Application of Gene Expression Microarray for the Classification of Ph-Like B-Cell Acute Lymphoblastic Leukemia.

INTRODUCTION: Ph-like ALL has gene expression profile similar to Ph-positive ALL but without the BCR::ABL1 fusion. The disease presents higher rates of severe clinical features and is associated with unfavorable outcomes. There is still no standard pipeline for molecular characterization of the disease, and no valid predictor gene panel is available worldwide. METHODS: We performed expression microarray on 25 B-cell ALL and 6 Ph-positive B-cell ALL to cluster and identify the transcriptional signature of Ph-like ALL. qRT-PCR was used to confirm the expression of candidate genes. RESULTS: Four out of 25 samples (16%) shared gene expression signatures related to and clustered with control Ph-positive samples. Analysis of genes differentially expressed in Ph-like B-cell ALL and evidentially functional in normal blood cell development and leukemogenesis, we selected genes as potential biomarkers for Ph-like B-cell ALL in our dataset: ADGRE2, CD9, EPHA7, FAM129C, TCL1A, and VPREB1. Those genes were filtered by Ph-like gene signatures obtained from distinct reliable data, resulting in five genes, CA6, CHN2, JAK1, JCHAIN, and PON2, selected for validation by qRT-PCR. The Ct values of genes, including CA6 (p = 0.0017), PON2 (p = 0.0210), TCL1A (p = 0.0064), and VPREB1 (p = 0.0338), were significant in Ph-like ALL. GSEA analysis identified VPREB1 as enrichment in the KRAS signaling pathway, and several genes that interact with VPREB1 were reported as critical molecules involved in the leukemogenesis of B-cell ALL. CONCLUSION: In summary, we demonstrate using a gene expression microarray for classifying Ph-like B-cell ALL and highlight VPREB1 as a potential biomarker for this disease.

[Progress in therapy with L-asparaginase].

L-asparaginase is a key drug in the treatment of acute lymphocytic leukemia/lymphoblastic lymphoma and is currently used in treatment regimens for a wide range of age groups, including children, adolescents, young adults, and older adults. Discontinuation of L-asparaginase leads to worse survival outcomes. Strategies such as appropriate prevention and management of asparaginase-specific adverse events such as hypersensitivity reactions and optimizing administration by therapeutic drug monitoring are important to ensure completion of all asparaginase doses planned in each regimen. Two new L-asparaginase preparations with different properties are now available in Japan, and attempts to leverage these properties for more effective and safe administration are attracting attention. This article reviews previous advances in therapy with L-asparaginase and outlines current and future challenges for maximizing the therapeutic efficacy of L-asparaginase.

The impact of Trifolium pratense extract on apoptosis and autophagy in NALM-6 cells: implications for B-ALL intervention.

B-cell acute lymphoblastic leukemia (B-ALL), a prevalent malignancy predominantly affecting children, poses challenges such as drug resistance and cytotoxicity despite available treatment methods. The persistence of these challenges underscores the necessity for innovative therapeutic approaches to enhance efficacy. Natural compounds derived from plants, recognized for their potential to inhibit cancer cell growth, have drawn attention. Trifolium pratense extract, known for its significant anticancer properties in previous studies, was the focus of this investigation. This experimental study aimed to explore the impact of T. pratense extract on apoptosis and autophagy in NALM-6 cells. The cells were exposed to varying concentrations of the extract at specific time intervals, with viability and metabolic activity assessed using Trypan blue exclusion and MTT assays. Flow cytometry was employed to evaluate apoptosis using Annexin V/PI staining and ROS production using DCFH-DA staining. Real-time PCR was used to quantify gene expression related to apoptosis, autophagy, and oxidative stress, with data analysis performed using GraphPad PRISM software. Trifolium pratense extract demonstrated the capacity to induce apoptosis, autophagy, and significantly increase ROS production in NALM-6 cells. These effects were facilitated by the upregulation of corresponding genes. The MTT assay revealed an IC50 of 231 µg/mL at 48 h, and Flow cytometry analysis showed a 51.8% increase in apoptosis in this cell line. Overall, this study emphasizes the effectiveness of T. pratense extract in inducing autophagy and apoptosis pathways in NALM-6 cells derived from B-cell acute lymphoblastic leukemia, suggesting its potential as a candidate for further investigation as a supplement in ALL treatment.

