Phase 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy.

PURPOSE: High-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1-10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment. To confirm the robustness of this therapy, further corporate-sponsored clinical trial (OP-07-001 study) was conducted. METHODS: The primary endpoint in the CPG2-PII study was to evaluate the proportion of patients of the percentage clinical important reduction (CIR) as an indicator of MTX concentration, which can be managed with leucovorin and supportive care. The primary endpoint of the OP-07-001 study was to evaluate the decreasing rate of plasma MTX concentration at 20 min after glucarpidase administration from the baseline for four patients. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively in the two studies, and safety was analyzed for each of them. RESULTS: The rate of CIR was 76.9% (95% confidence interval, 46.2-95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Hypersensitivity, blood bilirubin increased, and headache for each patient were the only study drug-related events. CONCLUSION: Glucarpidase showed an effect of reducing plasma MTX concentration in Japanese patients with DME as that observed in a previous US study, confirming its favorable safety and tolerability.

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.

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.

Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy.

Introduction: Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. Methods: In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, n = 15) who received 50 U/kg of CPG2 rescue for delayed MTX excretion were conducted. In the phase 2 study, the first CPG2 treatment at a dose of 50 U/kg was intravenously administered for 5 min within 12 h after the first confirmation of delayed MTX excretion. The second dose of CPG2, with a plasma MTX concentration >1 µmol/L, was administered to the patient more than 46 h after the start of CPG2 administration. Results: The population mean PK parameters (95% CI) of MTX, obtained from the final model post hoc, were estimated as follows: CLrMTX = 2.424 L/h (95% CI: 1.755-3.093), VcMTX = 12.6 L (95% CI: 10.8-14.3), VpMTX = 2.15 L (95% CI: 1.60-2.70), and α = 8.131 x 105 (4.864 x 105-11.398 x 105). The final model, including covariates, was CLrMTX (L/h): 3.248 x Body Weight/Serum creatinine/60 (CV 33.5%), VcMTX (L): 0.386 x Body Weight/body surface area (CV 29.1%), VpMTX (L):3.052 x Body Weight/60 (CV 90.6%), and α (L/h): 6.545 x 105 (CV 79.8%). Discussion: These results suggest that the pre-CPG2 dose and 24 h after CPG2 dosing were the most important sampling points in the Bayesian estimation of plasma MTX concentration prediction at 48 h. These CPG2-MTX popPK analysis and Bayesian estimation of rebound in plasma MTX concentrations are clinically important to estimate >1.0 µmol/L 48 h after the first CPG2 dosing. Clinical trial registration: https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2363, identifier JMA-IIA00078 and https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2782, identifier JMA-IIA00097.

T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation for a Patient With Tcf3-Hlf-Positive Acute Lymphoblastic Leukemia Extramedullary Relapse After Unrelated Bone Marrow Transplantation.

TCF3-HLF-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has an extremely poor prognosis. A 2-year-old boy with TCF3-HLF-positive BCP-ALL had an isolated extramedullary relapse in multiple bones after allogeneic hematopoietic stem cells transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor. In this study, he received a T-cell-replete haploidentical HSCT (TCR-haplo-HSCT) from his father when in nonremission state, which resulted in a sustained complete remission for over 3 years. Immune therapies for patients with an extramedullary relapse of TCF3-HLF-positive BCP-ALL have been attempted; however, long-term efficacies of these therapies remain unknown. Our TCR-haplo-HSCT may be an effective therapeutic option for such patients.

Evaluation of a quantitative PCR-based method for chimerism analysis of Japanese donor/recipient pairs.

Chimerism analysis is a surrogate indicator of graft rejection or relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Although short tandem repeat PCR (STR-PCR) is the usual method, limited sensitivity and technical variability are matters of concern. Quantitative PCR-based methods to detect single nucleotide polymorphisms (SNP-qPCR) are more sensitive, but their informativity and quantitative accuracy are highly variable. For accurate and sensitive chimerism analysis, a set of KMR kits (GenDx, Utrecht, Netherlands), based on detection of insertions/deletions (indels) by qPCR, have been developed. Here, we investigated informativity and validated the accuracy of KMR kits in Japanese donor/recipient pairs and virtual samples of DNA mixtures representative of Japanese genetic diversity. We found that at least one recipient-specific marker among 39 KMR-kit markers was informative in all of 65 Japanese donor/recipient pairs. Moreover, the percentage of recipient chimerism estimated by KMRtrack correlated well with ratios of mixed DNA in virtual samples and with the percentage of chimerism in HSCT recipients estimated by STR-PCR/in-house SNP-qPCR. Moreover, KMRtrack showed better sensitivity with high specificity when compared to STR-PCR to detect recipient chimerism. Chimerism analysis with KMR kits can be a standardized, sensitive, and highly informative method to evaluate the graft status of HSCT recipients.

