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Jak2STAT6c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190

The Philadelphia chromosome encodes the BCR-ABL fusion protein, which has two primary subtypes, P210 and P190. P210 and P190 cause Philadelphia-positive chronic myeloid leukemia (Ph CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph ALL), respectively. The Ph ALL is more malignant than Ph CML in disease phenotype and progression. This implies the key pathogenic molecules and regulatory mechanisms caused by BCR-ABL in two types of leukemia are different. It is reported that STAT6 was significantly activated only in P190 transformed cells. However, the potential role and the mechanism of STAT6 activation in Ph ALL and its activation mechanism by P190 are still unknown. The protein and mRNA levels of STAT6, c-Myc, and other molecules were measured by western blot and quantitative real-time PCR. The STAT6 inhibitor AS1517499 was used to specifically inhibit p-STAT6. The effect of p-STAT6 inhibition on Ph CML and Ph ALL cells was identified by CCK-8 and FCM assay. Dual luciferase reporter and ChIP assay were performed to confirm the direct binding between STAT6 and c-Myc. The impact of STAT6 inhibition on tumor progression was detected in Ph CML and Ph ALL mouse models. Our results demonstrated that P210 induced CML-like disease, and P190 caused the more malignant ALL-like disease in mouse models. STAT6 was activated in P190 cell lines but not in P210 cell lines. Inhibition of STAT6 suppressed the malignancy of Ph ALL in vitro and in vivo, whereas it had little effect on Ph CML. We confirmed that p-STAT6 regulated the transcription of c-Myc, and STAT6 was phosphorylated by p-Jak2 in P190 cell lines, which accounted for the discrepant expression of p-STAT6 in P190 and P210 cell lines. STAT6 inhibition synergized with imatinib in Ph ALL cells. Our study suggests that STAT6 activation plays an essential role in the development of Ph ALL and may be a potential therapeutic target in Ph ALL. Video abstract.

Enhancing CAR-T cell functionality in a patient-specific manner.

Patient responses to autologous CD19 chimeric antigen receptor (CAR) T-cell therapies are limited by insufficient and inconsistent cellular functionality. Here, we show that controlling the precise level of stimulation during T-cell activation to accommodate individual differences in the donor cells will dictate the functional attributes of CAR-T cell products. The functionality of CAR-T cell products, consisting of a diverse set of blood samples derived from healthy donors, acute lymphoblastic leukemia (ALL), and chronic lymphocytic lymphoma (CLL) patient samples, representing a range of patient health status, is tested upon culturing on artificial antigen-presenting cell scaffolds to deliver T-cell stimulatory ligands (anti-CD3anti-CD28) at highly defined densities. A clear relationship is observed between the dose of stimulation, the phenotype of the T-cell blood sample prior to T-cell activation, and the functionality of the resulting CAR-T cell products. We present a model, based on this dataset, that predicts the precise stimulation needed to manufacture a desired CAR-T cell product, given the input T-cell attributes in the initial blood sample. These findings demonstrate a simple approach to enhance CAR-T functionality by personalizing the level of stimulation during T-cell activation to enable flexible manufacturing of more consistent and potent CAR-T cells.

Transcriptome- and metabolome-based candidate mechanism of BCR-ABL-independent resistance to olverembatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Olverembatinib represents the third-generation breakpoint cluster region protein-Abelson-murine leukemia 1 (BCR-ABL1) tyrosine kinase inhibitor with oral bioavailability, which can be used to overcome the T315I mutation in Philadelphia chromosome-positive (Ph ) leukemia. BCR-ABL-independent resistance to olverembatinib has been reported among patients in various clinical cases. However, the mechanism of olverembatinib resistance has rarely been reported. This study has illustrated bone marrow cell transcriptome and metabolome profiles among Ph acute lymphoblastic leukemias (ALL) cases pre- and post-olverembatinib resistance. The transcriptome studies demonstrated that PI3KAKT, purine metabolism, and other signaling pathways could play a vital role in olverembatinib resistance. As suggested by metabolomics, olverembatinib resistance in Ph ALL was associated with purine metabolism alterations. Subsequently, high-performance liquid chromatography along with real-time quantitative PCR was utilized to measure purine metabolism-related mRNA levels and metabolism expression levels between olverembatinib resistance and sensitive cell lines. Our results elucidate the mechanism of olverembatinib resistance in Ph ALL at transcriptome and metabolome levels, which facilitate a better understanding of olverembatinib resistance and hence may prove crucial in identifying novel drugs to tackle this conundrum.

Hyperglycemia and Other Glycemic Measures Throughout Therapy for Pediatric Acute Lymphoblastic Leukemia and Lymphoma.

Transient hyperglycemia during induction chemotherapy is associated with increased morbidity and mortality in patients with acute lymphoblastic leukemia (ALL). Treatment with glucocorticoids, asparaginase, and stress are the proposed causal factors. Although these risks are not exclusive to induction, glycemic control throughout the remainder of ALLlymphoma (ALLALLy) therapy has not been described. Furthermore, prior research has been limited to transient hyperglycemia. This study aimed to characterize glycemic control throughout ALLALLy and to evaluate risk factors and outcomes associated with increased mean glucose and glucose coefficient of variation (glucose CV) during induction chemotherapy. The records for 220 pediatricyoung adult patients, age 1 to 26 years, who underwent treatment for ALLALLy from 2010 to 2014 at Childrens Hospital Colorado were retrospectively reviewed. Measures of glycemic control were calculated for each cycle. For the cycle with the highest mean glucose, induction (n208), multivariable models were performed to identify potential risk factors and consequences of increased glucose. Highest mean glucose by cycle were induction 116 mgdL, pretreatment 108 mgdL, delayed intensification 96 mgdL, and maintenance 93 mgdL these cycles also had the most glycemic variability. During induction, patients with Down syndrome, or who were ≥12 years and overweightobese, had higher mean glucoses age and overweightobese status were each associated with increased glucose CV. In multivariable analysis, neither induction mean glucose nor glucose CV were associated with increased hazard of infection, relapse, or death.