Impact of pre-infusion disease burden on outcomes in pediatric relapsed/refractory B-cell lymphoblastic leukemia following anti-CD19 CAR T-cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have demonstrated high efficacy in pediatric patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Despite this success, the challenge of post-infusion relapse persists. In our study, we evaluate 116 children with R/R B-ALL who received anti-CD19 CAR T-cell therapy at our center. All patients were included in the response analysis and assessed for survival and toxicity. The CR rate was 98.3%, with 90.5% achieving minimal residual disease negative (MRD)- CR by day 28 (d28). The overall survival (OS) and event-free survival (EFS) were 69.3%±4.5% and 59.0%±4.6%, respectively, with a median follow-up duration of 47.9 months. The patients with pre-infusion MRD ≥ 1% was associated with lower 4-year OS (p = 0.006) and EFS (p = 0.027) comparing to those with MRD < 1%. The incidences of grade ≥ 3 cytokine release syndrome (CRS) and neurotoxicity were21.6 and 5.0%, respectively. Therefore, pre-infusion disease burden is a predictor of long-term outcome following anti-CD19 CAR T-cell therapy for pediatric R/R B-ALL.

Teenager with persistent facial edema and induration.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common oncological disease in the pediatric population; however, skin infiltration occurs only in 1-3% of the patients and almost always manifests after the diagnosis is made. CLINICAL CASE: A male teenage patient who presented with facial edema and infiltration, associated with systemic symptoms such as asthenia and adynamia. On physical examination, the patient presented facial edema and indurated plaques, as well as cervical, inguinal, and axillary adenopathy. Complete blood count showed pancytopenia and a chest X-ray revealed a mediastinal mass. Due to a high suspicion of malignancy a bone marrow and skin biopsy was taken, both with pre-B ALL. Chemotherapy was started and the patient is now in maintenance phase. CONCLUSIONS: Leukemia cutis manifestations are heterogenous, from a small papule to a big nodule. It is more common in patients with acute myeloid leukemia and it is rare in patients with pre-B ALL, specially in the pediatric population. The diagnosis should be done with a biopsy and the treatment is with systemic chemotherapy. The diagnosis should always be considered in patients with unexplained edematous or indurated lesions, especially in the context of systemic symptoms.

INTRODUCCIÓN: La leucemia linfoblástica aguda es la enfermedad oncológica más común en la edad pediátrica; sin embargo, la infiltración a la piel solo ocurre en el 1-3% de los pacientes y se manifiesta habitualmente posterior al diagnóstico de leucemia. CASO CLÍNICO: Adolescente varón que acude a urgencias de nuestra unidad por presentar edema facial persistente, junto con astenia y adinamia. En la exploración física presenta edema facial con placas difusas induradas y adenopatía cervical, inguinal y axilar. Se decide realizar una biometría hemática, que muestra pancitopenia, y una radiografía de tórax, que revela una masa mediastinal. Por sospecha de malignidad se decide realizar una biopsia de médula ósea y de piel, dando como resultado leucemia linfoblástica pre-B en ambas. Se inició quimioterapia y actualmente se encuentra en fase de mantenimiento. CONCLUSIONES: Las manifestaciones clínicas de leucemia cutis son heterogéneas, desde una pápula pequeña hasta lesiones nodulares de diferentes tamaños. Lo más común es verlas en pacientes con leucemia mieloide aguda, y es muy raro en pacientes con leucemia linfoblástica aguda pre-B, especialmente en la edad pediátrica. El diagnóstico se realiza con una biopsia de piel y el tratamiento es con quimioterapia sistémica. Es importante tener en mente este diagnóstico en pacientes con síntomas sistémicos de leucemia.

Psychiatric disorders among survivors of childhood acute lymphoblastic leukemia in Denmark and Sweden.

