Survival benefit of pediatric-based regimen for adults with acute lymphoblastic leukemia: A single-center retrospective cohort

ABSTRACT Introduction: Improving survival of Acute Lymphoblastic Leukemia (ALL) in adult patients has been a challenge. Despite intensive chemotherapy treatment, overall survival is poor. However, several studies demonstrate that young adult patients have better survival when treated with pediatric-based intensive regimens. Considering these results, We decided to treat newly diagnosed ALL patients according to age and risk factors. The goal of this study was to describe the results of this intensive chemotherapy treatment approach for ALL adult patients diagnosed at our institution. Methods: Fifty-eight ALL patients, diagnosed from 2004 to 2013, were included in the analysis. Patients were assigned to either the St. Jude Total Therapy XIIIB high-risk arm (St Jude) or the CALGB 8811 (CALGB). The Kaplan-Meier survival curve was used for the survival analyses and the Cox proportional hazard regression, for multivariable analysis. Results: The overall survival was 22.9% at 10 years. The St. Jude improved survival, compared to the CALGB (p = 0.007), with 32.6% vs. 7.4% survival rate at 10 years. However, no survival benefit was found for patients younger than 20 years old (p = 0.32). The multivariable analysis demonstrated that undetectable minimal residual disease (MRD) and hematopoietic stem cell transplantation (HSCT) had beneficial impact on survival (p = 0.0007 and p = 0.004, respectively). Conclusion: ALL is a disease of poor prognosis for adults. The joint effort to standardize treatment and seek solutions is the way to start improving this scenario.

Outcome of adolescents and young adults with acute lymphoblastic leukemia in a single center in Brazil

ABSTRACT Introduction: Acute lymphoblastic leukemia (ALL) presents a poor prognosis in adults. The adoption of pediatric protocols has been changing this scenario, especially for adolescents and young adults (AYA). Objective and method: We aimed to evaluate a consecutive series of patients treated at the State Institute of Hematology of Rio de Janeiro between 2012 and 2020, focusing on the AYA subgroup. Result: The B-ALL was the most frequent subtype (81.6%) and AYA, the predominant age group (57.7%). The median overall survival (OS) was 9.4 months. High early mortality was observed and sepsis was the main cause of death. Better OS results were noted in AYA, in comparison to over 39y (13.3 × 6.2 months, respectively), the Berlin-Frankfurt-Münster (BFM) being the protocol of choice in this group. Conclusion: The use of the pediatric protocol seems to improve the OS of AYA, however, high rates of deaths from infection were observed, demonstrating the need for advances in the Brazilian public system clinical support.

The prognostic values of the IL?10 (G1082A) and TNF?? (G308A) polymorphisms in Egyptian patients with acute lymphoblastic leukemia: A single?center study

Background: Interleukin?10 (IL?10) and tumor necrosis factor?alpha (TNF??) genes contribute to oncogenesis. We evaluated the influence of the IL?10 (G1082A) and TNF?? (G308A) polymorphisms on the prognosis and outcomes of Egyptian patients with acute lymphoblastic leukemia (ALL). Materials and Methods: We investigated 64 children and 76 adults with ALL, between 2016 and 2019, for the IL?10 (G1082A) and TNF?? (G308A) polymorphisms using allele?specific polymerase chain reaction and polymerase chain reaction杛estriction fragment length polymorphism. Survival analyses were performed using the Kaplan朚eier estimator and the log?rank test. Results: In children with ALL, the A allele of TNF?? and IL?10 polymorphisms was associated with older age (P = 0.04 and 0.03), more extramedullary disease (P = 0.02 and 0.001), positive breakpoint cluster region朅belson (BCR?ABL) rearrangement (p190; P = 0.04 and 0.001), and more relapse (P = 0.002). The IL?10 GG genotype was associated with higher overall survival in children (P = 0.026). Adults carrying the TNF?? A allele showed more extramedullary disease (P = 0.009) and relapse (P = 0.003). We also found a higher frequency of IL?10 A allele in adults with older age (P = 0.03), lower hemoglobin level (P = 0.04), positive BCR?ABL rearrangement (P = 0.001), more extramedullary disease (P = 0.001), more relapse (P = 0.002), and a longer time for the first complete remission (P = 0.003). Conclusion: A possible association exists between the A allele of IL?10 and TNF?? polymorphisms and poor prognosis in Egyptian patients with ALL, while the IL?10 GG genotype may be associated with better survival in children with ALL.

