 4.

Human Health Sciences, Kyoto University, Kyoto, Japan.

We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P = .16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P = .060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.
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http://dx.doi.org/10.1002/pbc.28692DOI Listing
December 2020

In-Hospital Management Might Reduce Induction Deaths in Pediatric Patients With Acute Lymphoblastic Leukemia: Results From a Japanese Cohort.

J Pediatr Hematol Oncol 2021 03;43(2):39-46

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima.

Induction deaths (ID) remain a critical issue in the treatment of pediatric patients with acute lymphoblastic leukemia (ALL). The reported rate of ID in this population is 1% or higher. We speculate that this proportion might be lower in Japan because of mandatory hospitalization during induction therapy to manage complications. We retrospectively analyzed the incidence of ID among children with ALL enrolled in 4 Japanese study groups between 1994 and 2013. Among 5620 children, 41 (0.73%) cases of ID were noted. The median age was 6.5 years; 24 children were female, and 7 had T-cell ALL. Infection was the most common cause of ID (n=22), but the incidence (0.39%) was lower than that reported in western countries. Mortality within 48 hours from the onset of infection was low, comprising 25% of infection-related deaths. The incidence of infections caused by Bacillus species was low. Only 1 patient died because of Aspergillus infection. Fatal infections mostly occurred during the third week of induction therapy. Our findings suggest that close monitoring, stringent infection control, and immediate administration of appropriate antibiotics through hospitalization might be important strategies in reducing the rate of infection-related ID in pediatric patients with ALL.
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http://dx.doi.org/10.1097/MPH.0000000000001926DOI Listing
March 2021

Hematopoietic Cell Transplantation for Chronic Granulomatous Disease in Japan.

Front Immunol 2020 29;11:1617. Epub 2020 Jul 29.

Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.

Hematopoietic cell transplantation (HCT) is established as a curative treatment for severe chronic granulomatous disease (CGD). However, outcomes of HCT for CGD in Japan had not been precisely reported. We evaluated the outcome of HCT for CGD in Japan by means of a nationwide survey. A total of 91 patients (86 males and 5 females) with CGD who received HCT between 1992 and 2013 was investigated. Their median age at HCT was 11 years (0-39). Sixty-four patients had X-linked CGD caused by CYBB gene mutations, 13 had autosomal recessive CGD (7 CYBA and 6 NCF2), and 14 were genetically undetermined. Seventy patients are still alive at a median follow-up of 38.9 (3.7-230) months. Three-year OS and EFS was 73.7 and 67.6%, respectively. Twenty-one patients died mainly from transplant-related mortality. The cumulative incidence of grade II to IV acute GVHD and extensive chronic GVHD was 27.2 and 17.9%, respectively. Risk factors for EFS after HCT for CGD were age >30 years ( < 0.01), non-CYBB gene mutations ( < 0.01) and CBT ( < 0.01). Regarding the reduced intensity conditioning (RIC) regimen, risk factors for EFS included anti-thymocyte globulin ( = 0.048) and not using low-dose irradiation therapy ( < 0.01), in addition to the preceding risk factors. We report outcomes of HCT for CGD in Japan. Future studies are needed to improve such outcomes, especially for patients harboring non-CYBB gene mutations and suffering from adult CGD. A RIC regimen including low-dose irradiation may be a good option to explore further.
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http://dx.doi.org/10.3389/fimmu.2020.01617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403177PMC
April 2021

A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial.

Blood 2020 10;136(16):1813-1823

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

The prognosis for infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of hematopoietic stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcome was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial, infants with ALL were stratified into 3 risk groups (low risk [LR], intermediate risk [IR], and high risk [HR]) according to KMT2A status, age, and presence of central nervous system leukemia. Children's Oncology Group AALL0631 modified chemotherapy with the addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients only. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (n = 15), IR (n = 19), or HR (n = 56) risk groups. The 3-year event-free survival (EFS) rate for patients with KMT2A-r ALL (IR + HR) was 66.2% (standard error [SE], 5.6%), and for those with germline KMT2A (KMT2A-g) ALL (LR), the 3-year EFS rate was 93.3% (SE, 6.4%). The 3-year EFS rate was 94.4% (SE, 5.4%) for IR patients and 56.6% (SE, 6.8%) for HR patients. In multivariable analysis, female sex and MRD ≥0.01% at the end of early consolidation were significant factors for poor prognosis. Risk stratification and introduction of intensive chemotherapy in this study were effective and were able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.
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http://dx.doi.org/10.1182/blood.2019004741DOI Listing
October 2020

Comparison of child and family reports of health-related quality of life in pediatric acute lymphoblastic leukemia patients after induction therapy.

