[The safety and efficacy of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia in children].

To explore the safety and efficacy of blinatumomab in the treatment of CD19 positive (CD19+) B-cell acute lymphoblastic leukemia (B-ALL) in children. A retrospective analysis was conducted on the clinical data of pediatric B-ALL patients who received blinatumomab treatment from Hematology & Blood Diseases Hospital of Chinese Academy of Medical Sciences from August 2021 to October 2023. Based on their disease status, the patients were divided into refractory/relapsed(RR) group, minimal residual disease clearance (MC) group, and chemotherapy intolerance (IC) group. Clinical data of the children were collected to evaluate the adverse drug reactions, therapeutic efficacy and survival of the children. In total, 35 patients were included, with 20 males and 15 females, aged from 0.6 to 16.4 (9.9±4.2) years old. There were 10 cases in the RR group, 20 cases in the MC group and 5 cases in the IC group. A total of 56 cycles of infusion were completed, with one cycle in 24 cases, two cycles in 5 cases, three cycles in 2 cases and four cycles in 4 cases. The median infusion time [M (Q1, Q3)] from the first to the fourth cycle was 14 (14, 28) days, 28 (28, 28) days, 28 (28, 28) days and 28 (26, 28) days, respectively. In terms of adverse reactions, the incidence of grade 1-2 cytokine release syndrome(CRS) was 57.1% (32/56), with grade 1 CRS accounting for 84.4% (27/32). The incidence rate of immune effector cell-associated neurotoxicity syndrome(ICANS) (grade 4) was 1.8% (1/56). In the RR group, 6 cases were treated effectively, and minimal residual disease(MRD) turned negative, before treatment, MRD levels were all less than 20%. Among them, 3 cases had MRD turning positive again 14 to 42 days after discontinuation of Belintoumab. Four cases were treated ineffectively, with MRD >20% before treatment. All MRD positive cases in MC group turned negative and all MRD negative cases in the IC group remained negative after treatment. The median follow-up time of RR group was 5.7 (3.8, 9.4) months, and 1 year median survival rate and event-free survival rate were 40.0%±21.9% and 33.3%±19.2%, respectively. The median follow-up time for MC and IC group patients was 6.7 (5.2, 12.5) months and 7.1 (5.1, 7.6) months, respectively, with an event free survival rate of 100%. The safety and efficacy of using belintoumab in partial RR, MRD clearance, and chemotherapy intolerance are good.

[Clinical features and prognostic factors of advanced myelodysplastic syndromes in children].

Objective: To investigate the clinical features and prognostic factors of advanced myelodysplastic syndromes (MDS) in children. Methods: Clinical data of children diagnosed with advanced MDS in the Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, between September 2009 and April 2022 were retrospectively collected. Follow-up assessments were performed through telephone interviews and the review of medical records until May 1, 2023. The clinical features of children with advanced MDS were summarized by analyzing chromosomal karyotype tests, second-generation gene sequencing results. Multivariate Cox regression analysis was used to investigate the prognostic factors of advanced MDS in children. Results: A total of 69 children, comprising 49 males and 20 females, aged [M (Q1, Q3)] 8 (5, 10) years, were enrolled in the study. Sixty-seven cases underwent chromosomal karyotype testing, of which 42 cases (62.7%) had abnormal karyotypes, with monosomy 7 the most common in 17 cases (25.4%). Forty-three cases underwent next-generation sequencing, with mutations in the SETBP1, NRAS, PTPN11 and RUNX1 genes more common, identified in 12 cases (27.9%), 9 cases (20.9%), 8 cases(18.6%), and 8 cases(18.6%), respectively. The follow-up time [M (Q1, Q3)] was 26 (13, 56) months and the 5-year overall survival rate was 56%(95%CI: 44.4%-70.5%). The 5-year overall survival rate for children who underwent hematopoietic stem cell transplantation (HSCT) was higher than that of children who did not undergo HSCT (73.9% vs 29.1%, P<0.001). HSCT (HR=0.118, 95%CI: 0.037-0.372, P<0.001) was a protective factor for the overall survival rate of children with advanced MDS. Serum ferritin level>356.3 µg/L (HR=6.497, 95%CI: 2.068-20.415, P=0.001) and moderate to severe splenomegaly (HR=4.075, 95%CI: 1.174-14.141, P=0.027) were risk factors for the overall survival rate of children with advanced MDS. Conclusions: Monosomy 7 was the most common abnormal karyotype and SETBP1 was the gene that had the highest mutation frequency in children with advanced MDS. HSCT, increased ferritin and moderate to severe splenomegaly are prognostic factors influencing the overall survival rate of children with advanced MDS.

[Clinical and molecular characteristics of GATA2 related pediatric primary myelodysplastic syndrome].