T-cell replete haploidentical stem cell transplantation with low dose anti-thymocyte globulin for relapsed/refractory Ewing sarcoma family tumors.

BACKGROUND: Despite intensive multimodal therapies, the prognosis of relapsed/ refractory Ewing sarcoma family tumors (RR-ESFTs) is dismal. Some case reports using allogeneic stem cell transplantation (allo SCT) for RR-ESFTs have been reported, however, the efficacy of allo SCT is yet to be established. AIM: The purpose of this study was to evaluate the response and toxicity of T-cell replete haploidentical SCT (TCR-haplo-SCT) in RR-ESFTs. METHODS AND RESULTS: In this study, we retrospectively analyzed six patients with RR-ESFTs who received TCR-haplo-SCT. Four patients had relapsed and two patients had refractory Ewing sarcoma. Before the TCR-haplo-SCT, all patients received a reduced intensity-conditioning regimen containing fludarabine, melphalan, and low-dose rabbit anti-thymocyte globulin (2.5 mg/kg), as well as graft-versus-host disease (GVHD) prophylaxis, which consisted of tacrolimus, methotrexate, and prednisolone. Primary neutrophil engraftment was achieved in all the patients. Four patients developed acute GVHD (aGVHD) (grade I, 1; grade II, 1; grade III, 2), and two patients developed chronic GVHD (cGVHD). Among the four that developed aGVHD, three survived for 14, 116, and 129 months without relapse, while one died due to a transplant-related complication. In contrast, the two patients who did not develop aGVHD experienced relapse early after TCR-haplo-SCT. CONCLUSIONS: In this study, three of the six patients with RR-ESFTs survived for more than one year without relapse, and the treatment toxicity was considered acceptable even for patients who underwent high-intensity pretreatment. TCR-haplo-SCT could be a potential therapeutic option for patients with RR-ESFTs.

Effects of second transplantation with T-cell-replete haploidentical graft using low-dose anti-thymocyte globulin on long-term overall survival in pediatric patients with relapse of leukemia after first allogeneic transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the preferred treatment for children with high-risk hematologic malignancies, but post-allo-HSCT relapse has a poor prognosis and limited treatment options. We evaluated the feasibility, outcome, and risk factors influencing survival after T-cell-replete haploidentical HSCT with low-dose anti-thymocyte globulin (ATG) in 30 patients with post-allo-HSCT relapse of acute lymphoblastic leukemia and acute myeloid leukemia. Overall, 50% of the patients had complete remission (CR) before the second transplant and the overall survival (OS) rate was 52%. In surviving patients (median follow-up 614 days), Kaplan-Meier analysis revealed estimated 2-year leukemia-free survival and OS rates of 48.1% and 61.1%, respectively. Cumulative incidences of 2-year non-relapse mortality and relapse were 24.7% and 36.3%, respectively. Achieving CR before the second allo-HSCT was a predominant independent prognostic factor identified in the multivariate analysis, with a significantly improved 2-year OS rate of 86.7%. T-cell-replete haplo-HSCT with low-dose ATG for second allo-HSCT may benefit a selected patient population.

Effectiveness of T-Cell Replete Haploidentical Hematopoietic Stem Cell Transplantation for Refractory/Relapsed B Cell Acute Lymphoblastic Leukemia in Children and Adolescents.