BACKGROUND: The diagnosis and treatment of childhood acute lymphoblastic leukemia (ALL) may impact mental health. We investigated the long-term risk of psychiatric disorders among survivors of ALL in a population-based cohort study. METHODS: We identified patients diagnosed with ALL in Denmark and Sweden before age 20 during 1982-2008. Survivors of ALL (n = 2026), their siblings (n = 3027), and population comparison subjects (n = 9713) were followed for hospital contacts for psychiatric disorders from 5 years after ALL diagnosis (or corresponding index date) until 2017. RESULTS: By age 30, the absolute risk of psychiatric hospital contacts was 19.9% (95% confidence interval [CI]: 17.9-22.1) for ALL survivors, 18.5% (95% CI: 16.9-20.2) for siblings, and 18.3% (95% CI: 17.3-19.2) for population comparison subjects. Overall, survivors were at higher risk of any psychiatric disorders than siblings (hazard ratio [HR] = 1.25; 95% CI: 1.04-1.50), and population comparison subjects (HR = 1.20; 95% CI: 1.06-1.35). The subgroup of survivors (n = 332) who received a hematopoietic stem cell transplantation (HSCT) and/or had a relapse were at highest risk of psychiatric disorders (HR = 2.07; 95% CI: 1.26-3.41 compared to siblings; HR = 1.67; 95% CI: 1.25-2.23 compared to population comparison subjects). CONCLUSIONS: The overall absolute risk of psychiatric hospital contacts among ALL survivors was close to that in siblings and population comparison subjects. The modestly increased relative risk was mainly driven by the subgroup of survivors who received HSCT and/or had a relapse. Our findings are reassuring for the large subgroup of ALL survivors without HSCT or relapse, and provide novel insight on both absolute and relative risk of hospital contacts for psychiatric disorders.

Fusion of Color Correction and HSV Segmentation Techniques for Automated Segmentation of Acute Lymphoblastic Leukemia.

This article presents an enhanced segmentation methodology for the accurate detection of acute lymphoblastic leukemia (ALL) in blood smear images. The proposed approach integrates color correction techniques with HSV color space segmentation to improve white blood cell analysis. Our method addresses common challenges in microscopic image processing, including sensor nonlinearity, uneven illumination, and color distortions. The key objectives of this study are to develop a robust preprocessing pipeline that normalizes blood smear images for consistent analysis, implement an HSV-based segmentation technique optimized for leukocyte detection, and validate the method's effectiveness across various ALL subtypes using clinical samples. The proposed technique was evaluated using real-world blood smear samples from ALL patients. Quantitative analysis demonstrates significant improvements in segmentation accuracy compared to traditional methods. Our approach shows strong capability in reliably detecting and segmenting ALL subtypes, offering the potential for enhanced diagnostic support in clinical settings.

Clinical effect of prophylactic pegfilgrastim in patients with newly diagnosed acute lymphoblastic leukemia who receive intensive chemotherapy.

BACKGROUND: Using granulocyte colony-stimulating factor (G-CSF) after completing chemotherapy reduces the duration of neutropenia and infections. However, the efficacy and safety of prophylactic pegfilgrastim in acute lymphoblastic leukemia (ALL) patients have not yet been evaluated after intensive cytotoxic chemotherapy compared to the daily G-CSF. This study aimed to evaluate the efficacy of pegfilgrastim for ALL patients who received intensive chemotherapy compared with a short-acting G-CSF. PATIENTS AND METHODS: Clinical data of 145 patients treated with hyper-CVAD, modified VPDL/VPD, or KALLA 1406/1407 regimen were retrospectively evaluated. Pegfilgrastim or the short-acting G-CSF was selected according to the clinician's discretion. Patients not receiving pegfilgrastim were treated with the short-acting G-CSF. RESULTS: The median age of enrolled patients was 45 years. Sixty newly diagnosed ALL patients were treated with hyper-CVAD regimen, while KALLA and VPDL regimens were administered to 39 and 46 patients, respectively. Among the 60 patients treated with hyper-CVAD, 20 patients received pegfilgrastim. Patients who received pegfilgrastim had a significantly shorter duration of neutropenia and hospitalization and reduced incidence of severe infections compared to patients receiving the short-acting G-CSF. Consistent results were also confirmed in an analysis targeting only patients who achieved remission during hyper-CVAD induction therapy. There was no significant difference in neutrophil recovery ability and hospitalization duration when the daily short-acting G-CSF was used prophylactically after completing hyper-CVAD, KALLA, and VPDL regimens as induction therapy. CONCLUSION: Using pegfilgrastim after hyper-CVAD therapy was more effective than the short-acting G-CSF in terms of infection, neutropenia recovery, and hospitalization in patients with newly diagnosed ALL.