Successful stem cell transplantation after nelarabine, pegylated asparaginase, vincristine, doxorubicin, and prednisone in refractory early T-cell precursor acute lymphoblastic leukemia: A case report

Early T-cell precursor Acute Lymphoblastic Leukemia (ALL) has a dismal prognosis. Nelarabine is a purine nucleoside analog that increases the apoptosis rate in T-cell lymphoblasts. We present a 30-year-old patient diagnosed with T-cell ALL. He was a high-risk patient because of an early precursor phenotype and a complex karyotype that had been refractory to three previous lines of treatment. He started a course of nelarabine (1500 mg/m for three days), pegylated-asparaginase, doxorubicin, vincristine, and prednisone (Nelarabine Peg-Asp AdmVP). He reached complete remission and received an allogeneic sibling hematopoietic stem cell transplant with fludarabine, total body irradiation, and cyclophosphamide as the conditioning regimen. He developed a pulmonary mycosis, which resolved, and grade-2 neurotoxicity in his upper and lower limbs. He was discharged after 40 days and to date remains with 23 months of complete remission. The Nelarabine Peg-Asp AdmVP regimen seems to be effective and safe. Further research is needed to establish it as an induction treatment in refractory early T-cell precursor acute lymphoblastic leucemia.

Myosin 1g as a high-risk biomarker in a pediatric patient with lineage switch from acute lymphoblastic leukemia to myeloid phenotype / Miosina 1g como un marcador de alto riesgo en una paciente pediátrica con cambio de linaje de leucemia linfoblástica aguda a fenotipo mieloide

Abstract Background: Myosin 1g (Myo1g) has recently been identified as a potential diagnostic biomarker in childhood acute lymphocytic leukemia (ALL). Case report: We describe the case of a 1-year-old Mexican female patient. Although initially studied for hepatomegaly, an infectious or genetic etiology was excluded. Liver biopsy showed infiltration by neoplastic B-cell precursors (BCPs), and bone marrow (BM) aspirate showed 14.5% of BCPs. In a joint session of the oncology, hematology, and pathology departments, low-risk (LR) BCP-ALL of hepatic origin with aberrant myeloid markers was diagnosed. Although treatment was initiated, the patient presented early with BM relapse. Modest overexpression of Myo1g was observed from the onset. However, at the end of the steroid window, expression increased significantly and remained elevated during this first relapse to BM. The parents refused hematopoietic stem cell transplantation, but she continued chemotherapy. After a second BM relapse at 5 years of age, the phenotype switched to myeloid. Her parents then opted for palliative care, and the patient died two months later at home. Conclusions: This case shows the potential use of Myo1g in clinical practice as a high-risk indicator. Myo1g monitoring may reveal a high risk and relapse trend, even when typical parameter values are not altered: Myo1g could be used to classify patients from low to high risk from diagnosis, allowing patients to promptly receive the best treatment and potentially modifying prognosis and survival.

Resumen Introducción: Recientemente se ha identificado a miosina 1g (Myo1g) como un potencial biomarcador de diagnóstico en la leucemia linfoblástica aguda (LLA) infantil. Caso clínico: Se describe el caso de una paciente mexicana de 1 año de edad. Aunque inicialmente se estudió por hepatomegalia, se descartó una etiología infecciosa o genética. La biopsia hepática mostró infiltración por precursores de células B neoplásicas (PCB) y un aspirado de médula ósea (MO) mostró 14.5% de PCB. En una sesión conjunta de los departamentos de oncología, hematología y patología, se diagnosticó PCB-LLA de bajo riesgo de origen hepático con marcadores mieloides aberrantes. Aunque se inició tratamiento, la paciente presentó tempranamente recaída de MO. Se observó una modesta sobreexpresión de Myo1g. Sin embargo, al final de la ventana de esteroides, la expresión aumentó considerablemente y permaneció elevada durante esta primera recaída a MO. El trasplante de células madre hematopoyéticas fue rechazado por los padres, pero se continuó con la quimioterapia. Tras una segunda recaída de MO a los 5 años, el fenotipo cambió a mieloide. Sus padres optaron entonces por cuidados paliativos y la paciente falleció dos meses después en su domicilio. Conclusiones: Este caso muestra el potencial uso de Myo1g como indicador de alto riesgo en la práctica clínica. El seguimiento de Myo1g puede revelar una tendencia de alto riesgo y recaídas, incluso cuando los valores de los parámetros rutinarios son aparentemente normales; Myo1g podría utilizarse para clasificar a los pacientes de bajo a alto riesgo desde el diagnóstico, lo que permitiría que los pacientes reciban el mejor tratamiento de manera oportuna, modificando potencialmente el pronóstico y la supervivencia.