BMC Pediatr 2020 08 19;20(1):390. Epub 2020 Aug 19.

Department of Family Nursing, Division of Health Sciences and Nursing, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: This study aims at determining the health-related quality of life (HRQOL) of children with acute lymphoblastic leukemia (ALL) after the induction therapy, assessing the agreement between child self-reports and family proxy-reports HRQOL, and determining the factors related to this agreement, especially child age, family attendance, and children's social relationships beyond the family.

Methods: We analyzed questionnaire data (2012-2017) from the Japanese Pediatric Leukemia/Lymphoma Study Group's clinical study (ALL-B12). Participants were children with B-cell precursor ALL aged 5-18 and their family members, who mostly took care of the child during hospitalization. Participants answered the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales (PedsQL-G), and Cancer Module (PedsQL-C) to measure pediatric HRQOL. We calculated the differences between child self-reported and family proxy-reported subscale scores along with intraclass correlation coefficients (ICC). We conducted multiple regression analyses according to all participant pairs and age groups (young children, school age, and adolescents), with ICCs for all PedsQL-G subscales (ICC-G) and all PedsQL-C subscales (ICC-C) as the outcome variables.

Results: Five hundred twenty-two pairs of children and their families were analyzed. We observed a moderate level of agreement on most PedsQL subscales between child self-reports and family proxy-reports; however, worry had the weakest agreement for all PedsQL subscales (ICC = .32, 95% confidence interval = .24-.40). The agreement of ICC-C was positively related to family attendance in the hospitalization, only for the young children group (B = .185, p = .003).

Conclusions: We observed some differences between child self-reports and family proxy-reports of HRQOL of children with ALL. Both child self-reports and family proxy-reports captured HRQOL in the induction therapy. We suggest that attending to young children's hospitalization affects the level of agreement between reports on their HRQOL.
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http://dx.doi.org/10.1186/s12887-020-02287-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437003PMC
August 2020

Unrelated cord blood transplantation with myeloablative conditioning for pediatric acute lymphoblastic leukemia in remission: prognostic factors.

Bone Marrow Transplant 2021 02 11;56(2):357-367. Epub 2020 Aug 11.

Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

The number of individuals undergoing unrelated cord blood transplantation (UCBT) has increased in recent years; however, information on prognostic factors is limited. We retrospectively analyzed data from 475 children and adolescents receiving UCBT with myeloablative conditioning for acute lymphoblastic leukemia (ALL) in complete remission (CR), based on a nationwide registry. In the total patient cohort, 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 61.1% and 67.7%, respectively. UCBT at first CR and UCBT after 2007 were associated with good survival, while grade II-IV acute graft-versus-host disease (GVHD) was associated with low relapse rate but did not affect survival. Analysis according to human leukocyte antigen (HLA) disparity revealed that tacrolimus-based GVHD prophylaxis resulted in higher OS and lower relapse rate and nonrelapse mortality (NRM) than cyclosporine-based GVHD prophylaxis in patients transplanted with 6/6 and ≤4/6 HLA-matched umbilical cord blood. Furthermore, grade II-IV acute GVHD was associated with good LFS and low relapse rate, without high NRM, in patients receiving 5/6 HLA-matched UCBT. These data indicate that prognostic factors for ALL differ depending on HLA disparity in UCBT.
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http://dx.doi.org/10.1038/s41409-020-01019-6DOI Listing
February 2021

Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets.

NPJ Precis Oncol 2020 7;4:20. Epub 2020 Jul 7.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of and . Inhibition of and in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.
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http://dx.doi.org/10.1038/s41698-020-0125-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341754PMC
July 2020

Simple change in logistic procedure improves response rate to QOL assessment: a report from the Japan Children's Cancer Group.