Case report: sub-clinical extramedullary B-ALL in the setting of relapse following targeted therapy.

Standard testing for disease evaluation in B-cell acute lymphoblastic leukemia (B-ALL) includes examination of the bone marrow and cerebrospinal fluid. Radiographic or functional imaging are indicated when clinical signs of non-CNS extramedullary disease are present but are not standard in the relapsed/refractory setting. We describe two cases of patients with relapsed/refractory B-ALL with prior exposure to blinatumomab and/or inotuzumab ozogamicin presenting for CAR-T cell treatment. Both patients were thought to only have minimal residual disease (MRD) at the pre-CAR disease assessment, with MRD of 6,648 (0.66%) and 100 (0.01%) cells per million cells, respectively, as measured by next-generation sequencing (NGS) in their bone marrows. Both patients for distinct reasons unrelated to non-CNS extra-medullary (EM) symptoms had PET-MRIs prior to lymphodepletion and CAR T cell infusion. In both cases patients were found to have significant bulky subclinical EM disease that required changes in clinical management. In the newly-emergent era of antigen-targeted immunotherapy, it is foundational that incidence and relapse patterns following targeted therapy are well-understood. Herein we contribute to a growing body of literature addressing this fundamental clinical gap and highlight a future role for formal prospective imaging studies to better establish response, toxicity and relapse patterns following CAR-T cell therapy in EM B-ALL.

Selected stem cell populations in pediatric acute lymphoblastic leukemia.

Introduction: Acute lymphoblastic leukemia is characterized by a disturbed maturation of hematopoietic stem cells (HSCs) resulting in development of a malignant clone. Despite relatively positive outcome, there are still instances of disease relapse occurring due to ineffective disease eradication or primary leukemic clone alterations. Unclear significance of stem cells in the course of ALL led us to investigate and establish crucial changes in two stem cell populations - very small embryonic-like stem cells (VSELs) and HSCs during the induction phase of treatment. Methods: In a retrospective study selected stem cells in peripheral blood and bone marrow of 60 pediatric ALL subjects and 48 healthy controls were subjected to flow cytometric analysis at 4 different time points. Results: Both VSELs and HSCs were elevated at the moment of ALL diagnosis compared to healthy controls, but profoundly decline until day 15. Further observations revealed an increase in HSCs with a concomitant depletion of VSELs until week 12. ALL patients with high HSCs showed positive correlation with bone marrow blasts at diagnosis. Patients with lower VSELs or HSCs at diagnosis had slightly improved response to applied therapy. We observed higher initial bone marrow lymphoblast values in patients with lower VSELs or higher HSCs in the high-risk group. The significance of VSELs in predicting treatment outcome can be illustrated by lower day 15 MRD level of patients with lower VSELs at diagnosis. Discussion: We found HSCs and VSELs to be valid participants in pediatric ALL with possible contribution in the neoplastic process and prediction of initial treatment outcome.

Enhancer looping protein LDB1 modulates MYB expression in T-ALL cell lines in vitro by cooperating with master transcription factors.