Potenciales biomarcadores moleculares de infiltración a sistema nervioso central en leucemia linfoblástica aguda / Central nervous system potential molecular biomarkers in acute lymphoblastic leukemia

Resumen La leucemia linfoblástica aguda es el tipo de leucemia más frecuente en niños entre los 2 y 3 años. A nivel internacional la población hispana es reportada como la más prevalente. En México se carece de información reciente, sin embargo, se conoce que es uno de los cánceres más frecuentes en niños. La infiltración de células linfoblásticas a sistema nervioso central es una complicación de pronóstico ominoso que puede presentarse en los pacientes con leucemia linfoblástica aguda, actualmente el diagnóstico se establece mediante citología de líquido cefalorraquídeo, sin embargo, es una prueba operador dependiente y que es afectada por el número de punciones realizadas en la toma de líquido cefalorraquídeo, con potencial contaminación con sangre. En distintos estudios se han caracterizado 6 genes que presentan una sobreexpresión en líquido cefalorraquídeo cuando se presenta dicha infiltración, en esta revisión analizamos estos nuevos marcadores y su potencial como herramientas de diagnóstico oportuno.

Abstract Acute lymphoblastic leukemia is the most common type of leukemia in children between 2 and 3 years of age. Internationally, hispanic population is reported as the most prevalent. In Mexico there is few recent information, however, it is known that it is one of the most frequent cancers in children. Infiltration of lymphoblastic cells into the central nervous system is an ominous prognostic complication that can occur in patients with acute lymphoblastic leukemia. Currently, diagnosis is established by cerebrospinal fluid cytology, however, this technique is affected by the number of punctions done while obtaining the fluid. In several research studies, 6 genes have been identified to be overexpressed in cerebrospinal fluid when infiltration occurs. In this review we analyzed these new molecular biomarkers and their potential as tools for timely diagnosis.

The association of hyperglycemia with the development of infectious complications in adult Filipino patients with acute lymphoblastic leukemia

Abstract Introduction Hyperglycemia occurs in Acute Lymphoblastic Leukemia (ALL) due to chemotherapeutic agents and may be stress-induced. Given the potential impact of hyperglycemia on the clinical outcomes of ALL patients, we sought to determine the association of hyperglycemia with the development of infectious complications. Methods This is a retrospective cohort involving adult Filipino ALL patients admitted at a tertiary referral center. Patients were stratified according to blood glucose levels and infections were classified into microbiologically and clinically defined infections. Logistic regression was performed to determine whether hyperglycemia was associated with the development of infectious complications. Results Of the 174 patients admitted for ALL, only 76 patients (44%) underwent blood glucose monitoring and were thus included in this study. Hyperglycemia was observed in 64 patients (84.21%). Infectious complications were seen in 56 patients (73.68%), of whom 37 patients (48.68%) had microbiologically defined infections and 19 (25%) had clinically defined infections. The respiratory tract was the most common site of infection and gram-negative bacteria were the predominant isolates. Hyperglycemia significantly increased the likelihood of infectious complications, particularly at blood glucose levels ≥ 200 mg/dL. Conclusion Hyperglycemia is associated with an increased likelihood of infectious complications in Filipino ALL patients. With sepsis being one of the main causes of mortality in this population, our study provides compelling evidence for us to consider routine blood glucose monitoring in order to manage and potentially decrease the occurrence of infections in these patients.

Infiltración del nervio óptico como forma inicial de recaída de la leucemia linfoblástica aguda / Optic nerve infiltration as an initial form of relapse of acute lymphoblastic leukemia

Introducción: La infiltración del nervio óptico como forma inicial de recaída de la leucemia linfoblástica aguda es rara, aunque altamente indicativa de que el sistema nervioso central está involucrado. Objetivo: Actualizar el conocimiento sobre infiltración del nervio óptico como forma inicial de recaída de la leucemia linfoblástica aguda. Métodos: Se realizó una revisión de las publicaciones más relevantes relacionadas con el tema durante los últimos años. La búsqueda y la localización de la información se apoyaron en la elección de palabras clave/descriptores que configuraron el perfil de búsqueda. Se utilizó el MeSH Database de PubMed. Se realizó una extensa revisión en Google Académico y otros megabuscadores de revisión sistemática mediante TripDatabase y Cochrane. Conclusiones: La infiltración directa de células tumorales y las alteraciones hematológicas propias de la enfermedad constituyen los mecanismos fundamentales de la fisiopatogenia. El edema del disco óptico es su signo oftalmoscópico más distintivo. La imagen por resonancia magnética de cráneo, el análisis citológico del fluido cerebroespinal y la biopsia de médula ósea negativas no deben excluir el diagnóstico. La terapia combinada que incluye la radiación localizada constituye una buena opción de tratamiento. Un número considerable de ojos recuperan su agudeza visual y muestran resolución del cuadro infiltrativo(AU)