Infectious complications during monoclonal antibodies treatments and cell therapies in Acute Lymphoblastic Leukemia.

Infections represent one of the most frequent complications during the treatment of patients with Acute Lymphoblastic Leukemia (ALL) of these, almost half develop an infectious event in the majority of cases in induction. The new monoclonal and bispecific antibodies and CAR-T, besides offering new perspectives in the overall survival and disease-free survival of patients, may also transform the epidemiology of infections in ALL by improving the toxicity of treatments. In this review, we examined studies published in the literature over the past 12 years and described the infectious complications of therapy with Blinatumomab, Inotuzumab, Rituximab and CAR-T in adult and pediatric patients with ALL. Infections are less frequent than in traditional chemotherapy treatment with vincristine, corticosteroids and anthracyclines, which has been the backbone of therapy for patients with ALL for years. On the other hand, the infection scenario in the CAR-T setting is quite peculiar In these patients, infections are more frequent in the first month after infusion and are predominantly bacterial. As the time moves away from day zero, viral infections become more frequent, occurring mainly in patients who have had prolonged cytopenia and major cytokine release syndrome.

Genetic characteristics and treatment outcome in infants with KMT2A germline B-cell precursor acute lymphoblastic leukemia Results of MLL-Baby protocol.

The aim of this study was to present the diagnostic and outcome characteristics of infants with germline status of KMT2A gene (KMT2A-g) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treated consistently according to the MLL-Baby protocol, a moderate-intensity protocol. Of the 139 patients enrolled in the MLL-Baby study, 100 (71.9%) carried different types of rearranged KMT2A (KMT2A-r), while the remaining 39 infants (28.1%) had KMT2A-g. KMT2A-g patients were generally older (77% older than 6 months), less likely to have a very high white blood cell count (greater than 100 × 10

PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, constituting approximately 25% of childhood cancers. In recent decades, survival rates have improved dramatically, from approximately 10% in the 1960s to over 90% today. This tremendous achievement has been accomplished through collaborative randomized clinical trials, with progressive evolution of highly efficient, risk-adapted multi-agent chemotherapeutic regimens, effective central nervous system prophylactic strategies and improved supportive care. Recently, our understanding of the genetic basis of ALL has been greatly enhanced, and precise methods for treatment response assessment with serial measurements of minimal residual disease have been developed. Certain patient subgroups have genetically targetable lesions, such as Philadelphia-positive ALL, whose outcomes have been dramatically improved by combined tyrosine kinase inhibitors and chemotherapy, or specific patient subsets of Philadelphia-like ALL. Despite the great progress in curing childhood ALL, significant challenges still remain. Acute adverse effects of chemotherapy may be life-threatening, and long-term side effects often impair survivors quality of life. Survival rates in patients with relapsed or refractory ALL remain poor. This led to the introduction of novel immune-based therapies into the treatment of relapsedrefractory B-ALL blinatumomab, a CD19 bi-specific T-cell engager inotuzumab- a CD22-immunotoxin, and CD19-CAR (chimeric antigen receptor) T cells. These modalities have demonstrated improved remission rates with reduced toxicity compared to chemotherapy. The role of immunotherapy in the treatment of newly-diagnosed and relapsed patients will be more precisely defined in the near future.

CAR-T CELL THERAPY FOR B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA WITH A LARGE OVARIAN EXTRAMEDULLARY MASS.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, arising from the bone marrow. ALL may present at diagnosis or relapse at extramedullary sites. In recent years, autologous T-cells engineered to express a chimeric-antigen receptor (CAR-T cells) have emerged as novel immune-based therapies for relapsed and refractory ALL, targeting the B-cell surface antigen CD19. Here we present a patient with relapsed ALL involving the ovaries, treated with CD19 CAR-T cells. Toxicity included cytokine-release syndrome and neurotoxicity. CAR-T cell therapy led to a complete remission, with evidence of CAR-T cell trafficking to disease sites including the bone marrow and ovaries.

Effect of

To evaluate the influence of A total of 256 patients with childhood pre-B-cell ALL under the CCLG-2008 protocol were enrolled in this study, and 174 healthy children were used as case controls. The A allele frequency of

Successful treatment of steroid-dependent gastrointestinal acute graft-versus-host disease with mesenchymal stromal cells administered more than 100 days after allo-HCT.

