Metronomic Chemotherapy for Pediatric Refractory Solid Tumors: A Retrospective Single-Center Study.

Metronomic chemotherapy (MC) is based on chronic administration of chemotherapeutic agents at minimally toxic doses without prolonged drug-free breaks, that inhibits tumor angiogenesis and induces tumor dormancy. This study aimed to determine the efficacy of MC for pediatric refractory solid tumors. We retrospectively analyzed the data of pediatric patients with relapsed/refractory solid tumors who received treatment, including low-dose continuous administration of anticancer drugs, at our institute. Of the 18 patients, the disease statuses at the initiation of MC were complete remission (n=2), partial remission/stable disease (n=5), and progressive disease (n=11). The overall survival rate was 61% at 12 months and 34% at 24 months, and the progression-free survival rate was 21% at 12 and 24 months. Although only 5 of the 18 patients showed certain tumor regression or maintained remission, tumors that stabilized, maintained remission/stable disease, and showed certain advantages in terms of overall survival rate, even if limited to progressive disease. Approximately half of the patients demonstrated temporal tumor stabilization and improved survival time. Overall, previous reports and the present study support the conclusion that MC has the potential to play an important role in pediatric cancer treatment during the advanced stage.

TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia.

BACKGROUND: In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. PROCEDURE: We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). RESULTS: Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. CONCLUSION: Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.

Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Eculizumab treatment in paediatric patients diagnosed with aHUS after haematopoietic stem cell transplantation: a HSCT-TMA case series from Japanese aHUS post-marketing surveillance.

Haematopoietic stem-cell transplantation (HSCT)-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with high mortality. Accumulating evidence suggests that complement dysregulation is potentially involved in the development of HSCT-TMA. We retrospectively analysed the clinical characteristics and outcomes of thirteen paediatric patients who were diagnosed with atypical haemolytic uremic syndrome and treated with eculizumab to manage HSCT-TMA during post-marketing surveillance in Japan. The median time from HSCT to TMA was 31 days (Interquartile range, IQR;21-58) and the median doses of eculizumab was three (IQR;2-5). Seven patients (54%) were alive at the last follow-up while six died due to complications related to HSCT. Six of seven survivors initiated eculizumab after insufficient response to plasma therapy. Following eculizumab treatment, median platelet counts and LDH levels in all survivors significantly improved and renal function improved in 4/7 patients. All survivors possessed potential risk factors of complement overactivation. During the follow-up period after eculizumab discontinuation (median;111.5 days, IQR;95-555), no TMA recurrence was observed. In this analysis, eculizumab showed benefit in over half of this paediatric patient population. Ongoing clinical studies are expected to optimize the treatment regimen of terminal complement pathway inhibitor, and it may become a therapeutic option for paediatric HSCT-TMA in the future.

Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type.

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.

Utility of ASNS gene methylation evaluated with the HPLC method as a pharmacogenomic biomarker to predict asparaginase sensitivity in BCP-ALL.

Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for safer and more efficacious therapy, a clinical biomarker predicting asparaginase sensitivity is highly anticipated. Asparaginase depletes serum asparagine by deaminating asparagine into aspartic acid, and ALL cells are thought to be sensitive to asparaginase due to reduced asparagine synthetase (ASNS) activity. We have recently shown that allele-specific methylation of the ASNS gene is highly involved in asparaginase sensitivity in B-precursor ALL (BCP-ALL) by using next-generation sequence (NGS) analysis of bisulphite PCR products of the genomic DNA. Here, we sought to confirm the utility of methylation status of the ASNS gene evaluated with high-performance liquid chromatography (HPLC) analysis of bisulphite PCR products for future clinical applications. In the global methylation status of 23 CpG sites at the boundary region of promoter and exon 1 of the ASNS gene, a strong positive correlation was confirmed between the mean percent methylation evaluated with the HPLC method and that with the NGS method in 79 BCP-ALL cell lines (R2 = 0.85, p = 1.3 × 10-33) and in 63 BCP-ALL clinical samples (R2 = 0.84, p = 5.0 × 10-26). Moreover, methylation status of the ASNS gene evaluated with the HPLC method was significantly associated with in vitro asparaginase sensitivities as well as gene and protein expression levels of ASNS. These observations indicated that the ASNS gene methylation status evaluated with the HPLC method is a reliable biomarker for predicting the asparaginase sensitivity of BCP-ALL.

Patient-Level Meta-analysis of Clofarabine in Acute Lymphoblastic Leukemia.

