[Experience with an international study on standard-risk relapsed childhood acute lymphoblastic leukemia (IntReALL SR 2010 study) in Japan].

Many effective new agents for relapsed childhood acute lymphoblastic leukemia (ALL) are now becoming available, and international standard chemotherapy should be developed to optimize use of these agents. Randomized controlled trials (RCTs) are needed to establish a standard treatment, but few have been conducted for relapsed childhood ALL in Japan due to the small patient population. Participation in international RCTs is necessary to access sufficient patients for informative study results, but differences in approved drugs and healthcare systems between countries make this challenging. In 2014, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) participated in an international study on standard-risk relapsed childhood ALL (IntReALL SR 2010) involving two RCTs and multiple drugs not approved in Japan, which was addressed by replacing the unapproved drugs with alternative approved drugs with the same or similar efficacy. This article discusses the historical background of treatment development for relapsed childhood ALL, our experience in participating in the IntReALL SR 2010 trial, and prospects for treating relapsed childhood ALL.

Recurrent Cerebral Venous Sinus Thrombosis Occurred in an Acute Lymphoblastic Leukemia Child with Mutated Lipoprotein Lipase Gene during Asparaginase Therapy.

Cerebral venous sinus thrombosis (CVST) and hyperlipidemia are severe complications of L-Asparaginase (L-Asp) during the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Herein, we reported a 9-year-old B-ALL boy who underwent abnormal hypertriglyceridemia and CVST presenting as seizures and disturbance of consciousness twice during the induction therapy. Fortunately, he survived treatment with anticoagulant and lipid-lowering therapy. No thrombophilia-related gene mutation was detected, but a heterozygous mutation in lipoprotein lipase (LPL) gene was identified. His neurological symptoms were managed with short-term anticoagulant therapy and long-term lipid-lowering therapy. This case illustrated the manifestation and potential pathogenesis of CVST and highlighted the essentiality of screening baseline lipid profile and dyslipidemia- and thrombophilia-related gene mutation.

Flow Cytometry-Based Detection of Minimal/Measurable Residual Disease Predicts Survival Outcomes in Pediatrics, Adolescents, and Young Adults With T-acute Lymphoblastic Leukemia.

BACKGROUND: Measurable/minimal residual disease (MRD) is considered the single most powerful high-risk factor in acute leukemia, including T-cell acute lymphoblastic leukemia (T-ALL). In this study, we evaluated the impact of flow cytometry (FC)-based detection of MRD on survival outcomes in pediatrics, adolescents, and young adults (AYA) with T-ALL. METHODS: We included 139 patients, 88 pediatric patients between the ages of one and 14 years, and 51 AYA patients between 15 and 39 years of age, over a period of three years and were treated with the Indian Collaborative Childhood Leukemia Group (ICiCLe) protocol. MRD assessment was performed on post-induction (PI) bone marrow aspirate samples using a 10-color 11-antibody MRD panel on a Gallios instrument (Beckman Coulter, Miami, FL, USA). MRD value > 0.01% was considered positive. PI-MRD status was available in 131 patients. RESULTS: The five-year event-free survival (5-year EFS) in PI-MRD positive patients was inferior to those of negative patients (13.56% vs 79.06%), which was statistically significant (P < 0.001). However, the five-year overall survival (5-year OS) did not show any statistically significant difference between PI-MRD positive and negative T-ALL patients (92.93% vs 94.28%). The hazard ratio (HR) for 5-year EFS and MRD positivity was 8.03 (p-value < 0.0001). HR for 5-year EFS and early T-cell precursor ALL (ETP-ALL) was 2.63 (p = -0.02). CONCLUSIONS: PI-MRD detected using FC is a strong predictive factor of inferior survival outcomes in pediatrics, AYA patients with T-ALL. PI-MRD positivity can be used to modify the treatment of T-ALL patients, especially in resource-constrained developing countries where molecular tests are not widely available.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

CoTCoNet: An optimized coupled transformer-convolutional network with an adaptive graph reconstruction for leukemia detection.

