Allogeneic Hematopoietic cell Transplantation Using Alemtuzumab in Asian Patients with Inborn Errors of Immunity.

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8 mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).

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.

Development and evaluation of a rapid one-step high sensitivity real-time quantitative PCR system for minor BCR-ABL (e1a2) test in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

OBJECTIVE: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.

Second Malignant Neoplasms Following Treatment for Hepatoblastoma: An International Report and Review of the Literature.

Treatment intensification has improved survival in patients with hepatoblastoma (HB); however, these treatments are associated with an increased risk of late effects, including second malignant neoplasms (SMNs). Data is limited regarding SMNs following HB treatment. Cases of SMNs following treatment for HB reported in the literature and from personal communication were analyzed to further assess this late effect. Thirty-eight patients were identified. The median age at diagnosis of HB was 16 months (range: 3 to 168 mo). All patients had received a platinum agent, and almost all had anthracycline exposure. The SMNs reported were hematopoietic malignancies (n=19), solid tumors (n=12), and post-transplant lymphoproliferative disorder (n=7). Of the 36 patients with outcome data, 19 survived. SMNs following HB treatment were primarily seen in patients with chemotherapy exposure, a history of liver transplantation, hereditary tumor predisposition syndromes, and/or a history of radiation treatment. Hematopoietic malignancies were the most common SMN reported in this cohort and were diagnosed earlier than other SMNs. Prospective collection of data through a companion late effects study or international registry could be used to further evaluate the rates and risks of SMNs as well as tumor predisposition syndromes in patients treated for HB.

[Discontinuation of tyrosine kinase inhibitors before epiphyseal closure leading to improved short stature in pediatric chronic myelogenous leukemia].

A 3-year-old boy was referred to our hospital with splenomegaly. Blood tests revealed hyperleukocytosis and bone marrow examination showed major BCR::ABL1 fusion, leading to the diagnosis of chronic myelogenous leukemia (CML). Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. The patient achieved molecular remission but became markedly short in stature, measuring 129.3 cm (height standard deviation score [SDS] -3.3) at the age of 12. TKI therapy was discontinued at age 12 years and 10 months, which was 9 years and 8 months after the start of TKI and 1 year and 6 months after achievement of MR4.0, as discontinuation before epiphyseal closure would not improve short stature. At 2 years and 6 months after discontinuation, the patient's height improved to 156.1 cm (SDS-2.0) without relapse. Growth suppression by TKIs is a problem in the management of pediatric CML. This case illustrates how improvement in severe short stature can be achieved by discontinuing TKI therapy before epiphyseal closure.

A nationwide survey of late effects in survivors of juvenile myelomonocytic leukemia in Japan.

We conducted a cross-sectional study using a questionnaire to explore the late effects in survivors of allogenic hematopoietic stem cell transplantation (HSCT) for juvenile myelomonocytic leukemia (JMML). The attending pediatric hematologists/oncologists completed the questionnaires. Of the 30 survivors, approximately 83% showed more than one late effect. The identified late effects included endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature, pulmonary, cardiovascular, and nephrological complications was significantly elevated among survivors who were 12 years or more lapsed after HSCT. Therefore, a multidisciplinary follow-up system for survivors of JMML is crucial.

Clinical Outcomes of Patients With Osteosarcoma Experiencing Relapse or Progression: A Single-institute Experience.

BACKGROUND: Patients with osteosarcoma who experience relapse or progression [R/P] have a poor prognosis. METHODS: Data from 30 patients who experienced R/P among 59 with a diagnosis of high-grade osteosarcoma, who were younger than 40 years old between 2000 and 2019, were retrospectively analyzed to identify prognostic and therapeutic factors influencing their outcomes. RESULTS: The 5-year overall survival [OS] rates after the last R/P of patients experiencing first [n=30], second [n=14], and third [n=9] R/P were 50.3%, 51.3%, and 46.7%, respectively. Multivariate analysis did not identify any independent risk factors affecting OS. The 5-year PFS rate of the 30 patients after first R/P was 22.4%, and multivariate analysis identified histologic subtype and curative local surgery as independent risk factors influencing PFS. Long [>6 mo] partial response was observed in three patients treated using temozolomide+etoposide, irinotecan+carboplatin, or regorafenib. CONCLUSIONS: OS rate in the patients with osteosarcoma experiencing R/P included in this study was markedly higher than that reported previously, mainly due to the surgical total removal of tumors, even after subsequent R/P. The recent establishment of salvage chemotherapy or molecular targeted therapy may also increase survival rates in a subgroup of patients.