Introduction: Optic nerve infiltration as an initial form of relapse of acute lymphoblastic leukemia is rare, although it is highly indicative of central nervous system involvement. Objective: To update the knowledge about optic nerve infiltration as an initial form of relapse of acute lymphoblastic leukemia. Methods: A review of the most relevant publications related to the subject during the last years was carried out. The search and localization of information was supported by the choice of keywords/descriptors that configured the search profile. The MeSH Database of PubMed was used. An extensive review was performed in Google Scholar and other systematic review mega search engines using TripDatabase and Cochrane. Conclusions: Direct tumor cell infiltration and disease-specific hematologic alterations are the fundamental mechanisms of pathophysiology. Optic disc edema is the most distinctive ophthalmoscopic sign. Negative cranial magnetic resonance imaging, cytologic analysis of cerebrospinal fluid and bone marrow biopsy should not exclude the diagnosis. Combination therapy including localized radiation is a good treatment option. A considerable number of eyes recover visual acuity and show resolution of the infiltrative picture(AU)

Integrated Traditional Chinese and Western Medicine Treatment for Acute Lymphoblastic Leukemia Complicated with Severe COVID-19 in Recovery Stage： A Case Report / 中医杂志

This paper reported a case of severe COVID-19 in the recovery stage with acute lymphoblastic leukemia treated by integrated traditional Chinese and western medicine， with the intention of shedding light on the clinical diagnosis and treatment of similar conditions. The patient， who had acute lymphoblastic leukemia， developed COVID-19 infection during the bone marrow suppression period after chemotherapy. Treatment with western medicine was mainly anti-infection， symptomatic management， and supportive care. During the recovery stage， considering the patient's chemotherapy history and disease progression， the overall syndrome was identified as deficiency of both qi and yin and binding of phlegm and blood. Based on the “state-target” combined treatment strategy， herbal prescriptions were selected and modified to address the “deficiency state”， “disease target”， and “symptom target”. In addition to western medicine， the patient was administered with Shengmai Powder （生脉散） and Compound Zhebei Granules （复方浙贝颗粒） in its modifications to boost qi， nourish yin， and reinforce healthy qi， nourish and cool the blood， ultimately achieving satisfactory therapeutic effects.

Caspase 3 Expressions in Children with Acute Lymphoblastic Leukemia During Induction Phase Chemotherapy

@#Introduction: Caspase-3 is a crucial mediator of the extrinsic apoptosis pathway. The role of caspase-3 for extrinsic apoptosis signalling is still a challenge and should be exploited in childhood ALL. This study aimed to compare the caspase-3 expression in the patient’s bone marrow before and after the induction phase of chemotherapy in childhood ALL. It will also to correlate the mean difference in caspase-3 expression between ALL standard-risk and ALL high-risk patients. Methods: Seventeen newly diagnosed ALL subjects were enrolled in this study. Caspase-3 expression in bone marrow was assessed using flow cytometry and monoclonal antibodies. A T-test and a paired T-test were used to compare between groups. The correlation coefficient between ALL groups was evaluated using Spearman’s test and linear regression with a significant p-value of 0.05. Results: The caspase-3 expression is higher after induction therapy. However, it showed an insignificant difference (16.56+12.91% vs 27.71+12.33%; p = 0.08, p > 0.05). The mean difference of caspase-3 in ALL high-risk groups was significantly higher than in ALL standard-risk groups with a positive correlation (p = 0.007, r = 0.756). Conclusion: The caspase-3 expression after induction phase chemotherapy was increased in all standard-risk and high-risk patients; other lymphoblast apoptosis markers need to be confirmed alongside caspase-3.