BACKGROUND: Swift and accurate blood smear analyses are crucial for diagnosing leukemia and other hematological malignancies. However, manual leukocyte count and morphological evaluation remain time-consuming and prone to errors. Additionally, conventional image processing methods struggle to differentiate cells due to visual similarities between malignant and benign cell morphology. METHOD: In response to above challenges, we propose Coupled Transformer Convolutional Network (CoTCoNet) framework for leukemia classification. CoTCoNet integrates dual-feature extraction to capture long-range global features and fine-grained spatial patterns, facilitating the identification of complex hematological characteristics. Additionally, the framework employs a graph-based module to uncover hidden, biologically relevant features of leukocyte cells, along with a Population-based Meta-Heuristic Algorithm for feature selection and optimization. Furthermore, we introduce a novel combination of leukocyte segmentation and synthesis, which isolates relevant regions while augmenting the training dataset with realistic leukocyte samples. This strategy isolates relevant regions while augmenting the training data with realistic leukocyte samples, enhancing feature extraction, and addressing data scarcity without compromising data integrity. RESULTS: We evaluated CoTCoNet on a dataset of 16,982 annotated cells, achieving an accuracy of 0.9894 and an F1-Score of 0.9893. We tested CoTCoNet on four diverse, publicly available datasets (including those above) to assess generalizability. Results demonstrate a significant performance improvement over existing state-of-the-art approaches. CONCLUSIONS: CoTCoNet represents a significant advancement in leukemia classification, offering enhanced accuracy and efficiency compared to traditional methods. By incorporating explainable visualizations that closely align with cell annotations, the framework provides deeper insights into its decision-making process, further solidifying its potential in clinical settings.

Genetic and clinical characteristics of acute B-cell lymphoblastic leukemia with MEF2D fusions and report of two novel MEF2D rearrangements.

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

A Chronological Overview of Using Deep Learning for Leukemia Detection: A Scoping Review.

Leukemia is a rare but fatal cancer of the blood. This cancer arises from abnormal bone marrow cells and requires prompt diagnosis for effective treatment and positive patient prognosis. Traditional diagnostic methods (e.g., microscopy, flow cytometry, and biopsy) pose challenges in both accuracy and time, demanding an inquisition on the development and use of deep learning (DL) models, such as convolutional neural networks (CNN), which could allow for a faster and more exact diagnosis. Using specific, objective criteria, DL might hold promise as a tool for physicians to diagnose leukemia. The purpose of this review was to report the relevant available published literature on using DL to diagnose leukemia. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, articles published between 2010 and 2023 were searched using Embase, Ovid MEDLINE, and Web of Science, searching the terms "leukemia" AND "deep learning" or "artificial neural network" OR "neural network" AND "diagnosis" OR "detection." After screening retrieved articles using pre-determined eligibility criteria, 20 articles were included in the final review and reported chronologically due to the nascent nature of the phenomenon. The initial studies laid the groundwork for subsequent innovations, illustrating the transition from specialized methods to more generalized approaches capitalizing on DL technologies for leukemia detection. This summary of recent DL models revealed a paradigm shift toward integrated architectures, resulting in notable enhancements in accuracy and efficiency. The continuous refinement of models and techniques, coupled with an emphasis on simplicity and efficiency, positions DL as a promising tool for leukemia detection. With the help of these neural networks, leukemia detection could be hastened, allowing for an improved long-term outlook and prognosis. Further research is warranted using real-life scenarios to confirm the suggested transformative effects DL models could have on leukemia diagnosis.

Disseminated Enterovirus Infection Complicated by Rhabdomyolysis in a Child with Acute Lymphoblastic Leukemia.

Enterovirus is not a common cause of myositis and rhabdomyolysis in children. We report a case of a two-year-old boy with acute lymphoblastic leukemia with disseminated enterovirus infection complicated by hepatitis, myositis, and rhabdomyolysis. The case was managed successfully with supportive care and high-dose intravenous immunoglobulins.

A case of Ph+ acute lymphoblastic leukemia and EGFR mutant lung adenocarcinoma synchronous overlap: may one TKI drug solve two diseases?