INTRODUCTION: Clofarabine monotherapy at a dose of 52 mg/m2 per day was approved in the USA in 2004 for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL) in patients aged 1-21 years after at least two prior regimens. To address a post-marketing requirement for additional evidence of the clinical benefit of clofarabine in its approved indication, a meta-analysis of patient-level data was conducted. METHODS: A systematic literature review was conducted, using the Dr.Evidence software platform, DOC Search, and Embase, to identify clinical trials with patients with R/R ALL who received clofarabine monotherapy at 52 mg/m2. The primary endpoint was complete remission (CR). Secondary endpoints were overall remission (OR, defined by CR or CR with either incomplete platelet recovery or incomplete neutrophil and platelet recovery), duration of response, overall survival (OS), and safety. RESULTS: A total of 754 patients in 12 clinical studies were analyzed including 682 patients with R/R ALL treated with clofarabine monotherapy at 52 mg/m2; of them, 374 were aged < 22 years (pediatric population). Rates of CR and OR were 16% (95% confidence interval [CI] 7, 26) and 28% (95% CI 20, 37), respectively, in the pediatric population and 12% (95% CI 5, 21) and 21% (95% CI 13, 31) in the overall population. Median OS (evaluable in three studies in pediatric patients) was 3.7 months (95% CI 0.1, 31.4), reaching 10.1 months (95% CI 0.3, 68.9) for those achieving OR. Sensitivity analyses supported these findings. The most frequent grade 3-4 adverse events were liver abnormalities, anemia, diarrhea, and febrile neutropenia. CONCLUSION: In this meta-analysis, CR duration and median OS in pediatric patients with R/R ALL appeared to be slightly longer than in the phase II study. No new safety signals were identified. Results support the use of clofarabine monotherapy in its approved indication.

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study.

The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Outcomes of Cancer Patients Who Seek Outpatient Visits Despite Post-chemotherapy Decline.

INTRODUCTION: The medical needs of cancer patients are complex and increase with the disease's progression. However, Japan's aging population and increased medical needs have produced challenges like a shortage of hospital beds. Therefore, patients who have completed chemotherapy are recommended home-based care or referred to local palliative care facilities, especially when cancer treatment is no longer a viable option and outpatient visits become unfeasible. However, some patients still strive to continue outpatient visits, which could result in increased pain and possible urgent hospitalization. These patients may spend their final days in the hospital, which may not have been their desired outcome. Therefore, we examined the outcomes of patients who were recommended home-based care. METHODS: The study population comprised 34 cancer patients undergoing treatment at the Oncology Outpatient Department of Edogawa Hospital who were recommended home-based care owing to their difficulty attending outpatient visits. Data regarding home-based care recommendations were obtained from the lists of medical social welfare interventions and hospitalized patients. Patients were classified based on whether they opted for home-based care and their caregivers' caregiving capacity. Survival was analyzed using the Kaplan-Meier curve and the log-rank test, and the groups were compared using Fisher's exact test. RESULTS: The median interval between the initial consultation with an oncologist and the date of recommendation for home-based care was six and a half months. Home-based care was mostly recommended because of the progression of cachexia (23 cases) and the worsening of symptoms (11 cases). The median survival for the groups with cachexia and worsening symptoms was 25 days and 35 days, respectively. Ten patients refused home-based care. Of them, six refused it because they wished to continue with outpatient visits. Of the home-based care group (24 patients), only one required an emergency room (ER) visit, while four of the non-home-based care group required ER visits. Regarding end-of-life care, 19 from the home-based care group and four from the non-home-based care group received end-of-life care at home. Additionally, one of the two patients who lived alone and two of the six patients whose caregivers were deemed to have insufficient caregiving capacity received end-of-life care at home. Of the remaining 24 patients, 22 received end-of-life care at home. CONCLUSION: The short survival period of the group with cachexia indicates that it would be beneficial for patients, their family members, and home-based care providers to facilitate earlier referral to home-based care. However, while home-based care is beneficial for patients who wish to spend their final days at home and for their family members, short-term and achievable goals, such as attending the next outpatient visit, may alleviate anxiety in cancer patients and enable them to live their daily lives without constant awareness of death. Additionally, while non-home-based care could lead to extended pain due to the lack of readily accessible medical personnel, ER visits, and hospital-based end-of-life care, home-based care can be mentally and physically strenuous for the primary caregiver. Therefore, comprehensive information about palliative care options should be provided early on during the outpatient visits of cancer patients who wish for home-based care for informed decision-making.

A short-term three dimensional culture-based drug sensitivity test is feasible for malignant bone tumors.