BACKGROUND: Despite significant progress in the prognosis of pediatric T-cell acute lymphoblastic leukemia (T-ALL) in recent decades, a notable portion of children still confronts challenges such as treatment resistance and recurrence, leading to limited options and a poor prognosis. LIM domain-binding protein 1 (LDB1) has been confirmed to exert a crucial role in various physiological and pathological processes. In our research, we aim to elucidate the underlying function and mechanisms of LDB1 within the background of T-ALL. METHODS: Employing short hairpin RNA (shRNA) techniques, we delineated the functional impact of LDB1 in T-ALL cell lines. Through the application of RNA-Seq, CUT&Tag, and immunoprecipitation assays, we scrutinized master transcription factors cooperating with LDB1 and identified downstream targets under LDB1 regulation. RESULTS: LDB1 emerges as a critical transcription factor co-activator in cell lines derived from T-ALL. It primarily collaborates with master transcription factors (ERG, ETV6, IRF1) to cooperatively regulate the transcription of downstream target genes. Both in vitro and in vivo experiments affirm the essential fuction of LDB1 in the proliferation and survival of cell lines derived from T-ALL, with MYB identified as a significant downstream target of LDB1. CONCLUSIONS: To sum up, our research establishes the pivotal fuction of LDB1 in the tumorigenesis and progression of T-ALL cell lines. Mechanistic insights reveal that LDB1 cooperates with ERG, ETV6, and IRF1 to modulate the expression of downstream effector genes. Furthermore, LDB1 controls MYB through remote enhancer modulation, providing valuable mechanistic insights into its involvement in the progression of T-ALL.

Targeting telomerase with MST-312 leads to downregulation of CCND1, MDM2, MYC, and HSP90AA1 and induce apoptosis in Jurkat cell line.

Acute lymphoblastic leukemia is a challenging disease to treat, especially in older adults who are most commonly diagnosed and have a high risk of relapse, even with current treatment options. MST-312, targets the RNA component of telomerase, inhibiting its activity and leading to growth arrest and telomere shortening in cancer cells. This study aimed to investigate the effects of MST-312 on apoptosis rates and the expression of telomerase target genes, CCND1, MDM2, MYC, and HSP90AA1, in Jurkat cell line. Jurkat cell line was cultured and treated with various concentrations of MST-312(0 µM, 0.5 µM, 1 µM, 2 µM, and 4 µM). The optimal concentration of MST-312 was determined using MTT assay. Flow cytometry was employed to evaluate the apoptosis induced by MST-312 treatment. The expression levels of the target genes were measured using real-time polymerase chain reaction before and after the treatment with MST-312. P-value < 0.05 was considered statistically significant. The percentages of apoptotic cells after 48 h, as determined by flow cytometry analysis, were 30.32%, 52.35%, 57.60%, and 68.82%, respectively, compared to the control group which was 4.6%. The expression levels of all genes, including CCND1, MDM2, MYC, and HSP90AA1, were decreased compared to the control group. The results showed that MST-312 induced dose- and time-dependent apoptosis and downregulated the expression of CCND1, MDM2, MYC, and HSP90AA1in Jurkat cell line.

The Road More or Less Traveled- Examining the Role of Consolidative Allogeneic Hematopoietic Stem Cell Transplantation After Chimeric Antigen Receptor T Cell Therapy in B-cell ALL.

Treatment with CD19-targeted chimeric antigen receptor T cell therapy (CD19-CART) has improved salvage rates in children and adults with relapsed and/or refractory B-cell acute lymphoblastic leukemia (ALL). However, not all patients treated with CD19-CAR T cells achieve long-term remission. The role of allogeneic hematopoietic stem cell transplantation as consolidative therapy remains undefined. We aim to review the current literature published to date regarding prognostic markers indicating durable ALL response to CD19-CART and risk factors for relapse after CD19-CART to identify patient cohorts who may benefit from consolidative hematopoietic stem cell transplantation.

Dysregulation of metallothionein MT1 sub-types in TCF3::PBX1 pre-B-cell acute lymphoblastic leukemia.