BACKGROUND: Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) refers to ALL patients with t(9;22) cytogenetic abnormalities, accounting for about 25% of ALL. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, which has a frequency of approximately 45% cases with mutations in EGFR. Both Ph+ ALL and EGFR mutant LUAD are involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway. Although the second primary hematological malignancy after the treatment of solid tumors is common in clinics, the synchronous multiple primary malignant tumors of hematological malignancy overlap solid tumors are uncommon, even both tumors involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway are extremely rare. CASE PRESENTATION: An 84-year-old man with fatigue and dizziness was diagnosed with Ph+ ALL. Meanwhile, a chest CT indicated a space-occupying lesions, characterized by the presence of void, in the right lower lope with the enlargement of mediastinal lymph node and right pleural effusion. After a few weeks, the patient was diagnosed with LUAD with EGFR exon 19 mutation. Both tyrosine kinase inhibitors (TKI) (Flumatinib) and EGFR-TKI (Oxertinib) was used for the patients, and finally have controlled both diseases. CONCLUSION: As far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.

Acute Leukemia and Latent Tuberculosis Infection in Italy: Quantiferon-Tb Test Screening in a Low Tuberculosis Incidence Country.

Background: Identification of latent tuberculosis infection (LTBI) is a critical step of tuberculosis surveillance, especially in low-incidence countries. However, it is limited to situations with a higher probability of developing active disease, e.g., patients with hematological malignancies. According to guidelines, in TB non-endemic countries, no clear screening program is established at diagnosis for patients with acute leukemia (AL). The primary endpoint of this study was to establish the prevalence of LTBI in patients with a diagnosis of AL using QuantiFERON (QFT)-TB. Secondarily, radiological and clinical features driving the increased risk of LTBI were evaluated. Methods: QFT-TB screening was performed before induction or consolidation in all patients with AL (myeloid and lymphoid) treated at our Institution between October 2019 and August 2023. Results: We accrued 62 patients, of whom 7 (11,3%) tested positive, without any symptoms or signs of active TB, and 2 (3,2%) resulted as indeterminate. All positive patients started prophylaxis with isoniazid 300 mg daily, while patients whose test was indeterminate did not receive any prophylaxis. Active TB was excluded by imaging, as well as microscopic, cultural, and molecular examination on bronchoalveolar lavage if signs of any infection were detected. During the 46 months of observation, no patients developed TB reactivation. Conclusions: Despite the low sample size, 1/10 of our patients had prior TB exposure, hinting that LTBI could be more common than expected in Italy. This finding suggests implementing TB screening in the pre-treatment setting, particularly at a time when more active treatments are becoming available also for patients ineligible for intensive chemotherapy.

Distinct pattern of genomic breakpoints in CML and BCR::ABL1-positive ALL: analysis of 971 patients.

BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.

Consolidation with First and Second Allogeneic Transplants in Adults with Relapsed/Refractory B-ALL Following Response to CD19CAR T Cell Therapy.

CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; n = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, P = .641), RFS (54% vs. 59%, P = .820), CIR (33.5% vs. 8.5%, P = .104), and NRM (12.5% vs. 32.2%, P = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (P = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients.

A Case Report of Malignant Cerebellopontine Angle Lesion Highlighting the Interdisciplinary Diagnostic Challenge in the Case of Unilateral Progressive Hearing Loss.

The authors present the case of a young boy who experienced progressive unilateral hearing loss initially believed to be unrelated to any other medical condition. Methods: The patient received a thorough evaluation, which included a comprehensive battery of audiological tests, a CT scan, and a gadolinium-enhanced MRI. Results: A repeated imaging investigation revealed the presence of a mass that mimicked a vestibular schwannoma (VS), but despite this, the boy was ultimately diagnosed with cerebral manifestations of B-cell acute lymphoblastic leukemia (B-ALL). Conclusions: Cerebral lesions originating from the internal auditory canal are rare in cases of B-ALL. In this case, the initial signs and symptoms of the disease were solely related to the audiovestibular system, making the diagnostic process particularly complicated. Unilateral hearing loss cases may indicate the presence of potentially life-threatening conditions, even if the hearing loss appears to be clinically non-syndromic. For these reasons, unilateral hearing losses necessitate a comprehensive interdisciplinary diagnostic approach from the very start of auditory manifestation and, in particular, if the hearing impairment demonstrates threshold progression.