Background: The prognosis of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains dismal owing to acquired resistance to chemotherapeutic agents. This study aimed to evaluate the efficacy of T-cell replete HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) for pediatric refractory/relapsed BCP-ALL (RR-BCP-ALL). Methods: Nineteen pediatric patients with RR-BCP-ALL underwent TCR-haplo-HSCT between 2010 and 2019 at the Fukushima Medical University Hospital. The disease status at TCR-haplo-HSCT included complete remission (CR) in eight patients and non-CR with active disease in 11 patients. Total body irradiation-based, busulfan-based, and reduced-intensity conditioning regimens were employed in 11, 6, and 2 patients, respectively. Low-dose anti-thymocyte globulin (thymoglobulin, 2.5 mg/kg) was used in all patients. Graft-vs.-host disease (GVHD) prophylaxis was administered with tacrolimus, methotrexate, and prednisolone. Results: All patients received peripheral blood stem cells as the stem cell source. The HLA disparities in graft vs. host directions were 2/8 in one, 3/8 in five, and 4/8 in 13 patients. Among 18 patients who achieved primary engraftment, acute GVHD occurred in all 18 evaluable patients (grade II, 9; grade III, 8; grade IV, 1), and chronic GVHD was observed in 10 out of 15 evaluable patients. Three patients died because of transplant-related mortality. The 3-year overall survival (OS) and leukemia-free survival rates were 57.4 and 42.1%, respectively. Compared to patients older than 10 years in age (N = 10), those younger than 10 years in age (N = 9) showed an excellent OS rate (3-year OS rate: patients < 10 years old, 100%; patients > 10 years old, 20% [95% confidence interval, 3.1-47.5]; p = 0.002). Conclusions: We suggest that TCR haplo-HSCT with low-dose ATG conditioning has the potential to improve the transplantation outcomes in patients with RR-BCP.

Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice.

BACKGROUND: Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. "Allogeneic effects" refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells. METHODS: AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo. RESULTS: Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions. CONCLUSIONS: Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.

[Diagnosis and treatment of sinusoidal obstruction syndrome (veno-occlusive disease)].

Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD) of the liver, is one of the most relevant complications of hepatic sinusoidal endothelial origin that appears early after hematopoietic cell transplantation (HCT). Despite its relatively low incidence and the spontaneous resolution of most SOS/VOD cases, severe SOS/VOD evolved to multi-organ failure with an >80% mortality rate and represents one of the major clinical problems after HCT. The sinusoidal endothelial cells and hepatocytes are damaged by toxic metabolites generated by the conditioning regimen in these patients. Several risk factors have been identified for SOS/VOD development. Although defibrotide is recommended for both prevention and treatment, no satisfactory therapy exists for managing severe SOS/VOD. Thus, this review describes the new definition of SOS/VOD diagnosis and the severity grading of suspected SOS/VOD from the European Society for Blood and Marrow Transplantation. Furthermore, it describes the results of current treatment including the Japanese therapeutic use program, defibrotide treatment protocol.

Single-Arm Non-Blinded Multicenter Clinical Trial on T-Cell-Replete Haploidentical Stem Cell Transplantation Using Low-Dose Antithymocyte Globulin for Relapsed and Refractory Pediatric Acute Leukemia.

Although approximately 70% of pediatric hematological malignancies are curable, approximately 30% remain fatal. No standard treatment is available in patients showing relapse and those with refractory disease. Although different methods are adopted in different hospitals, its efficacy is extremely limited. In recent years, haploidentical stem cell transplantation, involving high-dose cyclophosphamide administration post-transplanta tion, has been used, mainly in adults; however, its application is limited to removal of alloreactive T cells. Multicenter single-arm clinical trials of T-cell replete haploidentical stem cell transplantation (TCR-haplo-SCT) will be conducted in children with relapsed and refractory acute leukemia. After myeloablative conditioning using total body irradiation or busulfan, intensive graft versus host disease prophylaxis is administered, consisting of low-dose rabbit anti-human thymocyte globulin, tacrolimus, methotrexate, and prednisolone. An external control group is set up for the study. The treatment period is around 3 months, and the follow-up period is 2 years from transplantation completion.The aim of this study is to verify the efficacy and safety of TCR-haplo-SCT and present it as a new immune cell therapy for improving survival rate in children with relapsed and refractory acute leukemia.

Intracranial Hemorrhage in a Pediatric Patient with Chronic Myeloid Leukemia in Chronic Phase: A Case Report.

