Atsushi Narita

Reticular dysgenesis (RD) is characterized by severe combined immunodeficiency and agranulocytosis with hematopoietic stem cell transplantation (HSCT) being the only curative therapy. Severe neutropenia in RD is typically unresponsive to recombinant human granulocyte colony-stimulating factor (rhG-CSF). To delineate lineage-specific transcriptional responses and cellular heterogeneity induced by rhG-CSF, we integrated single-cell RNA sequencing from seven samples, including two RD patients (with and without rhG-CSF) and three pediatric controls. We identified a moderate increase in hematopoietic stem and progenitor cells (HSPCs) and common myeloid progenitor/granulocyte–monocyte progenitor fractions following rhG-CSF. Notably, B cell fractions increased after rhG-CSF, accompanied by enhanced maturation from common lymphoid progenitors to precursor B cells. In parallel, genes involved in B cell differentiation were markedly upregulated compared with untreated cells. It also modulated the HSPC compartment by markedly suppressing interferon-γ (IFNγ) signaling pathways. RhG-CSF administration before HSCT may benefit patients with RD by modestly increasing neutrophils and supporting infection control, while suppressing IFNγ signaling in HSPCs and potentially promoting B cell differentiation.

Atsushi Narita, Shunsuke Miwata, Masayuki Imaya, Yusuke Tsumura, Ayako Yamamori, Manabu Wakamatsu, Motoharu Hamada, Rieko Taniguchi, Yusuke Okuno, Hideki Murama

Background: Patients with primary refractory and relapsed neuroblastoma have a poor prognosis since safe and effective chemotherapies for these patients are currently limited. The development of new chemotherapy regimens for these patients is imperative to improve survival outcomes.Methods: We retrospectively analyzed 40 patients with refractory (n = 36) or relapsed (n = 4) neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second‐line treatment. We evaluated their therapeutic response and the toxicity of IREC. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on outcomes and toxicity.Results: A total of 112 cycles of IREC were administered to 40 patients with a median of 2 cycles per patient (range, 1–9). Six (15%) patients (UGT1A1 wild‐type [n = 2] and heterozygous [n = 4]) showed objective responses, including partial response (n = 1), tumor shrinkage (n = 4), and improved findings on their MIBG scan (n = 1). Grade 4 neutropenia, grade 4 leukopenia, and grades 3–4 gastrointestinal toxicity were observed in 110 (98%), 88 (79%), and 3 (3%) cycles, respectively. There was no IREC‐related mortality. Patients with UGT1A1 polymorphisms showed a higher frequency of grade 4 leukopenia, but these patients did not have increased treatment‐related mortality or non‐hematologic toxicity.Conclusions: IREC showed an objective response rate of 15% including 1 case with partial response. IREC was well tolerated regardless of UGT1A1 genotype. This study suggests that IREC is a promising second‐line chemotherapy for refractory or relapsed neuroblastoma.

Summary: 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.

Objectives Patients with acquired aplastic anemia (AA) without HLA‐matched sibling donors or aged >40 years receive immunosuppressive therapy (IST) with anti‐thymocyte globulin (ATG). We investigated the relationship between plasma rabbit ATG (r‐ATG) concentration and IST response. Methods From May 2012 to October 2017, 81 patients with severe AA who required initial IST were included. A 1:1 block randomization was employed for 2.5 and 3.5 mg/kg doses of r‐ATG. Results No significant difference in response rates was observed between the 2.5 and 3.5 mg/kg groups (63% vs. 58%, P = 0.894). Median r‐ATG concentrations on days 14 and 28 after IST were 15.2 (0.0–97.7) and 1.8 (0.0–74.9 µg/mL), respectively. According to r‐ATG concentration, response rates were significantly higher in the group with higher r‐ATG concentration than in those with lower r‐ATG concentration (day 14, 88% vs. 52%; P = 0.006 and day 28, 79% vs. 46%; P = 0.005). In multivariate analysis, higher r‐ATG concentrations at day 28 were independent predictors of favorable response to IST at 6 months (odds ratio, 0.29; 95% confidence interval, 0.09–0.93; P = 0.037). Conclusions The present data indicate that higher r‐ATG concentration at day 28 resulted in improved IST response.

Summary: The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti‐thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA.Trial registration: UMIN000011134.