Differential impact of asparaginase discontinuation on outcomes of children with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

BACKGROUND: Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL. METHODS: The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable. RESULTS: In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60). CONCLUSION: The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required.

A higher CD34 + cell dose correlates with better event-free survival after KIR-ligand mismatched cord blood transplantation for childhood acute myeloid leukemia.

Although killer Ig-like receptor ligands (KIR-L) mismatch has been associated with alloreactive natural killer cell activity and potent graft-versus-leukemia (GVL) effect among adults with acute myeloid leukemia (AML), its role among children with AML receiving cord blood transplantation (CBT) has not been determined. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients who were diagnosed with de novo non-M3 AML and who underwent their first CBT in remission between 2000 and 2021 at under 16 years old were included. A total of 299 patients were included; 238 patients were in the KIR-L match group, and 61 patients were in the KIR-L mismatch group. The cumulative incidence rates of neutrophil recovery, platelet engraftment, and acute/chronic graft-versus-host disease did not differ significantly between the groups. The 5-year event-free survival (EFS) rate was 69.8% in the KIR-L match group and 74.0% in the KIR-L mismatch group (p = 0.490). Stratification by CD34 + cell dose into four groups revealed a significant correlation between CD34 + cell dose and EFS in the KIR-L mismatch group (p = 0.006) but not in the KIR-L match group (p = 0.325). According to our multivariate analysis, KIR-L mismatch with a high CD34 + cell dose (≥ median dose) was identified as an independent favorable prognostic factor for EFS (hazard ratio = 0.19, p = 0.029) and for the cumulative incidence of relapse (hazard ratio = 0.09, p = 0.021). Our results suggested that higher CD34 + cell doses are crucial for achieving a potent GVL effect in the context of KIR-L-mismatched CBT.

Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.

Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome.

Patients with acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL) have an excellent survival rate; however, patients with non-DS-AMKL experience poor outcomes. Therefore, this study retrospectively analysed 203 children with non-DS-AMKL who underwent their first haematopoietic cell transplantation (HCT) from 1986 to 2015 using a nationwide Japanese HCT registry data to assess HCT outcomes for non-DS-AMKL. The 5-year overall survival (OS) and event-free survival (EFS) rates were 43% and 38% respectively. The 5-year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non-CR (16%) (p < 0.001), and for those from a human leukocyte antigen (HLA)-matched (52%) than for those from an HLA-mismatched donor (27%) (p < 0.001). Multivariate analysis for OS revealed that HCT in CR2 and non-CR was a significant risk factor (hazard ratio, 5.86; 95% confidence interval, 3.56-9.53; p < 0.001). The 3-year EFS in patients who received HCT in CR1 using reduced-intensity conditioning (RIC, 35%) was significantly lower than in those using myeloablative conditioning (busulfan-based, 71%; total body irradiation-based, 58%) (p < 0.001). Risk stratification in patients with non-DS-AMKL should be established to determine HCT indication in CR1.

Prognostic factors of children and adolescents with T-cell acute lymphoblastic leukemia after allogeneic transplantation.

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p < 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.

Hematopoietic Cell Transplantation for Inborn Errors of Immunity Other than Severe Combined Immunodeficiency in Japan: Retrospective Analysis for 1985-2016.

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

Malignant brain tumor in an infant showing histopathological features of yolk sac tumor but genetic and epigenetic features of AT/RT.

SMARCA4 pathogenic variants are rarely detected in pediatric brain tumors other than atypical teratoid rhabdoid tumors (AT/RTs) without INI1 deficiency or in some cases of medulloblastoma. Here, we report an atypical intracranial immature teratoma that recurred as a yolk sac tumor with metastatic spinal and lung lesions. Sequencing of the tumor revealed two SMARCA4 variants, including a splice-site variant and a non-synonymous variant of uncertain significance. Additionally, the methylation signature of the tumor was close to that of AT/RTs. Our case might be a yet-unrecognized subtype of pediatric tumors in which inactivation of SMARCA4 contributes to the pathogenesis.

[Gemcitabine and Docetaxel for the Treatment of Relapsed and Refractory Malignant Rhabdoid Tumor of Kidney and Atypical Teratoid Rhabdoid Tumor].