Unmasking the Rarity: A Case Report on Type B Lactic Acidosis in Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric malignancy, accounting for approximately 25% of childhood cancers. Despite significant advancements in treatment protocols, ALL remains a complex disease, often presenting with various complications, including the rare metabolic disturbance of type B lactic acidosis. This case report details the clinical journey of a 14-year-old female with ALL who developed type B lactic acidosis during treatment. The patient presented with intermittent fever, abdominal pain, jaundice, and hepatosplenomegaly, accompanied by severe anemia and thrombocytopenia. Initial management included supportive care and chemotherapy initiation. Despite aggressive interventions, the patient's condition deteriorated, with escalating lactic acidosis and respiratory distress, leading to a critical need for tailored management strategies. This report underscores the importance of early recognition and comprehensive management of type B lactic acidosis in pediatric ALL, highlighting its multifactorial etiology and potentially life-threatening consequences. Enhanced clinical awareness and a multidisciplinary approach are crucial for improving outcomes in such complex cases.

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

Treatment of Relapsed Acute Lymphocytic Leukemia in Adult Patients.

OPINION STATEMENT: For adult patients diagnosed with relapsed B cell-ALL (B-ALL), there have been significant improvements in available treatment options following the FDA approval of novel cellular and immunotherapy approaches - blinatumomab, chimeric antigen receptor (CAR) T therapy, and inotuzumab. For the last several years, research has focused on gaining a better understanding of the effects of specific disease and patient characteristics on long-term outcomes with each of the FDA-approved agents. In combination with the better prevention and management of unique, treatment-specific toxicities, providers can now select the best available treatment option for each individual patient diagnosed with relapsed, adult B-ALL needing therapy. This has allowed more patients to proceed to consolidative hematopoietic stem cell transplant (HSCT), and long-term data has even brought into question the need for HSCT for long-term durable remission for all patients. However, with the adoption of blinatumomab, CAR T therapy, and inotuzumab in front-line treatment regimens, it remains unclear what effects this will have on patients with relapsed B-ALL following exposure to these novel cellular and immunotherapy therapies. Unlike B-ALL, similar advances have unfortunately not yet been realized in T cell-ALL (T-ALL). Currently, new therapeutic approaches are underway to utilize similar targeting strategies that have been successful in B-ALL - monoclonal antibodies, bispecific T-cell engagers (BiTE), and CAR T therapy. Like B-ALL, the only existing approved therapy for relapsed T-ALL, nelarabine, is now used in the upfront treatment setting potentially limiting its utility in relapsed disease. Over the next several years, the hope is for patients diagnosed with T-ALL to experience the drastic improvement in outcomes as has been seen for patients diagnosed with B-ALL over the last decade.

The potential role of renin angiotensin system in acute leukemia: a narrative review.

Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.

Blinatumomab in Children with MRD-Positive B-Cell Precursor Acute Lymphoblastic Leukemia: A Report of 11 Cases.

Background/Objectives: Relapsed B-cell acute lymphoblastic leukemia (B-ALL) remains an unresolved matter of concern regarding adverse outcomes. This case study aimed to evaluate the effectiveness of blinatumomab, with or without door lymphocyte infusion (DLI), in treating measurable residual disease (MRD)-positive B-ALL. Methods: All patients who received blinatumomab salvage therapy were included in this study. Eleven patients were included in the study. All patients were evaluated for MRD-negativity. Results: Before starting blinatumomab therapy, seven patients tested positive for MRD, three tested negative, and one had refractory disease. Hematopoietic cell transplantation (HCT) was reserved for five patients with persistent MRD. Six patients became MRD-negative and subsequent HCT was not performed. Only two patients relapsed; one patient died of relapse, and the other one received carfilzomib-based therapy and was MRD-negative thereafter. Nine patients were MRD-negative at a median follow-up of 28 months (15-52 months). Two of three MRD-positive post-transplant patients remained in complete molecular remission after preemptive DLI at the last follow-up date. In the first salvage, blinatumomab may achieve complete remission and bridging to HCT in pediatric patients with end-of-induction MRD-positive B-cell precursor ALL. Conclusions: The decision on how to treat post-transplant relapse continues to affect survival outcomes. Blinatumomab combined with DLI may extend the armamentarium of release options for high-risk pediatric patients. This approach is encouraging for high-risk ALL patients who are MRD-positive post-transplantation.

Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2-related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2's involvement in ALL development and offers targeted therapy prospects.