The feasibility of a short-term, three-dimensional (3D) culture-based drug sensitivity test (DST) for surgically resected malignant bone tumors, including osteosarcoma (OS), was evaluated utilizing two OS cell line (KCS8 or KCS9)-derived xenograft (CDX) models. Twenty-three (KCS8) or 39 (KCS9) of 60 tested drugs were likely effective in OS cells derived from a cell line before xenografting. Fewer drugs (19: KCS8, 26: KCS9) were selected as effective drugs in cells derived from a CDX tumor, although the drug sensitivities of 60 drugs significantly correlated between both types of samples. The drug sensitivity of a CDX tumor was not significantly altered after the depletion of non-tumorous components in the sample. In a surgically resected metastatic tumor obtained from a patient with OS, for whom a cancer genome profiling test detected a pathogenic PIK3CA mutation, DST identified mTOR and AKT inhibitors as effective drugs. Of two CDX and six clinical samples of OS and Ewing's sarcoma, DST identified proteasome inhibitors (bortezomib, carfilzomib) and CEP-701 as potentially effective drugs in common. This unique method of in vitro drug testing using 3D-cell cultures is feasible in surgically resected tissues of metastatic malignant bone tumors.

Case report: Hepatectomy with Rex bypass for a child with hepatoblastoma and portal vein thrombosis.

Pediatric liver tumors with portal vein obstruction are often candidates for liver transplantation. However, lifelong use of immunosuppressants and invasiveness to healthy donors in the case of living-donor liver transplantation is inevitable. Moreover, when lung metastasis is involved, the lung recurrence rate after liver transplantation is still high. Therefore, transplantation should be avoided as much as possible. In cases of tumors in the right lobe of the liver, complete resection of the portal vein trunk may be possible by creating a Rex bypass, but with the original method, end-to-side anastomosis to the umbilical portal vein is difficult in small children. We report a case of a 2-year-old girl with hepatoblastoma in whom a Rex shunt was created by end-to-end anastomosing the recanalized umbilical vein to the portal vein stump with interposing a vein graft, and the right lobe was successfully resected along with the tumor.

Common Blood Test Indices for Predicting Transient Abnormal Myelopoiesis-Related Mortality in Infants with Down Syndrome.

Transient abnormal myelopoiesis (TAM) can cause early death in children with Down syndrome, and liver failure is the most common cause of death. The aim of this single-center retrospective study was to identify a quantitative index for predicting TAM-related mortality at the time of diagnosis. Of the 462 children with Down syndrome admitted to our hospital from 1992 to 2021, we studied 12 infants with TAM-related death and 31 survivors who were diagnosed with TAM. In the death and survival groups, the median gestational ages were 34.9 and 37.1 weeks, respectively (p = 0.12). At diagnosis, the white blood cell (WBC) counts were 99.2 and 36.2 × 109/L (p = 0.011), the hemoglobin concentrations were 131 and 159 g/L (p = 0.009), and the serum albumin concentrations were 23 and 31 g/L (p < 0.001), respectively. The areas under the receiver operating characteristic curve for the abilities of the WBC count, hemoglobin, and serum albumin at diagnosis to predict survival were 0.75, 0.76, and 0.85, respectively. The serum albumin concentration threshold of 28 g/L at diagnosis had sensitivity of 0.79 and specificity of 0.82. Gestational age and serum albumin concentration were entered into a logistic regression model. The serum albumin concentration was an independent indicator of TAM-related death (adjusted odds ratio, 0.78; 95% confidence interval, 0.65-0.93; p = 0.005). In conclusion, a low serum albumin concentration at diagnosis may be a good predictor of TAM-related death.

The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia.

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.

Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia.

Treatment outcomes for children with relapsed and refractory acute lymphoblastic leukemia (R/R-ALL) remain poor, and the optimal induction therapy has not been determined. Bortezomib is a proteasome inhibitor that acts synergistically and additively with standard chemotherapy for ALL. We evaluated the efficacy and safety of combination chemotherapy with bortezomib in children with R/R-ALL. This single-arm, multicenter, phase 2 study was conducted in Japan between 2016 and 2020. Eligible patients were divided into two cohorts: a high-risk first-relapse cohort of untreated patients with high-risk first-relapsed ALL and an expansion cohort of patients with refractory ALL, including multiple relapses, relapse after allogeneic hematopoietic cell transplantation, and induction failure. All patients received a single course of chemotherapy as induction therapy. Sixteen patients (10 in the high-risk first-relapse cohort, six in the expansion cohort) were evaluable. The overall remission rate after induction therapy was 60% in the high-risk first-relapse cohort and 16.7% in the expansion cohort. All patients had minimal residual disease. Adverse events were acceptable except for interstitial lung disease and hypoxia in a patient in the expansion cohort, but addition of bortezomib to conventional chemotherapy did not produce obvious improvement in children with R/R-ALL.

Safety and efficacy of post-haematopoietic cell transplantation maintenance therapy with blinatumomab for relapsed/refractory CD19-positive B-cell acute lymphoblastic leukaemia: protocol for a phase I-II, multicentre, non-blinded, non-controlled trial (JPLSG SCT-ALL-BLIN21).