Administration of mesenchymal stromal cells (MSCs) represents a promising therapy for steroid-resistant acute graft-versus-host disease (aGVHD). However, its efficacy in pediatric patients with steroid-dependent aGVHD remains unclear, given the paucity of studies performed in children. In addition, the duration between the onset of aGVHD and MSC therapy is reportedly critical a delay in MSC administration negatively impacts overall survival and response rate. Herein, we describe a case of a 14-year-old girl with steroid-dependent aGVHD who was successfully treated with MSCs following a prolonged duration from aGVHD diagnosis. The patient was diagnosed with T-cell lymphoblastic leukemia with central nervous system involvement and underwent cord blood transplantation (CBT). She developed severe gastrointestinal aGVHD on day 14 after CBT and was treated with a steroid however, her aGVHD was repeatedly exacerbated upon tapering the steroid, later complicated by diabetic ketoacidosis. We eventually implemented MSC therapy for steroid-dependent aGVHD on day 109 after CBT. She rapidly responded to therapy, and her aGVHD was ameliorated even with steroid tapering. This case exemplifies the potential role of MSCs in treating pediatric patients with steroid-dependent aGVHD or late aGVHD.

Understanding Quality of Life in Patients With Acute Leukemia, a Global Survey.

The Acute Leukemia Advocates Network (ALAN) sought to determine which factors are most associated with poor quality of life (QoL) in patients with acute leukemia and to determine key issues and unmet needs through administration of an online survey distributed worldwide via partner patient organizations. ALAN developed a questionnaire informed by literature review and based extensively on the hematological malignancy-specific patient-reported outcomes (HM-PRO) measure to assess the impact of acute leukemia on QoL and its relationships with patients demographics, disease state, disease impact, and support from health care professionals. Univariate and multivariable statistical analysis was used to investigate relationships between HM-PRO scores and the other factors. Of 552 respondents from 42 countries, 332 had acute myeloid leukemia, 139 had acute lymphoblastic leukemia, and 81 had acute promyelocytic leukemia (survey data collected in 2019). Younger age, female gender, and lower income were all significantly negatively associated with QoL. Weak or moderate correlations were observed between overall support, management, and impact of treatment and diagnosis of acute leukemia. Feeling isolated and having reduced ability to carry out physical or enjoyable activities were the most important individual factors, while the best predictors for QoL impact were age, gender, and income (model r Findings indicated key factors, particularly age, gender, and socioeconomic state, that clinicians responsible for the care of patients with acute leukemia should be aware of when designing support strategies. The importance of social functioning in relation to patient QoL also should be included in considerations.

Cytomegalovirus Reactivation in Patients With Acute Lymphoblastic Leukemia in Non-transplant Setting.

Acute lymphoblastic leukemia is predominately a childhood disease and around two third of cases are of B-cell phenotype. Cytomegalovirus is an important cause of morbidity and mortality in allogeneic hematopoietic progenitor cell transplant however, it is rare in patients with B-cell acute lymphoblastic leukemia in non-transplant settings. In this study, we evaluated 72 patients of acute precursor (pre) B-cell acute lymphoblastic leukemia at Shaukat Khanum Memorial Cancer Hospital and Research Center, out of which three were positive for Cytomegalovirus.

Mutual antagonism between glucocorticoid and canonical Wnt signaling pathways in B-cell acute lymphoblastic leukemia.

Glucocorticoids (GCs i.e., steroids) are important chemotherapeutic agents in the treatment of B-cell precursor acute lymphoblastic leukemia (B-ALL) and

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress.

Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL) but pan-Notch inhibitors were toxic in clinical trials. To find alternative ways to target Notch signals, we investigated Cell division cycle 73 (Cdc73), which is a Notch cofactor and component of transcriptional machinery, a potential target in T-ALL. While we confirmed previous work that CDC73 interacts with NOTCH1, we also found that the interaction in T-ALL was context-dependent and facilitated by the lymphoid transcription factor ETS1. Using mouse models, we showed that Cdc73 is important for Notch-induced T-cell development and T-ALL maintenance. Mechanistically, Cdc73, Ets1, and Notch intersect chromatin at promoters and enhancers to activate oncogenes and genes that are important for DNA repair and oxidative phosphorylation. Consistently, Cdc73 deletion in T-ALL cells induced DNA damage and impaired mitochondrial function. Our data suggests that Cdc73 might promote a gene expression program that was eventually intersected by Notch to mitigate the genotoxic and metabolic stresses of elevated Notch signaling. We also provide mechanistic support for testing inhibitors of DNA repair, oxidative phosphorylation, and transcriptional machinery. Inhibiting pathways like Cdc73 that intersect with Notch at chromatin might constitute a strategy to weaken Notch signals without directly targeting the Notch complex.

A cross-sectional study evaluating health-related quality of life of Chinese pediatric patients with hematological malignancies using EQ-5D-Y.