The translocation between chromosomes 1 and 19 t(1;19) produces the TCF3::PBX1 fusion protein, which leads to childhood pre-B-cell acute lymphoblastic leukemia (ALL). The molecular mechanism of oncogenesis, however, remains obscure. This study aims to identify the genes specifically dysregulated in TCF3::PBX1 translocation. The publicly available expression microarray datasets on ALL were used for weighted gene co-expression network analysis (WGCNA) to identify modules associated with TCF3::PBX1. The available knockdown and ChIP-Seq datasets were used to assess the direct targets of TCF3::PBX1. The WGCNA revealed a module enriched in genes involved in the metal ion stress to be positively correlated with TCF3::PBX1, with metallothionein isoform MT1 subtypes MT1E, MT1F, MT1G, MT1H, and MT1X as the hub genes. Of the 145 positively correlated genes, 19 were downregulated upon TCF3::PBX1 knockdown. Eleven of these 19 genes including MT1G, showed TCF3::PBX1 occupancy at the promoter. The Metallothionein 1 family has been implicated in various cancers; however, their role in t(1;19) pre-B-cell ALL has not been previously demonstrated. Our analysis effectively accounts for the cellular and population-level heterogeneity and identifies a novel mechanism for the TCF3::PBX1 action.

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.

Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.

Machine learning-based evaluation of prognostic factors for mortality and relapse in patients with acute lymphoblastic leukemia: a comparative simulation study.

BACKGROUND: Predicting mortality and relapse in children with acute lymphoblastic leukemia (ALL) is crucial for effective treatment and follow-up management. ALL is a common and deadly childhood cancer that often relapses after remission. In this study, we aimed to apply and evaluate machine learning-based models for predicting mortality and relapse in pediatric ALL patients. METHODS: This retrospective cohort study was conducted on 161 children aged less than 16 years with ALL. Survival status (dead/alive) and patient experience of relapse (yes/no) were considered as the outcome variables. Ten machine learning (ML) algorithms were used to predict mortality and relapse. The performance of the algorithms was evaluated by cross-validation and reported as mean sensitivity, specificity, accuracy and area under the curve (AUC). Finally, prognostic factors were identified based on the best algorithms. RESULTS: The mean accuracy of the ML algorithms for prediction of patient mortality ranged from 64 to 74% and for prediction of relapse, it varied from 64 to 84% on test data sets. The mean AUC of the ML algorithms for mortality and relapse was above 64%. The most important prognostic factors for predicting both mortality and relapse were identified as age at diagnosis, hemoglobin and platelets. In addition, significant prognostic factors for predicting mortality included clinical side effects such as splenomegaly, hepatomegaly and lymphadenopathy. CONCLUSIONS: Our results showed that artificial neural networks and bagging algorithms outperformed other algorithms in predicting mortality, while boosting and random forest algorithms excelled in predicting relapse in ALL patients across all criteria. These results offer significant clinical insights into the prognostic factors for children with ALL, which can inform treatment decisions and improve patient outcomes.

Comparable Results Between 8 and 12 Gray TBI in Combination With Fludarabine and Post-Transplant Cyclophosphamide in MRD-Negative but Not in MRD-Positive Acute Lymphoblastic Leukemia Patients Transplanted in First Complete Remission.

BACKGROUND: The optimal TBI dose for ALL patients undergoing allogeneic SCT is still not clearly defined. METHODS: Single-center retrospective analysis of high-risk ALL patients in CR1 treated with 8 Gy (n = 22) or 12 Gy (n = 50) TBI in combination with fludarabine and PTCy. Median patient age in the 8 Gy TBI cohort was 63 (37-79) and 37 (18-56) in the 12 Gy TBI cohort and median follow-up time was 21 months (range 1-92). RESULTS: OS and LFS at 2 years after 8 Gy were 65% and 55% versus 74% and 74% after 12 Gy (p = 0.3 and p = 0.2, respectively). CIR and NRM at 2 years were 27% and 14% after 8 Gy versus 4% and 20% after 12 Gy (p = 0.004 and p = 0.4, respectively). MRD-positive (+) patients (n = 26) receiving 12 Gy (n = 19) showed better OS (p = 0.01), LFS (p = 0.009), GRFS, lower CIR (p = 0.02), and similar NRM than did MRD+ patients receiving 8 Gy (n = 7). MRD-negative (-) patients (n = 38) receiving 12 Gy (n = 27) had similar OS, LFS, GRFS, lower CIR, and higher NRM (p = 0.04) than did MRD- patients receiving 8 Gy (n = 11). CONCLUSION: Our study demonstrates that 8 Gy TBI in comparison to 12 Gy TBI results in low NRM but a high relapse rate with similar OS, LFS, and GRFS. In MRD+ high-risk ALL patients, allogeneic SCT with 12 Gy TBI leads to improved OS, LFS, GRFS, and a low relapse rate. Prospective studies comparing the different treatment regimens with larger MRD patient cohorts are needed to confirm this data.