J Patient Rep Outcomes 2020 Jun 17;4(1):48. Epub 2020 Jun 17.

Center for Quality of Life Research, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Background: Reducing non-completion of quality-of-life assessment in clinical trials is an important challenge in obtaining accurate data and unbiased interpretation of patients' quality-of-life for each regimen. We evaluated the effect of changing our questionnaire distribution procedure in a multicenter phase II/III trial on the response rate to a quality-of-life questionnaire.

Methods: In the trial, we distributed 1767 questionnaires and 1045 were returned. We adopted a regression discontinuing design and estimated the change in response rate between pre-intervention (quality-of-life questionnaires were sent to each center soon after patient registration) and post-intervention (a set of tailored questionnaires was sent just before the first quality-of-life assessment).

Results: The post-intervention response rate was higher (odds ratio = 1.62) than the pre-intervention response rate.

Conclusions: A simple logistic intervention reduced the non-completion of QOL assessment in this case, suggesting that a simple change can contribute to improving clinical trial accomplishment.
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http://dx.doi.org/10.1186/s41687-020-00214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300165PMC
June 2020

Tandem high-dose chemotherapy with autologous stem cell rescue for stage M high-risk neuroblastoma: Experience using melphalan/etoposide/carboplatin and busulfan/melphalan regimens.

Pediatr Transplant 2020 11 16;24(7):e13772. Epub 2020 Jun 16.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The efficacy of tandem HDCT against high-risk neuroblastoma has been reported; however, an optimal regimen remains to be established. In this paper, we report our experience using tandem HDCT comprising the MEC and BuMel regimens in patients with high-risk neuroblastoma. We retrospectively analyzed four patients with stage M high-risk neuroblastoma who received HDCT with MEC followed by BuMel combined with autologous stem cell rescue. Although none of their metastatic lesions had disappeared after induction chemotherapy, three patients showed a CR after tandem HDCT. Gastrointestinal mucosal injuries and renal dysfunction were observed as non-hematologic adverse events of grade 3 or higher. Gastrointestinal mucosal injuries were observed in all four patients following the first HDCT and in one patient following the second HDCT and were treated with parenteral nutrition and analgesics. One patient experienced renal dysfunction during the first HDCT, which was alleviated by sufficient hydration and diuretics and resulted in the reduction of melphalan dosage for the second HDCT. SOS was not observed in any patient. The HDCT regimens examined in this study were observed to be feasible and did not result in any life-threatening adverse events. Our findings indicate that tandem HDCT comprising MEC and BuMel is a potentially effective regimen for patients with high-risk neuroblastoma, including for those who respond poorly to induction chemotherapy, although additional studies in a larger population should be conducted to verify any long-term outcomes and toxicity.
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http://dx.doi.org/10.1111/petr.13772DOI Listing
November 2020

Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide.

Bone Marrow Transplant 2020 07 23;55(7):1272-1281. Epub 2020 May 23.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.
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http://dx.doi.org/10.1038/s41409-020-0948-8DOI Listing
July 2020

Impacts of physical late effects on presenteeism in childhood cancer survivors.

Pediatr Int 2020 Nov 9;62(11):1241-1249. Epub 2020 Nov 9.

Department of Family Nursing, School of Health Sciences and Nursing, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Many childhood cancer survivors (CCSs) experience physical late effects related to their cancer types and treatment modalities. Physical late effects are an important factor in various occupational outcomes among CCSs. However, the relationship between physical late effects and presenteeism has remained unclear. This study aimed to estimate the impacts of physical late effects on presenteeism among employed CCSs.

Methods: Childhood cancer survivors replied to a questionnaire regarding presenteeism, and their attending physicians assessed their physical late effects between September 2014 and December 2015. The Work Limitations Questionnaire was used to measure presenteeism. Propensity score analysis and a generalized linear model were used to adjust covariates related to physical late effects and / or presenteeism.