Chronic myeloid leukemia (CML) is an uncommon entity in pediatric patients. CML in chronic phase (CML-CP) has a relatively favorable outcome. Leukostasis occurs in 9.7% of patients with CML. One of the most serious leukostasis-related complications is intracranial hemorrhage (ICH). However, this is very rare in patients with CML-CP, and few early mortalities have been reported in CML patients with leukostasis. We report the case of a 14-year-old female patient with CML-CP who developed ICH 8 days after admission. A 14-year-old girl developed symptoms of fatigue and slight fever and was diagnosed with CML-CP. She was treated with imatinib and received low-molecular-weight heparin owing to coagulation abnormalities. However, 6 days later, she developed sensorineural hearing loss, which is a symptom of leukostasis. She received hydroxyurea to reduce her white blood cell (WBC) count, and her treatment was changed from imatinib to nilotinib. The WBC and platelet counts remained unchanged, blast counts did not increase, and mild coagulation abnormality persisted. Eight days after admission, she suddenly lost consciousness and experienced respiratory arrest. Cranial computed tomography revealed multiple ICH lesions and brain hernia. She received intensive care but was diagnosed with brain death by electroencephalography and died 14 days after hospitalization. ICH is very rare in patients with CML-CP; however, patients with leukostasis and coagulation abnormalities can develop severe hemorrhage, even in the chronic phase. Thus, it is necessary to accurately estimate the cause and provide appropriate treatment for these patients.

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.

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

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.

Decline of serum albumin precedes severe acute GVHD after haploidentical HSCT.

BACKGROUND: Haploidentical hematopoietic stem cell transplantation (HSCT) is a useful therapy for relapsed/refractory acute leukemia or lymphoma because of the strong graft-vs-leukemia (GVL) effect. However, it is often accompanied by severe acute graft-versus-host disease (aGVHD), which is the most serious complication after haploidentical HSCT. Thus, it is important to control the severity of aGVHD while maintaining the GVL effect. In our experience of pediatric haploidentical HSCT, it takes several days for aGVHD to become severe after the appearance of initial symptoms, mostly skin rashes. In this study, we aimed to identify useful biomarkers at the onset of aGVHD that predict subsequent development of severe aGVHD. METHODS: Forty-five consecutive children with relapsed/refractory acute leukemia or lymphoma who developed aGVHD after haploidentical HSCT were enrolled. We analyzed possible biomarkers from samples collected at the onset of acute GVHD. RESULTS: Nineteen patients developed grade 1-2 aGVHD, and 26 patients developed grade 3-4 aGVHD. There was no significant difference in patient characteristics between the two groups. Transplant-related mortality occurred only in the grade 3-4 aGVHD group (34.5%). Multivariate analysis revealed that serum albumin was an independent biomarker for predicting the severity of aGVHD (P = 0.009). The area under the receiver operating characteristic curve of serum albumin was 0.864. CONCLUSIONS: The serum albumin level at the onset of aGvHD could be a useful biomarker for the development of subsequent severe aGVHD in pediatric patients after haploidentical HSCT.

Hematopoietic stem cell transplantation in children and adolescents with nonremission acute lymphoblastic leukemia.

BACKGROUND: The appropriateness of allogeneic hematopoietic stem cell transplantation (HSCT) in children and adolescents with leukemia in whom complete remission is not possible remains unclear. This retrospective analysis aimed to investigate the outcomes associated with HSCT, and the risks of HSCT in children and adolescents with nonremission acute lymphoblastic leukemia (ALL). PROCEDURE: Data from the Japan Society for Hematopoietic Cell Transplantation registry on 325 patients with nonremission ALL (aged <21 years, with blasts in the peripheral blood and/or bone marrow) who had undergone HSCT between January 2001 and December 2015 were evaluated. To assess survival, we developed a scoring system using significant adverse pre-HSCT variables. RESULTS: Overall, 247 patients died. The median length of follow up among survivors was 1145 days, and the 3-year overall survival was 22% (95% confidence interval [CI]: 18-27%). A low performance score, presence of >25% bone marrow blasts, T-cell phenotype, poor-risk or normal cytogenetics, and history of HSCT were predictors of a poor outcome. Patients scoring 0-1 (n = 109), 2 (n = 91), and 3-7 (n = 125) had a 3-year overall survival of 41% (95% CI: 31-51%), 21% (95% CI: 13-31%), and 7% (95% CI: 3-12%), respectively. CONCLUSION: These results support HSCT in certain nonremission patients. Even in patients without complete remission, outcomes differed according to pre-HSCT factors. A scoring system could help determine the appropriateness of HSCT in children and adolescents with nonremission ALL.

A phase II JN-I-10 efficacy study of IDRF-based surgical decisions and stepwise treatment intensification for patients with intermediate-risk neuroblastoma: a study protocol.