The study aimed to assess health-related quality of life (HRQoL) and to estimate the health utility of pediatric patients with hematological malignancies (HMs) in China. A cross-sectional study recruited a series of pediatric inpatients diagnosed with HM from November 2018 to May 2019 in the Shanghai Childrens Medical Center. Subjects were interviewed to collect sociodemographic information about themselves and their guardians. The EQ-5D-Y was completed by each patient to rate their own HRQoL, which later derived the health utility. The health status was also assessed by clinicians following the Eastern Cooperative Oncology Group (ECOG) system. Upon the descriptive analysis and univariate analysis, multivariate generalized linear models were built to explore the associations of risk factors with HRQoL measures of utility, Visual Analog Scale (VAS) score, and the five EQ-5D-Y domains. The 96 subjects had a mean age of 10.5 years and included 62 (64.4%) boys. There were 46 (47.9%) and 25 (26.0%) children diagnosed with acute lymphoblastic leukemia and non-Hodgkins lymphoma, respectively. The means (SD) of utility and EQ-VAS scores were 0.88 (0.10) and 85.8 (15.1), respectively. Twenty-six (27.1%) patients were graded poor health by the ECOG standard (score 23). Both univariate and multivariate analyses found strong correlations between ECOG and HRQoL. After adjusting for covariates, poor ECOG score was significantly associated with an impaired utility and VAS of -0.103 and -8.65, respectively. With regard to individual HRQoL domains, worse ECOG was more likely to report health problems with an increased risk of 2.94 to 12.50 residence, income, guardians education, and disease duration were also found to be significantly related to either the utility or certain health domains. The HRQoL of Chinese pediatric patients with HM is considered relatively poor and of great concern to healthcare. With the strong correlations between EQ-5D-Y-related HRQoL measures and the traditional clinical index ECOG, the EQ-5D-Y is able to provide valuable evidence for clinical decision-making at the individual level. At the same time, its health utility can inform resource allocation at a macro level.

Genetic analysis of a case of B-acute lymphoblastic leukaemia with double Philadelphia chromosomes and double derivative chromosome 9s.

To explore the genetic basis for a rare case of acute B-lymphocytic leukemia (B-ALL) with double Philadelphia chromosomes (Ph) and double derivative chromosome 9s der(9). A patient with double Ph and double der(9) B-ALL who presented at Shanghai Zhaxin Intergrated Traditional Chinese and Western Medicine Hospital in June 2020 was selected as the subject. Bone marrow morphology, flow cytometry, G-banding karyotyping, fluorescence in situ hybridization (FISH), genetic testing and chromosomal microarray analysis (CMA) were used to analyze bone marrow samples from the patient at various stages. At initial diagnosis, the patients bone marrow morphology and flow immunotyping have both supported the diagnosis of B-ALL. G-banded karyotyping of the patient indicated double Ph, in addition with hyperdiploid chromosomes involving translocations between chromosomes 9 and 22. BCR-ABL1 fusion gene was positive. Genetic testing at the time of recurrence revealed presence of a heterozyous c.944C>T variant in the kinase region of the ABL1 gene. FISH showed a signal for ABL1-BCR fusion on both chromosome 9s. CMA showed that the mosaicism homozygosity ratio of chromosome 9 was about 40%, and the mosaicism duplication ratio of chromosome 22 was about 43%. Since both der(9) homologs were seen in 40% of cells, the possible mechanism for the double der(9) in this patient may be similar to that of double Ph, which might have resulted from non-disjunction during mitosis in the Ph chromosome-positive cell clone.

Targeted immunotherapy efficacy analysis in patients with relapsedrefractory B cell acute lymphocytic leukemia.

Safety and efficacy of humanized CD19-targeted CAR-T cells in patients with relapsedrefractory acute B cell lymphoblastic leukemia.

Long-term safety and activity of humanized CD19 chimeric antigen receptor T cells for children and young adults with relapsedrefractory acute lymphoblastic leukemia.

The efficacy and safety of low-dose chemotherapy combined with tyrosine kinase inhibitors in the treatment of Philadelphia-chromosomal-positive acute lymphoblastic leukemia.

Efficacy and safety of Venetoclax in the treatment of 25 patients with recurrent hematologic malignancies after an allogeneic hematopoietic stem cell transplantation.

The impact of donor-to-recipient gender compatibility on outcomes of haploid hematopoietic stem cell transplantation in patients with hematological malignancies.

Association of two ARID5B gene variant single nucleotide polymorphisms with acute lymphoblastic leukemia in the Egyptian population.

ARID5B SNPs have been linked to ALL in many research studies in which it was identified as a risk factor. From this context, we had great interest to investigate the relationship between ARID5B rs4948488 and ARID5B rs2893881 genotypes and ALL susceptibility and relapse in this study. Peripheral blood mononuclear cells were analyzed for ARID5B rs4948488 and rs2893881 gene polymorphisms by real-time quantitative polymerase chain reaction in 80 ALL patients and 80 controls. Our results showed that the CC genotype of ARID5B rs4948488 and AG genotype and G-allele of rs2893881 were linked to higher ALL incidence. Regarding the relapse of ALL, rs4948488 CC genotype and C-alleles were significantly associated with relapse of ALL. Meanwhile, rs4948488 CC genotype and rs2893881 AA genotype and A-allele are associated with T-ALL, while rs2893881 AG genotype and G-allele are associated with B-ALL. The results of our study suggested that ARID5B rs4948488 and rs2893881 SNPs might be used risk factors for genetic susceptibility for B-ALL and T-ALL, and that ARID5B s4948488 is related to relapse in ALL patients.<br >.

The case of T-ALL presenting with NK phenotype after COVID-19 vaccination.