Study on the relationship between serum cytokines levels after chimeric antigen receptor (CAR)-T cell immunotherapy and the prognosis of bridged allogeneic hematopoietic stem cell transplantation in acute B lymphoblastic leukemia patients / 中华检验医学杂志

Objective:To investigate the relationship between the levels of serum cytokines and chemokines and the prognosis of patients with acute B-ALL after receiving chimeric antigen receptor (CAR)-T cell immunotherapy and acute graft-versus-host disease (aGVHD) in patients after bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:According to the case-control principle, Forty-two patients with B-ALL who received CD19-CAR-T cell immunotherapy bridged to allo-HSCT at Heibei Yanda Ludaopei Hospital from September 18, 2019 to May 9, 2022 were enrolled. Mann-Whitney U test was used to compare the changes of aGVHD-related cytokines and chemokine levels between CAR-T cell immunotherapy and bridging transplantation in different patients at the same time. Their plasma levels of cytokines and chemokines related to aGVHD were monitored at the day before CAR-T therapy and after CAR-T treatment at day 4, 7,14,21,28. The receiver operating characteristic curve was drawn to evaluate the predictive value of cytokines and chemokines in predicting the occurrence and the death of aGVHD patients. Kaplan-Meier method and Log-rank tests were used for Overall survival (OS) analysis. Results:Twenty-four of total 42 patients had aGVHD, of which 11 patients died and 31 patients survived. There was no significant difference in cytokines and chemokines between the aGVHD group and the non-aGVHD group on the day before CAR-T cell treatment. According to statistical analysis, the serum Elafin levels of aGVHD group was higher than that of non-aGVHD group at the 21st day [4 482 (2 811, 6 061) ng/L vs 2 466 (1 948, 3 375) ng/L, Z=3.145, P=0.001] and the 28st day [4 391 (2 808, 5594) ng/L vs 2 463 (1 658, 2 830) ng/L, Z=2.038, P=0.048] separately. At the 14th day, serum cytokines and chemokines levels between the two group were as follows,MIP-1 α [21.02 (12.36, 30.35) ng/L vs 5.56 (3.64, 10.79) ng/L], sCD25 [422.47 (257.99, 1 233.78) IU/ml vs 216.11 (133.75,457.39) IU/ml], Elafin [4 101 (2 393, 5 006) ng/L vs 2 155 (1 781, 3 033) ng/L], IL-6 [119.08 (23.97, 183.43) ng/L vs 8.39 (2.91, 17.42) ng/L] and IL-8 [13.56 (12.50, 24.52) ng/L vs 2.83 (1.73,6.87) ng/L] were at higher levels ( Z=2.653, P=0.007; Z=2.176, P=0. 030; Z=2.058, P=0.041; Z=3.329, P<0.001; Z=3.162, P=0.001). The KM survival curve showed that the cumulative survival rates of patients with higher serum levels of MIP-1α, sCD25, Elafin, IL-6 and IL-8 were lower than those with low levels at day 14, and the difference was statistically significant (χ 2=12.353, 4.890, 6.551, 10.563, 20.755, P<0.05). Conclusion:The outcomes of patients treated with CAR-T cell therapy bridged to allo-HSCT was correlated with serum MIP-1α, sCD25, Elafin, IL-6 and IL-8 levels after receiving CAR-T therapy. High concentrations of MIP-1α, sCD25, Elafin, IL-6 and IL-8 suggest poor prognosis and can be used as biomarkers to suggest appropriate clinical selection of therapy.

Efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation treatment for T lymphoblastic leukemia/lymphoma / 中华血液学杂志

Objective: To analyze the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treating T lymphoblastic leukemia/lymphoma (T-ALL/LBL) . Methods: This study retrospectively evaluated 119 adolescent and adult patients with T-ALL/LBL from January 2006 to January 2020 at Peking University Third Hospital and Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Patients were divided into chemotherapy-only, chemotherapy followed by allo-HSCT, and chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) groups according to the consolidation regimen, and the 5-year overall survival (OS) and progression-free survival (PFS) rates of each group were compared. Results: Among 113 patients with effective follow-up, 96 (84.9%) patients achieved overall response (ORR), with 79 (69.9%) having complete response (CR) and 17 (15.0%) having partial response (PR), until July 2022. The analysis of the 96 ORR population revealed that patients without transplantation demonstrated poorer outcomes compared with the allo-HSCT group (5-year OS: 11.4% vs 55.6%, P=0.001; 5-year PFS: 8.9% vs 54.2%, P<0.001). No difference was found in 5-year OS and 5-year PFS between the allo-HSCT and auto-HSCT groups (P=0.271, P=0.197). The same results were achieved in the CR population. Allo-HSCT got better 5-year OS (37.5% vs 0) for the 17 PR cases (P=0.064). Different donor sources did not affect 5-year OS, with sibling of 61.1% vs hap-haploidentical of 63.6% vs unrelated donor of 50.0% (P>0.05). No significant difference was found in the treatment response in the early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP) and non-ETP populations. The ETP group demonstrated lower 5-year OS compared with the non-ETP group in the chemotherapy alone group (0 vs 12.6%, P=0.045), whereas no significant difference was found between the ETP and non-ETP groups in the allo-HSCT group (75.0% vs 62.9%, P=0.852). Multivariate analysis revealed that high serum lactate dehydrogenase level, without transplantation, and no CR after chemotherapy induction were independently associated with inferior outcomes (P<0.05) . Conclusion: Allo-HSCT could be an effective consolidation therapy for adult and adolescent patients with T-ALL/LBL. Different donor sources did not affect survival. Allo-HSCT may overcome the adverse influence of ETP-ALL/LBL on OS.

Safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia / 中国当代儿科杂志

OBJECTIVES@#To study the safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia (R/R-ALL).@*METHODS@#Six children with R/R-ALL who received blinatumomab treatment from August 2021 to August 2022 were included as subjects, and a retrospective analysis was performed for their clinical data.@*RESULTS@#Among the six children, there were three boys and three girls, with a median age of 10.5 (5.0-13.0) years at the time of inclusion. Of all six children, one had refractory ALL and did not achieve remission after several times of chemotherapy, and 5 relapsed for the first time, with a median time of 30 (9-60) months from diagnosis to relapse. Minimal residual disease (MRD) before treatment was 15.50% (0.08%-78.30%). Three children achieved complete remission after treatment, among whom two had negative conversion of MRD. Five children had cytokine release syndrome (CRS), among whom 3 had grade 1 CRS and 2 had grade 2 CRS. Four children were bridged to allogeneic hematopoietic stem cell transplantation, with a median interval of 50 (40-70) days from blinatumomab treatment to transplantation. The six children were followed up for a median time of 170 days, and the results showed an overall survival rate of 41.7% (95%CI: 5.6%-76.7%) and a median survival time of 126 (95%CI: 53-199) days.@*CONCLUSIONS@#Blinatumomab has good short-term safety and effectiveness in the treatment of childhood R/R-ALL, and its long-term effectiveness needs to be confirmed by studies with a larger sample size.

Optimized treatment of childhood B-lineage acute lymphoblastic leukemia / 中国当代儿科杂志

Childhood acute lymphoblastic leukemia (ALL) accounts for about 75% of childhood leukemia cases, and B-lineage acute lymphoblastic leukemia (B-ALL) accounts for more than 80% of childhood ALL cases. Over the past half century, new molecular biological targets discovered by new techniques have been used in precise stratification of disease prognosis, and there has been a gradual increase in the 5-year overall survival rate of childhood ALL. With the increasing attention to long-term quality of life, the treatment of childhood B-ALL has been constantly optimized from induction therapy to the intensity of maintenance therapy, including the treatment of extramedullary leukemia without radiotherapy, which has been tried with successful results. The realization of optimized treatment also benefits from the development of new techniques associated with immunology and molecular biology and the establishment of standardized clinical cohorts and corresponding biobanks. This article summarizes the relevant research on the implementation of precise stratification and the intensity reduction and optimization treatment of B-ALL in recent years, providing reference for clinicians.

Applicability of Seven Glomerular Filtration Rate Evaluation Formulas in Dose Adjustment of High Concentration of Methotrexate Chemotherapy in Children with ALL / 中国实验血液学杂志

OBJECTIVE@#To investigate the diagnostic efficacy of seven glomerular filtration rate (GFR) evaluation formulas Schwartz2009, Schwartz1976, Counahan-Barratt, Filler, CKD-EPIscysc, Cockrofi-Gault, CKD-EPIScysC-Scr in high concentration of methotrexate (HDMTX) chemotherapy dose adjusted cut-off point (GFR ≤85 ml/min) in children with acute lymphoblastic leukemia (ALL).@*METHODS@#One hundred and twenty-four children with ALL were included in the study. GFR determined by renal dynamic imaging (sGFR) was used as the standard to evaluate the accuracy, consistency of eGFR calculated by seven formulas and sGFR, and the diagnostic efficacy of each formula when the sGFR ≤85 ml/min boundary.@*RESULTS@#All of the accuracy of eGFR estimated by Schwartz2009 were greater than 70% in the 0-3, >4 and ≤6, >6 and ≤9, >9 and ≤16 years old group and male group, and the consistency exceeded the professional threshold. When the sensitivity of the ROC curve sGFR ≤85 ml/min was 100% of CKD-EPIscysc in the 0-3, >3 and ≤4 years old group, Filler in the >3 and ≤4 years old group, and Cockrofi-Gault in the >6 and ≤9 years old group, the specificity was 73.02%, 78.95%, 78.95%, 69.32%, respectively, and the AUC under the ROC curve was the largest (P<0.05).@*CONCLUSION@#Schwartz2009 formula predicts the highest accuracy of eGFR in the 7 glomerular filtration rate. CKD-EPIscysc, Filler, and Cockrofi-Gault formulas have more guiding signi-ficance for the adjustment of HDMTX chemotherapy in pre-adolescence in children with ALL when sGFR ≤85 ml/min.