Results: Of the 125 questionnaires distributed, 114 were returned. The data from 61 employed CCSs were analyzed. After controlling for covariates by propensity score analysis and generalized linear model, there were no significant differences in presenteeism between employed CCSs with either no or single physical late effects. However, employed CCSs with multiple physical late effects reported higher scores in Output (Estimate = 9.3, P = 0.041), Physical Demands (Estimate = 12.2, P = 0.020), and Productivity Loss scores (Estimate = 2.4, P = 0.045) on the Work Limitations Questionnaire than employed CCSs with no physical late effects.

Conclusions: Employed CCSs with multiple physical late effects were at an increased risk for presenteeism. Healthcare and social welfare systems should be established to provide vocational assistance for CCSs after being employed to alleviate presenteeism.
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http://dx.doi.org/10.1111/ped.14293DOI Listing
November 2020

[Gilteritinib for pediatric FLT3 internal tandem duplication-positive recurrent acute myeloid leukemia].

Rinsho Ketsueki 2020 ;61(4):322-326

Department of Hematology/Oncology, Saitama Children's Medical Center.

Gilteritinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown efficacy in patients with refractory or recurrent adult acute myeloid leukemia (AML) with FLT3 mutations. However, there are limited data for pediatric patients treated with this drug. Herein, we report the clinical courses of two children with FLT3-mutated recurrent AML who received gilteritinib. Case 1: An 11-year-old boy with secondary relapsed AML presented with an FLT3 internal tandem duplication (ITD) since the first recurrence. One week after gilteritinib initiation, blasts, which had comprised 90% of the white blood cells before treatment, almost disappeared from the peripheral blood without tumor lysis syndrome. The patient developed multiple adverse effects and died from the disease 2.5 months after gilteritinib initiation. Case 2: A 12-year-old girl diagnosed with AML was positive for FLT3 ITD. She received gilteritinib during her first relapse post-stem cell transplantation. After the drug was administered, the recipient cell counts increased, as determined by molecular tests (i.e., FISH), whereas microscopically, there was a complete response for 5 months with good performance status. Gilteritinib treatment in children with FLT3-mutated recurrent AML is feasible and effective. As a patient experienced several adverse effects with gilteritinib treatment, clinical trials are required to determine the appropriate pediatric dose of this medication.
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http://dx.doi.org/10.11406/rinketsu.61.322DOI Listing
July 2020

Impact of immunophenotypic characteristics on genetic subgrouping in childhood acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) study L04-16.

Genes Chromosomes Cancer 2020 10 16;59(10):551-561. Epub 2020 Jul 16.

Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development (Research Institute, National Center for Child Health and Development, NCCHD), Tokyo, Japan.

Immunophenotyping was performed in 1044 consecutive childhood acute lymphoblastic leukemia (ALL) patients enrolled in the Tokyo Children's Cancer Study Group L04-16 trial, revealing novel findings associated with genetic abnormalities. In addition to TCF3-PBX1 and MEF2D fusions, the CD10 subtype of KMT2A-MLLT3-positive ALL frequently exhibited the cytoplasmic-μ pre-B ALL immunophenotype. Although ETV6-RUNX1 was significantly correlated with myeloid antigen expression, more than half of patients expressed neither CD33 nor CD13, while the CD27 /CD44 immunophenotype was maintained. Expression of CD117 and CD56 in B-cell precursor-ALL was limited to certain subtypes including ETV6-RUNX1 and KMT2A-MLLT3. Besides BCR-ABL1, CRLF2, hyperdiploidy, and hypodiploidy, CD66c was also expressed in Ph-like kinase fusion-, PAX5 fusion-, and DUX4 fusion-positive ALL, but not in MEF2D fusion-positive ALL, indicating constant selectivity of CD66c expression. In T-ALL, SIL-TAL1-positive patients were likely to exhibit a more mature immunophenotype. Expression of CD21 and CD10 was not rare in T-ALL, while lack of CD28 was an additional feature of early T-cell precursor-ALL. Considering the immunophenotype as a prognostic maker, MEF2D fusion-positive ALL with CD5 expression may be associated with a poorer prognosis in comparison with those lacking CD5 expression. In cases with characteristic marker expression, the presence of certain fusion transcripts could be predicted accurately.
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http://dx.doi.org/10.1002/gcc.22858DOI Listing
October 2020