NK-lymphoblastic leukemialymphoma (NK-LL) is an extremely rare hematopoietic tumor consisting of natural killer (NK) precursor cells, and their lineage overlaps with T-cells, making it challenging to diagnose. COVID-19 vaccination is recommended for people with a risk of aggravation such as cancer-bearing patients, including hematopoietic tumors. We present a 55-year-old man who had cervical lymph node swelling post vaccination for COVID-19. Hematological malignancy was suspected due to the presence of atypical lymphoid cells with an elevated IL-2R in laboratory data. Tumor cells were positive for CD7, CD56, cyCD3, and terminal deoxynucleotidyl transferase (TdT) evidenced through flow cytometry of the bone marrow and the lymph node. The histopathological findings showed monotonous tumor cell proliferation, the cells being positive for CD3 and TdT in the bone marrow and they were positive for CD3, TdT, and CD56 in lymph node. Even though these findings suggested NK-LL, clonal T-cell receptor (TCR) β gene rearrangement by Southern blot hybridization was observed in the bone marrow. TCRβ rearrangement led to the final diagnosis of T-cell lymphoblastic leukemia (T-ALL). The causal relationship between COVID-19 vaccination and carcinogenesis is not clear, and more cases need to be studied in order to elucidate the relationship between the two factors.

Investigating the Expression Pattern of the SETMAR Gene Transcript Variants in Childhood Acute Leukemia Revisiting an Old Gene.

The chimeric enzyme SETMAR (or Metnase) has been associated with several DNA processes, including DNA damage repair through the non-homologous joining pathway and suppression of chromosomal translocation in mouse fibroblasts. SETMAR overexpression has been reported in certain cancers suggesting that it might contribute to the establishment or progression of these cancers. In leukemia, the SETMAR gene transcript variants have not been widely studied. Therefore, this study aimed to quantify 3 predominant SETMAR variants in 2 types of childhood acute leukemia, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In this study, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the relative expression of 3 SETMAR transcript variants (Var 1, Var 2, and Var A) were evaluated in the bone marrow samples collected from 30 newly diagnosed patients with AML, 65 newly diagnosed patients with ALL, and 15 healthy individuals. The expression of SETMAR variants 1 and A were significantly higher in AML patients compared with controls (P0.02, and P0.009, respectively). Variant A expression was significantly higher in ALL compared with controls (P0.003). When comparing the expression in translocation-positive and negative subgroups, the expression of variant 1 was significantly higher in translocation-positive ALL patients (P0.03). The variants distribution patterns differed concerning translocation status (P0.041), as variants 1 and A were dominant in the translocation-positive ALL group, and variant 2 was more prevalent in translocation-negative ones. According to the results, SETMAR showed increased expression in pediatric acute leukemias bone marrow samples, indicating a role for this molecule in leukemia pathogenesis. As this is the first report of SETMAR expression in pediatric leukemias, further studies are needed to investigate the causality of this association.

A Pediatric Case of Treatment-related Myelodysplastic Syndrome While on Therapy for Pre-B Acute Lymphoblastic Leukemia.

Treatment-related myelodysplastic syndrome (t-MDS) is a rare late effect of cancer therapy. After alkylating agents, this typically occurs years after completion of therapy. Treatment of t-MDS in pediatrics is an allogeneic stem cell transplant, however, the prognosis remains poor. This case demonstrates t-MDS developing in a patient receiving treatment for pre-B acute lymphoblastic leukemia. This patient was treated with a combination of hematopoietic stem cell transplant and hypomethylating agents. These agents should be considered for use in patients with t-MDS, before transplant to limit additional chemotherapy and as maintenance therapy post-transplant to reduce the risk of relapse.

Successful Retransplantation With Killer Cell Immunoglobulin-like Receptor Ligand-mismatched Cord Blood in Infant Acute Lymphoblastic Leukemia That Relapsed After Transplantation.

The prognosis of children with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) remains dismal. This report describes the successful retransplantation of a patient with infant ALL who relapsed both bone marrow and central nervous system. The patient received HLA-matched cord blood transplantation (CBT) and relapsed 18 months later. After achieving the second remission, the patient received a killer cell immunoglobulin-like receptor ligand-mismatched CBT with a reduced-intensity conditioning regimen and has been in remission for 52 months. Thus, killer cell immunoglobulin-like receptor ligand-mismatched CBT with reduced-intensity conditioning might be a treatment option for patients with KMT2A-r ALL who relapsed after transplantation, even with extramedullary relapse.

Severe Recurrent Nocturnal Hypoglycemia During Chemotherapy With 6-mercaptopurine in 2 Children With Acute Lymphoblastic Leukemia.

Mercaptopurine (6MP) and methotrexate are the cornerstones of maintenance therapy in pediatric patients with acute lymphoblastic leukemia. However, although bone marrow suppression and liver dysfunction are common side effects of these antimetabolites, 6MP-induced hypoglycemia during the maintenance phase is rare. Guidelines and international protocols are well established for the management of bone marrow suppression and liver dysfunction, but promptly identifying 6MP-induced hypoglycemia is the key to its control. Here we report 2 cases of leukemia that developed hypoglycemia during the maintenance phase. Both patients were boys younger than 6 years of age and both suffered symptomatic morning hypoglycemia induced by 6MP (which was diagnosed after excluding all other possible causes). Successful management included changing the time of 6MP administration from evening to morning. Other management options are also discussed.

Nelarabine-induced myelopathy in patients undergoing allogeneic hematopoietic cell transplantation a report of three cases.

Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemialymphoma. Myelopathy is a rare but serious adverse event associated with this drug. Three patients who received nelarabine at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy 20 days before, 12 days after, and 29 days after allogeneic hematopoietic cell transplantation (allo-HCT), respectively. Magnetic resonance imaging showed that two of the patients had lesions in the dorsal column or medulla oblongata, and one had no abnormalities in the head or spine. Despite treatment with intravenous immunoglobulin and methylprednisolone, all patients became unable to walk. One patient died on day 101 after allo-HCT due to progressive neurotoxicity. The other two patients showed spontaneous improvement in neurological symptoms, but one died of mucormycosis on day 476. Autopsy revealed spongiosis in the posterior funiculus in both patients who died, and also in the medulla oblongata in one patient. In the surviving patient, positron emission tomography on day 84 showed abnormal accumulation, suggesting continued inflammation. These cases demonstrated pathophysiological features of nelarabine-induced myelopathy and indicate that allo-HCT may worsen the condition. It is necessary to elucidate the underlying mechanism and establish diagnostic methods and therapies.

Emerging roles of circRNAs in leukemia and the clinical prospects An update.

Circular RNAs (circRNAs) are a new category of endogenous non-protein coding RNAs (ncRNAs), and show the characteristics of high conservation, stability, and tissue specificity. Due to rapid advances in next-generation sequencing and transcriptome profiling technologies, circRNAs have been widely discovered in many organisms and participated in the development and progress of a variety of diseases. As a type of molecular sponge, circRNAs mainly absorb micro RNAs competitively and interplay with RNA-binding proteins to modulate the splicing as well as transcription of target genes. This review is based on a literature search using the Medline database. Search terms used were circular RNAs and leukemia, circRNAs and leukemia, circRNAs and acute lymphoblastic leukemia, circRNAs and chronic lymphoblastic leukemia, circRNAs and acute myeloid leukemia, circRNAs and chronic myeloid leukemia, and circRNAs, biomarker, and hematological system. CircRNAs have been proven as potential biomarkers and therapeutic targets in a variety of tumors. Recent research has found that circRNAs aberrantly exist in hematological cancers, especially leukemia, and are significantly associated with the incidence, progress, and metastasis of diseases as well as the prognosis of patients. The current work summarizes the latest findings on circRNAs in various types of leukemia, aiming to propose prospective therapies and new drug screening methods for the treatment of leukemia.

Case Report Whole genome sequencing identifies

In the present report, we applied whole genome sequencing (WGS) to genetically characterize a case of pediatric T-cell acute lymphoblastic leukemia (ALL) refractory to standard therapy. WGS identified a novel

PDQ Cancer Information Summaries

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

PDQ Cancer Information Summaries

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Efficacy and safety of blinatumomab in children with relapsedrefractory B cell acute lymphoblastic leukemia A systematic review and meta-analysis.

The survival of childhood leukemia An 8-year single-center experience.

The survival of childhood leukemia has improved. We aimed to report the survival rate and the associated factors in children with acute leukemia during an 8-year follow-up. This study investigates the 8-year survival rates of children with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in Shiraz, the largest oncology center in Southern Iran. We also aimed to assess the independent factors associated with higher mortality in childhood leukemia. Children 0-18 years with acute leukemia were followed from 2013 to 2021 in Shiraz, Iran. The 8-year overall survival (OS) and event-free survival (EFS) rates were estimated by the Kaplan-Meier method. Independent factors associated with survival were assessed by the Cox regression hazard modeling. We included 786 children, with 43.5% female, and a mean age of 6.32 ± 4.62 years. Patients with AML compared to ALL experienced more relapse (34.6% vs. 22.5%, p .01) and death (31.7% vs. 11.3%, p < .001). The cumulative 8-year OS and EFS were 81% (95% confidence interval (CI), 74.3% to 86.1%) and 68.3% (95% CI, 63.5% to 72.7%) in ALL patients and 63.5% (95% CI, 52.1% to 72.9%) and 43% (95% CI, 33.1% to 52.6%) in AML patients. Multivariable analysis revealed that hepatomegaly (hazard ratio 4, 95% CI, 1.0 to 22.3, p .05) was the main independent risk factor of death in ALL patients. No definite risk factor was defined for AML patients. The survival of childhood leukemia has recently increased dramatically in low-middle income countries. Hepatomegaly was introduced as a potential risk factor for lower survival in ALL patients. Further multicenter studies are needed to confirm the validity of this association.

Combination therapy of a PSEN1-selective gamma-secretase inhibitor with dexamethasone and an XPO1 inhibitor to target T-cell acute lymphoblastic leukemia.

Not available.

Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia.

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease (MRD) have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a high throughput drug screen, we identified dinaciclib, a cyclin-dependent kinase (CDK) inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL PDX mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.

A Rare Case of p190 BCR-ABL B-cell Acute Lymphocytic Leukemia With Excellent Response to Hyper-CVAD and Ponatinib.

Acute lymphoblastic leukemia (ALL) is a hematologic cancer that begins in the bone marrow and results in an overproduction of lymphocytes. It can present as palpable purpura, which is also seen in many other pathologies, including vasculitides such as IgA vasculitis. We present a case of a 52-year-old male who presented to our hospital from an outside facility specifically for plasma exchange for treating a previously diagnosed IgA vasculitis. After being admitted for further evaluation, it was noted that the patient had a diffuse petechial non-blanching purpuric rash bilaterally covering the lower extremities, trunk, upper extremities, and tongue. The patient was also noted to have severe pancytopenia. Fluorescence in situ hybridization (FISH) demonstrated the presence of t(922), indicating Philadelphia chromosome rearrangement. The patient was diagnosed with ALL. The patient underwent induction chemotherapy and was continued on hyper-CVAD protocol with intrathecal chemotherapy. The patient appeared to respond well to treatment and is currently undergoing subsequent intermittent chemotherapy. In this case, the diagnosis of B-cell ALL (B-ALL) blast crisis was pivotal in providing the correct therapy to this patient, and the case demonstrated that even rare presentations of B-ALL in this population with rare mutations responds avidly to tyrosine kinase inhibitors.