Clinical significance of next-generation sequencing-based IGH/IGK gene rearrangement analysis in the diagnosis of minimal residual disease of children with acute B-cell lymphoblastic leukemia / 中华实用儿科临床杂志

Objective:To assess the clinical significance of next-generation sequencing (NGS)-based IGH/ IGK gene rearrangement analysis versus flow cytometry (FCM) in diagnosing minimal residual disease (MRD) of children with acute B-cell lymphoblastic leukemia (B-ALL). Methods:Clinical data, NGS-MRD and FCM-MRD findings at the initial diagnosis and after induction chemotherapy of 85 children diagnosed as B-ALL in Children′s Hospital of Nanjing Medical University from July 2019 to July 2021, were retrospectively analyzed.The sensitivity of the two methods, and the positive rate were compared by χ2 test or Fisher′ s test.The correlation was identified by Spearman correlation analysis. Results:Dominant clone sequences were detected in all children at the initial diagnosis by NGS, while selection markers were identified by FCM in 75(88.2%) patients.Positive MRD rate detected by NGS-MRD was significantly higher than that of FCM-MRD at the same time point after induction chemotherapy[31.8%(27/85) vs.9.4%(8/85), P<0.001]. Compared with those of FCM-MRD, NGS-MRD had good sensitivity (100.0%), specificity (75.3%) and negative predictive value (100.0%), and the positive predictive value was 29.6%.MRD results detected by NGS were consistent with that of FCM ( r=0.569, P<0.001). By July 27, 2022, 2 patients with NGS-MRD (+ )FCM-MRD (-)relapsed during maintenance chemotherapy. Conclusions:NGS is highly consistent with FCM in the detection of MRD in children with B-ALL, which is more sensitive.The combination of NGS-MRD and FCM-MRD benefits more in monitoring MRD in children with B-ALL after induction chemotherapy.

Progress of blinatumomab in the treatment of relapsed/refractory acute lymphoblastic leukemia in children / 国际儿科学杂志

In recent years, with the continuous improvement of high-dose combined chemotherapy and deeper understanding of risk factors, the remission rate of childhood acute lymphoblastic leukemia has been gradually improved, but the prognosis of relapsed/refractory acute lymphoblastic leukemia(r/r ALL)is still not optimistic.Hematopoietic stem cell transplantation has become an alternative treatment for these children.With the development of cellular immunotherapy, the prognosis of children with r/r ALL is expected to be improved.Blinatumomab, as a bispecific antibody, is the first cloned antibody to be tested in clinical trials and approved by FDA for Philadelphia chromosome negative(Ph-) r/r ALL.Blinatumomab as a new generation of monoclonal antibody can significantly improve the survival of children with r/r ALL.This article focuses on the mechanism of action, drug resistance, clinical research progress and adverse reactions of Blinatumomab.

Clinical characteristics and prognosis analysis of TCF3-PBX1 fusion gene-positive childhood B-cell precursor acute lymphoblastic leukemia / 白血病·淋巴瘤