Gemcitabine and Docetaxel(GEM/DTX)are well known chemotherapeutic drugs for the treatment of soft tissue sarcomas. However, the efficacy of these drugs in the treatment of malignant rhabdoid tumors(MRTs)has not been well described. We used GEM/DTX as salvage chemotherapy for relapsed and refractory MRTs, including 2 patients with malignant rhabdoid tumor of the kidney(MRTK)and 2 with atypical teratoid rhabdoid tumor(ATRT). At the best, partial response was observed in 3 patients(2 MRTK and 1 ATRT). The remaining patient with ATRT had stable disease. Localized edema in the field of recent radiation therapy was discovered in 2 patients. In addition, one had pleural effusion without any evidence of tumor progression. GEM/DTX can be used as a potential chemotherapeutic drug for relapsed or refractory MRTs, although attention should be paid to its unique adverse events.

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.

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 (pinteraction = 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.

Monitoring Ponatinib in a Child with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) reported to show a higher efficacy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) than other TKIs. However, few studies describe ponatinib for pediatric Ph+ALL; therefore, the efficacy, safety, and optimal dosage have not been determined. Here, we report a 3-year-old girl with Ph+ALL treated by a ponatinib-containing regimen with therapeutic drug monitoring in the plasma and cerebrospinal fluid (CSF). In our case, a ponatinib-containing regimen was able to keep minimal residual disease negative, and the pharmacokinetics (PKs) of plasma ponatinib resembled that previously reported in adults. Penetration to the CSF was extremely limited. Thus, ponatinib was feasible and effective for a child with Ph+ALL, although the plasma concentration of ponatinib varied significantly throughout the treatment. The appropriate dosage should be confirmed in a prospective trial, including a detailed PK study.

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

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.

Rhabdoid tumor predisposition syndrome with renal tumor 10 years after brain tumor.

We report a case of rhabdoid tumor predisposition syndrome with a renal tumor developing 10 years after a brain tumor, which demonstrated an unexpectedly favorable outcome. A 2-year-old boy underwent gross total resection of a brain tumor located in the fourth ventricle, and received adjuvant chemotherapy and radiotherapy. At the age of 11 years, a renal tumor was found and nephrectomy was performed. He is currently alive without evidence of disease over 2 years without postoperative therapy. Histologically, rhabdoid cells were observed in both brain and renal tumors. Loss of SMARCB1 (also known as INI1) expression was found in the nucleus of both tumor cells. Genetic testing revealed pathogenic variants of SMARCB1 exon 5 in the renal tumor and SMARCB1 exon 9 in the brain tumor. In addition, heterozygous deletion of 22q11.21-q11.23 containing the SMARCB1 locus was shared by both tumors and this deletion was identified in normal peripheral blood. Considering the histopathological and genetic findings, our case was considered to be rhabdoid tumor predisposition syndrome with atypical teratoid/rhabdoid tumor and late-onset rhabdoid tumor of the kidney.

Hematopoietic Cell Transplantation for Chronic Granulomatous Disease in 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 (P < 0.01), non-CYBB gene mutations (P < 0.01) and CBT (P < 0.01). Regarding the reduced intensity conditioning (RIC) regimen, risk factors for EFS included anti-thymocyte globulin (P = 0.048) and not using low-dose irradiation therapy (P < 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.

Phase II study of reduced-dose craniospinal irradiation and combination chemotherapy for children with newly diagnosed medulloblastoma: A report from the Japanese Pediatric Brain Tumor Consortium.