Usefulness of central radiologic review in clinical trials of children with hepatoblastoma.

BACKGROUND: No previous research papers have reported a comparative survey of local radiologic diagnoses and central review in children with hepatoblastoma. OBJECTIVE: To evaluate the utility of central review of children with hepatoblastoma enrolled in a clinical trial. MATERIALS AND METHODS: The study included 91 children enrolled in a clinical trial conducted by the Japanese Study Group for Pediatric Liver Tumor. We compared the results of the initial pre-treatment extent of tumor (PRETEXT) disease staging performed at local sites with the results obtained on central review to determine the concurrence rates for tumor staging and additional criteria. RESULTS: The concurrence rate for PRETEXT staging was 70%. As the stage increased, the concurrence rate decreased. Using additional criteria, central review identified 143 lesions (157.1%), about 1.8 times higher than the number identified for the local site diagnoses. The additional criterion found most often on central review was "multifocal lesion" (n=19). The concurrence rate for lung metastases was high. However, our central review found many false-positive assertions of hepatic vein lesions, portal vein invasion and extrahepatic lesions among the local site diagnoses. CONCLUSION: In a clinical trial of hepatoblastoma, central review provided a more precise diagnosis than local site diagnoses with respect to severe PRETEXT stages III and IV cases and other cases including hepatic and portal vein invasion. The central review process appears to be effective and essential for improving the quality of clinical trials.

Prospective validation of the provisional entity of refractory cytopenia of childhood, proposed by the World Health Organization.

In 2008, the World Health Organization proposed a new entity of childhood myelodysplastic syndrome (MDS), which was referred to as refractory cytopenia of childhood (RCC). However, whether this morphological classification reflects clinical outcomes remains unclear. We performed a prospective evaluation of bone marrow morphology in 252 children with acquired bone marrow failure between 2009 and 2013. Of 252 patients, 63 were diagnosed with aplastic anaemia (AA), 131 with RCC without multilineage dysplasia (RCC-w/o-MLD) and 58 with RCC with MLD (RCC-MLD). One patient with AA, three with RCC-w/o-MLD and nine with RCC-MLD presented with chromosomal abnormalities at diagnosis (P = 0·001). The response rates to immunosuppressive therapy (IST) at 6 months and the cumulative incidence of clonal evolution at 5 years did not significantly differ among the three groups. A multivariate analysis revealed that the morphological classification of RCC-MLD was a significant risk factor for secondary graft failure after haematopoietic cell transplantation (HCT) (P = 0·003). In view of these findings, RCC could be divided into two categories, RCC-w/o-MLD and RCC-MLD, because children with this condition exhibited a distinct morphology, frequent chromosomal abnormalities at diagnosis and a high frequency of secondary graft failure after HCT.

Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein-Barr virus infection patients in Japan.

The effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on systemic chronic active Epstein-Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo-HSCT. The median age at HSCT was 21 years, and the three-year overall survival (3-year OS) rate was 72.5%. Of the 90 patients whose viral load after allo-HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV-DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15-39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval [CI]: 1.98-59.56, p = .006) and 15.93 (95% CI: 2.45-103.8, p = .004), respectively. Disease activity (HR 5.74), elevated soluble IL-2 receptor (sIL-2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6 Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL-2R level (≥2000 U/mL) showed a poorer prognosis. Although allo-HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high-risk patients, especially those with high levels of sIL-2R.