Objective:To investigate the clinical characteristics and prognostic factors of TCF3-PBX1 fusion gene-positive childhood B-cell precursor acute lymphoblastic leukemia (B-ALL).Methods:The clinical data of 1 287 newly diagnosed children with B-ALL who were admitted to five hospital in Fujian province (Fujian Medical University Union Hospital, the First Affiliated Hospital of Xiamen University, Zhangzhou Affiliated Hospital of Fujian Medical University, Quanzhou First Hospital Affiliated to Fujian Medical University, Nanping First Hospital of Fujian Province) from April 2011 to December 2020 were retrospectively analyzed. According to the results of TCF3-PBX1 fusion gene testing, all the patients were divided into TCF3-PBX1-positive group and TCF3-PBX1-negative group. The clinical characteristics, early treatment response [minimal residual disease (MRD) at middle stage and end of induction chemotherapy] and long-term efficacy [overall survival (OS) and event-free survival (EFS)] of the patients in both groups were compared. Kaplan-Meier method was used for survival analysis. The prognostic factors of TCF3-PBX1-positive B-ALL were analyzed by using Cox proportional hazards model. Among 83 children with TCF3-PBX1-positive B-ALL, the treatment regimens, risk stratification and efficacy evaluation of 62 cases were performed by using Chinese Children's Leukemia Group (CCLG)-ALL 2008 regimen and 21 cases were performed by using Chinese Children's Cancer Group (CCCG)-ALL 2015 regimen, and the efficacy and incidence of serious adverse events (SAE) between the two groups compared.Results:Among 1 287 B-ALL patients, 83 patients (6.4%) were TCF3-PBX1-positive. The proportion of patients with initial white blood cell count (WBC)≥50×10 9/L in the TCF3-PBX1-positive group was higher than that in the TCF3-PBX1-negative group, while the proportions of patients with MRD ≥1% on induction chemotherapy day 15 or day 19, and MRD ≥0.01% on induction chemotherapy day 33 or day 46 in the TCF3-PBX1-positive group were lower than those in the TCF3-PBX1-negative group (all P < 0.05). Univariate Cox regression analysis showed that MRD ≥1% on induction chemotherapy day 15 or day 19 and TCF3-PBX1 ≥0.01% on induction chemotherapy day 33 or day 46 were risk factors for OS and EFS (all P < 0.05). Multivariate analysis showed that MRD ≥1% on induction chemotherapy day 15 or day 19 was an independent risk factor for OS ( HR = 10.589, 95% CI 1.903-58.933, P = 0.007) and EFS ( HR = 10.218, 95% CI 2.429-42.980, P = 0.002). TCF3-PBX1≥0.01% on induction chemotherapy day 33 or day 46 was an independent risk factor for EFS ( HR = 6.058, 95% CI 1.463-25.087, P = 0.013) but not for OS ( HR = 3.550, 95% CI 0.736-17.121, P = 0.115). The 10-year EFS and OS rates of the TCF3-PBX1-positive group were 84.6% (95% CI 76.9%-93.1%) and 89.1% (95% CI 82.1%-96.6%), and the differences between the two groups were not statistically significant (both P > 0.05). Among 80 children who received standardized treatment, compared with children who were treated with CCLG-ALL 2008 regimen, the incidence of infection-related SAE was lower in children who were treated with CCCG-ALL 2015 regimen [0 (0/21) vs. 20.3% (12/59), χ2 = 5.22, P = 0.022], but there were no statistical differences in treatment-related mortality, relapse rate, EFS and OS between the two groups (all P > 0.05). Conclusions:Children with TCF3-PBX1-positive B-ALL have a good prognosis, and MRD≥1% at middle stage of induction chemotherapy and TCF3-PBX1≥0.01% at the end of induction chemotherapy may be influencing factors for poor prognosis. CCCG-ALL 2015 regimen can reduce infection-related SAE while achieving good efficacy.

The Exploration of Glymphatic System Alteration in Pediatric Acute Lymphoblastic Leukemia Using DTI-ALPS Method / 中山大学学报(医学科学版)

ObjectiveThe glymphatic system regulates cerebral spinal fluid and interstitial fluid transport which might be one of the pathways of central nervous system （CNS） leukemia at the early stage. This study aimed to investigate the alteration of glymphatic system based on diffusion tensor image-analysis along the perivascular space （DTI-ALPS） in pediatric acute lymphoblastic leukemia （ALL） without clinically diagnosed CNS infiltration. MethodsTwenty-five ALL and typically developing （TD） children were prospectively recruited， and all subjects underwent DTI. Group differences in brain water diffusivities and ALPS-index were evaluated using the analysis of covariance. The Spearman correlation analysis was used to evaluate the relationship between biological characteristics and significant parameters in pediatric ALL. ResultsCompared with TDs， decreased Dxassoc value （PFDR-corrected = 0.048） and increased Dzassoc value （PFDR-corrected = 0.033） were found in pediatric ALL. Hence， lower ALPS-index was found in children with ALL （PFDR-corrected < 0.001）. ALPS-index was negatively associated with the risk classification （rs = -0.47， P = 0.018） as well as immunophenotype （rs = -0.40， P = 0.046） in pediatric ALL. ConclusionsOur results show dysfunction of the glymphatic system is presented in pediatric ALL without clinically diagnosed CNS infiltration， which suggests that the glymphatic system might be one of pathway in the early-stage of ALL CNS infiltration. The DTI-ALPS method can be used to evaluate the change of glymphatic system， providing a new method for exploring the underlying mechanisms and early detection of pediatric ALL CNS infiltration.