BACKGROUND: Standard doses of craniospinal irradiation (CSI) are 23.4 Gy for patients with average-risk and 36 Gy for those with high-risk medulloblastoma (MB). We investigated whether intensified chemotherapy including intrathecal chemotherapy with simultaneous irradiation is able to reduce CSI dose to 18 Gy. METHODS: Newly diagnosed average-risk patients aged 3-11 years and high-risk patients aged 3-18 years were eligible. Patients with Stage M1-4 disease were classified as high-risk MB and the others, including M0 patients with >1.5 cm2 postoperative residual tumor, were classified as average-risk MB. Patients received chemotherapy consisting of cyclophosphamide, etoposide, cisplatin, and vincristine. Radiotherapy was started concomitantly with the second course of chemotherapy. Radiation doses were 50 Gy to the primary site and 18 Gy to the craniospinal axis. Average-risk patients received five courses of chemotherapy. High-risk patients received high-dose chemotherapy consisting of thiotepa and melphalan following four courses of chemotherapy. All patients received intrathecal methotrexate. RESULTS: From 2006 to 2014, 48 patients (35 average and 13 high risk) who met the eligibility/exclusion criteria were enrolled. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) were 90.5% (standard error 5.2%) and 93.9% (4.2%), respectively, for average-risk patients, and 100% and 100%, respectively, for high-risk patients. There was no leukoencephalopathy or treatment-related deaths. Two patients experienced secondary cancer. CONCLUSIONS: These results suggest that CSI 18 Gy is adequate at least in a proportion of patients with MB treated with intensified chemotherapy including intrathecal methotrexate and simultaneous irradiation, though the results in high-risk patients were only exploratory.

[Successful unrelated cord blood transplantation for extensive meningeal juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis in a child].

A 2-year and 4-month-old boy developed Langerhans cell histiocytosis (LCH) at the left parietal region of the skull. After treatment with chemotherapy, the patient achieved remission but experienced three relapses. After 3 years, he complained of headache, blurred vision, and lethargy. Brain magnetic resonance imaging revealed multiple dura-based meningeal masses. Biopsy was performed, and the patient was then diagnosed with juvenile xanthogranuloma (JXG). The analysis of both LCH/JXG tissues revealed BRAF V600E mutation. The JXG masses were not responsive to prednisolone, which was injected locally, radiotherapy (24 Gy), and chemotherapy (2-chlorodeoxy-adenosine). In addition, since the patient developed macrophage activation syndrome associated with systemic JXG progression, he received unrelated cord blood transplantation (u-CBT) at the age of 10 years and 11 months. Engraftment was performed at day 42, and significant GVHD was not observed. Four months after CBT, the patient was treated with infliximab (Remicade®) and dexamethasone palmitate (Limethasone®). The size of the intracranial JXG masses gradually decreased after u-CBT and disappeared after 4 years. Currently, the patient is doing well at the age of 25 years and is receiving androgen replacement therapy.

Outcomes of Local Radiation and Intensified Combined Intrathecal Methotrexate and High-dose Chemotherapy for Intracranial Germ Cell Tumors.

Many attempts to reduce radiation fields for intracranial germ cell tumors (iGCTs) remain unsuccessful. To assess the possibility of reduction, we analyzed registry data of 57 patients who mostly underwent local irradiation for iGCTs between 1997 and 2006. The recommended treatment for pure germinomas (PGNs) included 3 courses of cisplatin and etoposide followed by 24 Gy local irradiation. Intensified chemotherapy using a combination of cyclophosphamide and intrathecal methotrexate was recommended for human chorionic gonadotropin-producing germinomas (hCG-GNs) and nongerminomatous germ cell tumors (NGGCTs); both received 50.4 Gy local irradiation. High-dose chemotherapy was only administered for residual NGGCTs after chemoradiotherapy. Craniospinal irradiation was recommended only in metastatic cases. During the median follow-up of 114.8 months, 8 of 9 relapses from 24 PGNs occurred outside irradiation fields, with a 5-year progression-free survival (5-year PFS) of 75%±8.8%. Conversely, no recurrences occurred from 11 hCG-GNs, with a 5-year PFS of 100%. Eleven of 22 patients with NGGCTs received high-dose chemotherapy; the 5-year PFS was 81.3%±8.4%; 2 of 3 relapses occurred in the spinal cord. Thus, local irradiation for PGNs was insufficient without treatment intensification. The introduction of intensified chemotherapy improved outcomes of both patients with hCG-GNs and NGGCTs. However, the contributions of either modality remained unclear.

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

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.

Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan.

BACKGROUND: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. PROCEDURE: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. RESULTS: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. CONCLUSIONS: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.