Feasibility of dose-dense cisplatin-based chemotherapy in Japanese children with high-risk hepatoblastoma: Analysis of the JPLT3-H pilot study.

BACKGROUND: The SIOPEL-4 study has demonstrated that dose-dense cisplatin-based chemotherapy dramatically improves outcome in children with high-risk hepatoblastoma in western countries. However, the feasibility and safety of this regimen have not been clarified in Japanese patients. METHODS: A pilot study, JPLT3-H, was designed to evaluate the safety profile of the SIOPEL-4 regimen in Japanese children with newly diagnosed hepatoblastoma with either metastatic disease or low alpha-fetoprotein. RESULTS: A total of 15 patients (three female) were enrolled. Median age was 2 years (range, 0-14). Three patients were PRETEXT II (where PRETEXT is PRETreatment EXTent of disease), six PRETEXT III, and six PRETEXT IV. All patients had lung metastasis, none had low alpha-fetoprotein. Eight patients completed the prescribed treatment, and seven patients discontinued therapy prematurely, four due to progressive disease and three due to causes other than severe toxicity. Grade 4 neutropenia was documented in most patients in preoperative cycles A1-3 (11/15 in A1, 9/11 in A2, and 7/11 in A3) and in all considering all cycles. Grade 3-4 thrombocytopenia and grade 3 anemia were also frequently observed. Patients experienced several episodes of grade 3 febrile neutropenia, but none had grade 4 febrile neutropenia or severe infections. One patient had grade 3 heart failure only in the first cycle. Other grade 3 or 4 toxicities were hypomagnesemia, anorexia, nausea, mucositis, liver enzyme elevation, fever, infection, and fatigue. There were no unexpected severe toxicities. CONCLUSION: The toxicity profile of JPLT3-H was comparable to that of SIOPEL-4. Dose-dense cisplatin-based chemotherapy may be feasible among Japanese patients with high-risk hepatoblastoma.

CD146 is a potential immunotarget for neuroblastoma.

Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to arise from neural crest-derived immature cells. The prognosis of patients with high-risk or recurrent/refractory neuroblastoma remains quite poor despite intensive multimodality therapy; therefore, novel therapeutic interventions are required. We examined the expression of a cell adhesion molecule CD146 (melanoma cell adhesion molecule [MCAM]) by neuroblastoma cell lines and in clinical samples and investigated the anti-tumor effects of CD146-targeting treatment for neuroblastoma cells both in vitro and in vivo. CD146 is expressed by 4 cell lines and by most of primary tumors at any stage. Short hairpin RNA-mediated knockdown of CD146, or treatment with an anti-CD146 polyclonal antibody, effectively inhibited growth of neuroblastoma cells both in vitro and in vivo, principally due to increased apoptosis via the focal adhesion kinase and/or nuclear factor-kappa B signaling pathway. Furthermore, the anti-CD146 polyclonal antibody markedly inhibited tumor growth in immunodeficient mice inoculated with primary neuroblastoma cells. In conclusion, CD146 represents a promising therapeutic target for neuroblastoma.

Clinical Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Children with Juvenile Myelomonocytic Leukemia: A Report from the Japan Society for Hematopoietic Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for juvenile myelomonocytic leukemia (JMML), but few large studies of HSCT for JMML exist. Using data from the Japan Society for Hematopoietic Cell Transplantation registry, we analyzed the outcomes of 129 children with JMML who underwent HSCT between 2000 and 2011. The 5-year overall survival (OS) rate and cumulative incidence of relapse were 64% and 34%, respectively. A regimen of busulfan/fludarabine/melphalan was the most commonly used (59 patients) and provided the best outcomes; the 5-year OS rate reached 73%, and the cumulative incidences of relapse and transplantation-related mortality were 26% and 9%, respectively. In contrast, the use of the irradiation-based myeloablative regimen was the most significant risk factor for OS (hazard ratio [HR], 2.92; P = .004) in the multivariate model. In addition, chronic graft-versus-host disease (GVHD) was strongly associated with lower relapse (HR, 0.37; P = .029) and favorable survival (HR, 0.22; P = .006). The current study has shown that a significant proportion of children with JMML can be cured with HSCT, especially those receiving the busulfan/fludarabine/melphalan regimen. Based on the lower relapse and better survival observed in patients with chronic GVHD, additional treatment strategies that focus on enhancing graft-versus-leukemia effects may further improve survival.