BACKGROUND: Few clinical trials have been reported for patients with intermediate-risk neuroblastoma because of the scarcity of the disease and the variety of clinical and biological characteristics. A multidisciplinary treatment that consists of multidrug chemotherapy and surgery is expected to lead to a good prognosis with few complications. Therefore, a clinical trial for patients with intermediate-risk tumors was designed to establish a standard treatment that reduces complications and achieves good outcomes. METHODS: We planned a prospective phase 2, single-arm study of the efficacy of image-defined risk factors (IDRF)-based surgical decision and stepwise treatment intensification for patients with intermediate-risk neuroblastomas. For the localized tumor group, IDRF evaluations will be performed after each three-course chemotherapy, and surgery will be performed when appropriate. For patients with metastatic tumors, a total of five chemotherapy courses will be performed, and primary lesions will be removed when the IDRF becomes negative. The primary endpoint is 3-year progression-free survival rate, and the secondary endpoints include 3-year progression-free survival rates and overall survival rates of the localized group and the metastasis group and the incidence of adverse events. From international results, 75% is considered an appropriate 3-year progression-free survival rate. If this trial's expected 3-year progression-free survival rate of 85% is statistically greater than 75% in the lower limit of the 95.3% confidence interval, with an accuracy 10% (85 ± 10%), both groups require more than 65 patients. DISCUSSION: This study is the first clinical trial on the efficacy of IDRF-based surgical decision and stepwise treatment intensification for patients with intermediate-risk neuroblastomas. We expect that this study will contribute to the establishment of a standard treatment for patients with intermediate-risk neuroblastoma. TRIAL REGISTRATION: UMIN000004700, jRCTs051180203; Registered on December 9, 2010.

Autologous Stem Cell Transplantation for Children With Renal Tumors, and Adults With Wilms Tumor: Retrospective Analysis of the Japanese Transplant Registry Unified Management Program.

BACKGROUND: Almost all pediatric patients with renal tumors are diagnosed with nephroblastoma (Wilms tumor), clear cell sarcoma, or malignant rhabdoid tumor. The choice of treatment is important for relapsed and refractory patients with nephroblastoma. Furthermore, clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumor of the kidney (MRTK) have a poor prognosis compared with nephroblastoma. Thus, stem cell transplantation (SCT) is sometimes selected to treat these tumors. PATIENTS AND METHODS: The authors targeted a total of 84 patients with nephroblastoma, CCSK, and MRTK who underwent a first autologous SCT between 1992 and 2014, and were registered in the Japanese Transplant Registry Unified Management Program system. The authors retrospectively analyzed the SCT data for survival rate. RESULTS: Five-year overall survival rates for nephroblastoma, CCSK, and MRTK were 72.4%±6.3%, 46.8%±13.8%, and 36.4%±14.5%, respectively. The event-free survival rates at 5 years were 64.9%±6.7%, 35.7%±12.8%, and 27.3%±13.4%, respectively. The relapse rates at 5 years were 25.3%±11.4%, 46.2%±28.4%, and 60.0%±43.1%, respectively. CONCLUSION: Although the survival rate for nephroblastoma was relatively high, those of CCSK and MRTK were poor.

Secondary brain tumors after cranial radiation therapy: A single-institution study.

AIM: To study the probability of developing secondary brain tumors after cranial radiotherapy.Background Patients treated with cranial radiotherapy are at risk for developing secondary brain tumors. PATIENTS AND METHODS: We planned an institutional survey for secondary brain tumors in survivors after cranial irradiation and reviewed the 30-year duration data. Event analysis and cumulative proportion curves were performed to generally estimate the cumulative proportion of developing secondary brain tumors, cavernoma and meningioma at different periods of time. RESULTS: Secondary brain tumors occurred in 21% of cases: 10% were cavernomas, 6% were meningiomas, 3% were skull osteomas, and 1% were anaplastic astrocytoma. The cumulative proportion of developing secondary brain tumor was 6% at 10 years and 20% at 20 years, while the cumulative proportion for developing cavernomas and meningiomas was 16% and 7% at 20 years, respectively. CONCLUSION: Our study shows that patients who received cranial irradiation were at risk of secondary brain tumors such as cavernomas and meningiomas. Thus, a meticulous follow-up of cancer survivors with history of cranial irradiation by an annual MRI scan is justifiable. This will help clinicians to detect secondary brain tumors early and make its management much easier.