The successful treatment of

A 47-year-old male had recurrent, profuse watery diarrhea and abdominal discomfort for more than 7 months, with a fever for 5 days. Two years earlier, he received treatment with a modified BFM-90 protocol for acute B cell lymphoblastic leukemia and is currently in the final stages of maintenance therapy with oral methotrexate and mercaptopurine. The leukemia was assessed as still in remission two months ago. PETCT showed massive peritoneal fluid accumulation and a high uptake area in the diffused peritoneum (SUVmax 12.57), suggesting tumor invasion or microbial infections. However, broad-spectrum antibacterial therapies were ineffective. Metagenomic sequencing of plasma and peritoneal fluid showed no suggestion of the existence of a tumor but instead showed a high sequence number of DNA and RNA of the Microsporidia. His albendazole treatment failed and subsequent treatment with nitazoxanide successfully resolved the infection. This case shows that we should consider the possibility of atypical pathogen infection in patients with hematologic malignancy who repeatedly develop unexplained diarrhea with wasting. mNGS can help rule out malignant neoplasms and diagnose infections. Our results suggest that nitazoxanide effectively treats

Cytogenetic Risk Stratification of B-Acute Lymphoblastic Leukemia and Its Correlation with Other Prognostic Factors.

Purpose of current study was to categorize WHO defined B-Acute Lymphoblastic Leukemia (B-ALL) cases into 3 cytogenetic risk groups (good, intermediate and poor) and to see their correlation with age, NCI risk criteria and treatment response. Clinical and diagnostic details were collected for 78 newly diagnosed B-ALL patients which included bone marrow morphology, flow cytometry immunophenotyping, karyotyping, FISH and RT-PCR. Study cohort comprised 4478 (56.4%) children including 3 infants and 3478 (43.6%) adults. Median age for paediatric group was 6 years (3 months-17 years) and for adults was 40.5 years (18 to 75 years). According to NCI risk criteria, excluding infants, 54 (72%) were high risk and 21 (28%) were standard risk. Clonal cytogenetic abnormality was detected in 5978 cases (75.6%), while 1978 (24.4%) cases showed normal karyotype. There was significant association of cytogenetic risk groups to age distribution (

Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia A Study of the Acute Leukemia Working Party of the EBMT.

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBIflu was used in 494 patients and 12-Gray TBIflu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (

Genetic variants in m5C modification core genes are associated with the risk of Chinese pediatric acute lymphoblastic leukemia A five-center case-control study.

To explore the functions of the polymorphisms in 5-methylcytosine (m5C) modification-related coding genes on the susceptibility of pediatric acute lymphoblastic leukemia (ALL). Case-control study and multinomial logistic regression analysis were performed to construct models to evaluate the susceptibility of pediatric ALL. The relationship between five functional SNPs in m5C modification-coding genes and pediatric ALL risk was analyzed. Genotyping of 808 cases and 1,340 healthy samples from South China was identified using a TaqMan assay odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relationship between the five selected SNPs and pediatric ALL susceptibility. Among the five analyzed SNPs, In conclusion,

Myeloidlymphoid neoplasm with eosinophilia and BCRFGFR1 rearrangement with transformation to cortical T-lymphoblastic lymphoma and erythroid precursors a case report.

Myeloproliferative neoplasms are a group of diseases with diverse biological and clinical characteristics. As a provisional separate entity, myeloidlymphoid neoplasms with eosinophilia and genetic rearrangement have been described, which may present an initial clinical behavior of myeloproliferation and be characterized by varied genetic rearrangements. One of these entities is associated with FGFR1 rearrangements, characterized by its low prevalence and few treatment options. We present the case of a 53-year-old Mestizo male patient of Hispanic origin who initially presented weight loss and fatigue, with a complete blood count showing leukocytosis and eosinophilia, with an initial diagnosis of nonspecific myeloproliferative disorder. In a next-generation sequencing study, BCRFGFR1 rearrangement was documented, a diagnosis of myeloidlymphoid neoplasia with eosinophilia and BCRFGFR1 rearrangement was made, and hydroxyurea therapy was initiated. Subsequently, transformation to cortical T-lymphoblastic leukemialymphoma and erythroid precursors was documented, requiring management with chemotherapy. Myeloidlymphoid neoplasms with eosinophilia and genetic rearrangements constitute a group of deeply heterogeneous diseases with variable clinical and diagnostic characteristics and whose treatment is not clearly defined.

Ethnic-specific predictors of neurotoxicity among patients with pediatric acute lymphoblastic leukemia after high-dose methotrexate.