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.

Effects of cryotherapy on high-dose melphalan-induced oral mucositis in pediatric patients undergoing autologous stem cell transplantation.

Cryotherapy is a conventional method for preventing melphalan-induced oral mucositis (OM) in adult patients. We retrospectively examined the clinical benefits of cryotherapy in 41 pediatric patients undergoing autologous stem cell transplantation using a melphalan-etoposide-carboplatin regimen. Twenty-two patients received cryotherapy. The cumulative incidence of grade 3-4 OM was significantly lower in the cryotherapy group (57.1%) than in the noncryotherapy group (89.5%; P = .041). Multivariate analyses identified cryotherapy and the melphalan dose as independent factors for the lower occurrence of OM. The present study demonstrates the clinically significant efficacy of cryotherapy for preventing melphalan-induced OM in pediatric patients.

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

PURPOSE: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Accuracy and clinical value of an adhesion scoring system: A preoperative diagnostic method using transvaginal ultrasonography for endometriotic adhesion.

AIM: To investigate the accuracy and clinical value of an adhesion scoring system using transvaginal ultrasonography for endometriotic adhesion. METHODS: In this prospective observational study, we included 131 patients with endometriosis who underwent surgery. Before surgery, transvaginal ultrasonography and adhesion mapping were performed to determine the presence or absence of adhesions at 10 sites of the pelvis. Mapping accuracy was determined by comparing the mapping findings with the surgical findings. To determine the severity of pelvic adhesions, we developed an adhesion score (0-10). With the adhesion score, we assessed the effect of surgical adhesiolysis and evaluated the relationship between postoperative adhesions and infertility. RESULTS: Of the 10 sites assessed for adhesions, the most frequent site of adhesions was the site between the left ovary and the uterus (70.5%). The overall sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and accuracy of adhesion mapping were 80.4%, 86.1%, 78.8%, 87.2%, 5.79, 0.23 and 83.9%, respectively. The adhesion score in this system was significantly correlated with the adhesion-related score in the revised American Society for Reproductive Medicine classification (R2 = 0.734). Surgical adhesiolysis yielded only about 30% improvement postoperatively. The adhesion score 1 month after surgery in the non-in vitro fertilization (IVF) pregnancy group was significantly lower than that in the IVF pregnancy group (3.45 vs 5.21; P = 0.02). CONCLUSION: Our adhesion scoring system allowed an accurate prediction of the pelvic adhesion status and may potentially be an indicator of postoperative adhesions and infertility.

Case of ovarian steroid cell tumor diagnosed after presenting acute heart failure.

We report a rare case of an ovarian steroid cell tumor with a diagnosis prompted by heart failure symptoms. A 28-year-old Japanese nulligravida/nullipara with a chief complaint of respiratory discomfort during physical exertion and exhibiting heart failure symptoms was referred to our hospital. She also had signs of virilization, including secondary menorrhea since the age of 20, hirsutism and balding. Cushing's syndrome was suspected, and further examinations showed hypertestosteronemia and right ovarian tumor. Symptomatic treatment for heart failure with diuretics and antihypertensives was followed by abdominal right adnexectomy performed due to the androgen-producing ovarian tumor. The tumor was solid and larger than a fist, and confirmed as a steroid cell tumor through postoperative histopathology. Serum total testosterone levels normalized at day 3 postoperatively, and menstruation resumed 2 months later. Our case was diagnosed due to heart failure symptoms, and its treatment resulted in improvement in virilization signs.