Objective: To clarify the prevalence, clinical features and molecular characteristics of germline GATA2 mutations in pediatric primary myelodysplastic syndromes (MDS) . Methods: Next-generation sequencing technology was used to detect mutations in GATA2 and other myeloid malignancy genes in 129 children with primary MDS from Jan. 2007 to Jan. 2018. The relationship between genotypes and phenotypes was analyzed. Results: Germline GATA2 mutations accounted for 8.5% (11/129) of all primary MDS cases, and 14.0% (11/50) of MDS with excess blasts (MDS-EB) and acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC) . Compared with GATA2 wild-type patients, GATA2 mutated patients were older at diagnosis[8 (1-16) years old vs 6 years old (range: 1 month old-18 years old) , P=0.035]and higher risk of monosomy 7 (72.7%vs 5.2%, P<0.001) and classified into MDS-EB and AML-MRC compared with refractory cytopenia of childhood (RCC) (63.6%vs 36.4%, P=0.111) . The multivariate analysis showed SETBP1 mutation (P=0.041, OR=9.003, 95%CI 1.098-73.787) and isolated monosomy 7 (P=0.002, OR=24.835, 95%CI 3.305-186.620) were significantly associated with germline mutated GATA2. Overall survival (OS) and outcomes of hematopoietic stem cell transplantation (HSCT) were not influenced by GATA2 mutational status. Conclusions: Our data identify germline GATA2 mutations have a high prevalence in older pediatric patients with monosomy 7, and high risk of progression into advanced MDS subtypes. GATA2 mutation status does not affect OS in pediatric primary MDS.

[Analysis of clinical characteristics and prognosis of non-severe aplastic anemia children with chromosomal abnormalities].

Objective: To analyze the clinical characteristics and prognosis of non-severe aplastic anemia (NSAA) with chromosomal abnormalities in children. Method: A retrospective analysis of 304 cases with NSAA with successful karyotyping from 2001 to 2014 in the Institute of Hematology & Blood Disease Hospital was carried out. The treatment response, condition of blood transfusion were analyzed using χ2 test, the cumulative survival was estimated by the Kaplan-Meier method. Result: Out of 304 patients, 28 patients had chromosomal abnormalities with trisomy 8 (7 cases, 25.0%), abnormalities in chromosome 7 (5 cases, 17.9%), and other types (16 cases, 57.1%). There were no significant differences in the treatment response(40.9% (9/22)vs. 58.6%(119/203), χ2=2.539, P=0.111), the rate of getting rid of blood transfusion(54.5%(6/11) vs. 65.0%(39/60), χ2=6.455, P=0.086), five-year progression-free survival (49.2% vs.70.8%, χ2=0.849, P=0.357), and five-year cumulative survival (79.1% vs. 92.8%, χ2=0.330, P=0.556) between the patients with or without chromosomal abnormalities. There were significant differences in the rate of disease progression(41.7%(10/24) vs. 22.3%(48/215), χ2=4.394, P=0.045), the incidence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (20.8%(5/24)vs. 0.9%(2/215), χ2=30.082, P=0.000)and the five-year cumulative incidence of MDS or AML(33.4% vs. 0.8%, χ2=17.798, P=0.000)between children with and without chromosomal abnormalities. Conclusion: The incidence of chromosomal abnormalities in children with NSAA is 9.2%. The clinical features and treatment response are similar, but children with chromosomal abnormalities have a poorer prognosis, and have higher risk of progressing to MDS or AML.

[Clinical and genetic features of dyskeratosis congenital with bone marrow failure in eight patients].

OBJECTIVE: To summary clinical and genetic features of childhood dyskeratosis congenital (DC) patients with bone marrow failure. METHODS: The clinical data of 8 DC patients with bone marrow failure diagnosed between September 2010 and September 2015 were collected. Whole exons with flanking regions of the 16 telomere-related genes, including DKC1, TERC, TERT, NOP10, NHP2, TINF2 and so on, were analyzed by next generation sequence. RESULTS: Six males and two females were included, with a median age of 42(15-60) months. The median blood cell count at onset were as follow: WBC 3.99 (1.26-5.44) × 10(9)/L, ANC 1.11 (0.38-2.15) × 10(9)/L, RBC 2.45 (0.37-3.56) × 10(12)/L, HGB 82.5(15-127) g/L, PLT 27 (2-112) ×10(9)/L. Hypoplastic or marked hypoplastic bone marrow were seen in 6 patients. DKC1 mutiaton were indentified in 3 patients: one c.961C>A mutation, and two c.1058C>T mutation. TINF2 mutations were identified in 4 patients: c.849delC, c.844C>T, c.811C>T, c.862T>A combined c.871delA. One patient had TINF2 mutation c.848C>A combined TERT mutation c.1138C>T. DKC1 c.961C>A mutation, TINF2 c.849delC mutation and TINF2 c.871delA mutaion were not reported so far. 5 of 7 patients got better after androgen administration. During follow-up, one patient died of serious infection, the other seven patients continued the treatment. CONCLUSIONS: TINF2 and DKC1 mutations were the main genetic phenotypes in childhood DC with marrow failure patients. Androgen is effetive in some cases.