Acute lymphoblastic leukemia with nephrogenic diabetes insipidus as the first symptom: a case report.

BACKGROUND: Acute lymphoblastic leukemia is the most common pediatric malignancy, characterized by fever, anemia, hemorrhage, and symptoms brought on by blasts infiltrating organs. CASE PRESENTATION: This is a case report of a 9-year-old Asian patient with acute lymphoblastic leukemia who presented with polyuria alone as a presenting feature without any other clinical manifestation; primary renal disease or inherited metabolic disease was highly suspected. However, the water deprivation test and water deprivation pressurization test suggested nephrogenic diabetes insipidus, and the renal biopsy displayed diffuse lymphocytic infiltration in the renal interstitium. Bone marrow aspiration was performed immediately, and a comprehensive diagnosis of B-lymphoblastic leukemia was finally made. CONCLUSIONS: Renal infiltration with leukemic blasts mostly remains asymptomatic, but our case suggests that it can present with nephrogenic diabetes insipidus. This case fully demonstrates that the presentation of extramedullary infiltration in acute lymphoblastic leukemia is varied. When the patient has renal diabetes insipidus as the first symptom, the possibility of hematological tumor infiltration should be considered when finding the cause, and timely bone marrow cytology should be performed.

PML mutation and familial pediatric acute lymphoblastic leukemia: A case report.

Hereditary factors contribute to the pathogenesis of pediatric leukemia. However, few studies have reported gene mutation pathopoeias. This paper reports genetic mutations associated with hereditary acute lymphoblastic leukemia. We reported a case of siblings diagnosed with acute lymphoblastic leukemia when aged 3 and 7 years, both siblings are alive after chemotherapy, and whole exome sequencing analysis was performed on the siblings and their parents. It was observed that both siblings had diheterozygous mutations in PML gene (PML, NM_033250, exon7, c.2170A>G, p.S724G; PML, NM_033250, exon7, c.2195G>T, p.G732V), and their parents had heterozygous mutations in one mutation site of PML gene, respectively, suggesting that the diheterozygous mutations of PML gene might be causal genetic genes for the occurrence of acute lymphoblastic leukemia.

Combination Therapy With Asciminib and Ponatinib as a Bridge to Brexucabtagene Autoleucel and Maintenance in a Patient With Relapsed Refractory Philadelphia Positive B-Cell Acute Lymphoblastic Leukemia.

Tyrosine kinase inhibitors (TKIs) have changed the prognosis of Philadelphia-positive B-cell acute lymphoblastic leukemia (ALL); however, relapsed and refractory disease after multiple TKIs continues to be a clinical challenge. Brexucabtagene autoleucel (brexu-cel) is a novel FDA-approved therapy for relapsed and refractory ALL. Given the lengthy manufacturing time, bridging therapy is commonly employed prior to brexu-cel. Here we describe a case of a 75-year-old Hispanic male patient with relapsed/refractory Philadelphia-positive B-cell ALL with extramedullary disease involving abdominal lymph nodes and skin. He was initially treated with chemotherapy in combination with imatinib, and later received dasatinib and subsequently blinatumomab and nilotinib. As the patient progressed, he received ponatinib with low-dose salvage chemotherapy and did not show kinase domain mutation. In a final effort, a novel combination of ponatinib with asciminib was used as a bridge therapy before brexu-cel and later as maintenance therapy after brexu-cel. This novel combination was able to control disease prior to brexu-cel for 2 months and maintained remission for at least 10 months. This report shows that the novel combination of ponatinib and asciminib is tolerable and effective as a bridge and maintenance therapy after brexu-cel.