INTRODUCTION: Relapsed and refractory B-cell acute lymphoblastic leukaemia (R/R-B-ALL) is linked to a significant relapse rate after allogeneic haematopoietic cell transplantation (allo-HCT) in children, adolescents and young adults (CAYA). No standard treatment has been established to prevent relapse after allo-HCT for R/R-B-ALL, which is an unmet medical need. The administration of blinatumomab after allo-HCT is expected to enhance the antileukaemic effect on residual CD19-positive blasts by donor-derived CD3-positive T-cells. METHODS AND ANALYSIS: The goal of this multicentre, open-label, uncontrolled, phase I-II clinical trial is to assess the safety and effectiveness of post-transplant maintenance therapy with blinatumomab for CAYA patients (25 years old or younger) with CD19-positive R/R-B-ALL who have received allo-HCT beyond first complete remission (CR) and have CR with haematological recovery between 30 and 100 days after allo-HCT. Eighty-five paediatric institutions in Japan are participating in this study. Forty-one patients will enrol within 2.25-year enrolment period and follow-up period is 1 year. The primary endpoints are the treatment completion rate for phase I study and the 1-year graft-versus-host disease-free/relapse-free survival rate for phase II study, respectively. ETHICS AND DISSEMINATION: This research was approved by the Central Review Board at National Hospital Organization Nagoya Medical Center (Nagoya, Japan) on 21 January 2022 and was registered at the Japan Registry of Clinical Trials (jRCT) on 3 March 2022. Written informed consent is obtained from all patients and/or their guardians. The results of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: jRCTs041210154.

L-asparaginase as an efficient salvage therapy for refractory acute myeloid leukemia with chromosome 7 abnormalities: a case series.

Acute myeloid leukemia (AML) with chromosome 7 abnormalities has a dismal prognosis due to a poor complete remission (CR) rate after induction chemotherapy. Although various salvage therapies for refractory AML have been developed for adults, few salvage therapies are available for children. Here, we report the cases of three patients with refractory AML with chromosome 7 abnormalities (Patient 1, with inv(3)(q21;3q26.2) and monosomy 7; Patient 2, with der(7)t(1;7)(?;q22); patient 3, with monosomy 7) who were successfully treated with L-asparaginase (L-ASP) as salvage therapy. All three patients achieved CR several weeks after L-ASP treatment, and two patients successfully underwent hematopoietic stem cell transplantation (HSCT). Patient 2 relapsed after the second HSCT in the form of an intracranial lesion, but achieved and sustained CR for 3 years with weekly L-ASP maintenance therapy. Immunohistochemical staining for asparagine synthetase (ASNS), whose gene is located at 7q21.3, was performed for each patient. The result was negative in all patients, which suggests that haploid 7q21.3 and other chromosome 7 abnormalities leading to haploinsufficiency of ASNS contribute to a high susceptibility to L-ASP. In conclusion, L-ASP is a promising salvage therapy for refractory AML with chromosome 7 abnormalities, which are associated with ASNS haploinsufficiency.

High-dose thiotepa, in conjunction with melphalan, followed by autologous hematopoietic stem cell transplantation in patients with pediatric solid tumors, including brain tumors.

Among pediatric malignancies, solid tumors, particularly within the central nervous system (CNS), are common. Thiotepa, a myeloablative, high-dose chemotherapeutic (HDT) treatment administered prior to autologous hematopoietic stem cell transplantation (HSCT), can cross the blood-brain barrier and rapidly penetrate the CNS. We evaluated thiotepa HDT in conjunction with melphalan in Japanese patients with pediatric CNS/non-CNS solid tumors in a multicenter, open-label, non-comparative study. Thiotepa (200 mg/m2/day) was administered intravenously (IV) over 24 h on days -12, -11, -5, and -4 before scheduled HSCT. Melphalan (70 mg/m2/day) was administered IV over 1 h on days -11, -5, and -4. The safety analysis population comprised 41 patients, of whom 16 (39.0%) had solid tumors and 25 (61.0%) had brain tumors. The most frequently reported adverse events were diarrhea (40/41 [97.6%] patients) and febrile neutropenia (34/41 [82.9%]). No unexpected safety events were observed, and no events resulted in death or treatment discontinuation. All patients experienced bone marrow suppression and 39/41 (95.1%) achieved engraftment (neutrophil count ≥500/mm3 for 3 consecutive days after HSCT). The survival rate at day 100 post-autologous HSCT was 100%. These data confirm the safety of IV thiotepa plus melphalan HDT prior to autologous HSCT for patients with pediatric CNS/non-CNS solid tumors. Trial registration: JapicCTI-173654.