High-dose methotrexate (HD-MTX 5000 mgm The authors retrospectively reviewed the medical records of patients who were diagnosed with ALL and treated with HD-MTX at Texas Childrens Cancer Center (2010-2017). Methotrexate neurotoxicity was defined as a neurologic episode (e.g., seizures or stroke-like symptoms) occurring within 21 days of HD-MTX that resulted in methotrexate treatment modifications. Mixed effects multivariable logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between clinical factors and neurotoxicity. Overall, 351 patients (58.1% Latino) who received 1183 HD-MTX infusions were evaluated. Thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, the authors observed that serum creatinine elevations ≥50% of baseline were associated with a three-fold increased odds (OR, 3.32 95% CI, 0.98-11.21 p .05) for neurotoxicity compared with creatinine elevation <25%. Notably, predictors of neurotoxicity differed by ethnicity. Specifically, Latino children experienced a nearly six-fold increase in neurotoxicity odds (OR, 5.80 95% CI, 1.39-24.17 p .02) with serum creatinine elevation ≥50% compared with creatinine elevation <25%. The current findings indicate that serum creatinine elevations ≥50% may be associated with an increased risk for neurotoxicity among Latino children with ALL and may identify potential candidates for therapeutic or supportive care interventions.

Estimation of anisotropic properties of CMR patient-specific left ventricle using the virtual field method.

Left ventricle (LV) myocardial dysfunction has been recently investigated using the estimation of isotropic myocardial stiffness from magnetic resonance imaging (MRI). However, Myocardium is known to have a 3D complex geometry with anisotropic stiffness. The assessment of the anisotropy properties characterizes structural changes in myocardium as a consequence of heart failure (HF). From image data, the virtual field method (VFM) can determine material stiffness in a non-invasive manner. In the present work, the objective is to compare two inverse identification methods, given the isotropic and anisotropic models in the characterization of properties of myocardium in acute lymphoblastic leukemia (ALL) survivors using VFM and MRI. Two types of VFM approach are presented. Using the first, the virtual displacements (VFs) allow whole-field LV to be imposed into VFM formulation and caused to directly estimate two independent parameters from isotropic constitutive relation. With the second, anisotropic parameters are estimated using piece-wise (Finite element-based) VFM. The resulting values showed significant differences between the subjects in comparative study of leukemia survivors, and variance in estimated parameters by two different VFM approach. This approach would be an efficient tool to characterize early cardiac dysfunction. This work elucidates the benefits and shortcomings of using VFM to determine anisotropic parameters of LV myocardium in linear elastic and of using the FEM application to generate meshes of patient-specific LVs from MRI images.

Sequencing antigen-targeting antibodies and cellular therapies in adults with relapsedrefractory B-cell acute lymphoblastic leukemia.

The recent approvals of four CD19-or CD22-targeted therapies for B-cell acute lymphoblastic leukemia (B-ALL) have transformed the treatment of relapsedrefractory (rr) disease. Adults with rr B-ALL are usually eligible for all options, but there are no studies directly comparing these agents, and the treating physician must decide which to select. Each therapy has notable activity as a single agent but has limitations in particular settings, and the optimal choice varies. These therapies can be complementary and used either sequentially or concomitantly. Here, we review the current landscape of antigen-targeted therapies for rr B-ALL and discuss considerations for their use.

Is higher lymphocyte count a potential strategy for preventing chronic kidney disease in patients receiving long-term dasatinib treatment

Dasatinib, which is used to treat treating chronic myeloid leukemia, induces increases in blood lymphocytes during the treatment. In addition, neutrophil-lymphocyte count ratio (NLR) is associated with the related to development of chronic kidney disease (CKD). However, it has not been reported whether development of CKD during long-term dasatinib treatment is related to lymphocyte count or NLR. This study aimed to reveal the relationship between CKD and lymphocyte count or NLR during long-term dasatinib treatment. A retrospective study was conducted in patients treated with dasatinib for 6 months or longer. Risk factors for CKD development were explored using multivariate analysis. Changes in maximal lymphocyte count and NLR over time were examined separately. A total of 33 patients in CKD group (n 8) and No CKD group (n 25) who received dasatinib were enrolled. In univariate analysis, significant differences between the groups were observed in maximal lymphocyte count, lymphocytosis, age, and estimated glomerular filtration rate at baseline. As the factor independently associated with the development of CKD, maximal lymphocyte count (odds ratio 0.999, 95% confidence interval 0.999-1.000, p 0.033) was identified. In this analysis, age had borderline significance (odds ratio 1.073, 95% CI 0.999-1.153, p 0.054). After 6 months of dasatinib therapy, lymphocyte count was significantly lower in CKD group median (range), 2184 (878‒3444)μL than in the No CKD group 3501 (966‒7888)μL (p 0.020). However, no significant difference in lymphocyte count was observed between the groups at the last follow-up. During the study period, the median NLR in the No CKD group fluctuated between 1.11 and 1.42, and median NLR in CKD group was increased from 1.13 to 2.24 between after 6 months of dasatinib therapy and the last follow-up. The development of CKD during dasatinib therapy was associated with lower maximal lymphocyte counts. In contrast, the higher levels of lymphocytes induced during dasatinib treatment may prevent CKD progression.

Metabolic profiling reveals metabolic features of consolidation therapy in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) and its treatment continue to pose substantial risks. To understand ALL more deeply, the metabolome in fasting plasma of 27 ALL patients before and after high-dose methotrexate therapies (consolidation therapy) including methotrexate and 6-mercaptopurine (6-MP) was investigated. Plasma metabolites were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS). Orthogonal projections to latent structures discriminant analysis and significance analysis of microarrays were used to evaluate the metabolic changes. Pathway enrichment and co-expression network analyses were performed to identify clusters of molecules, and 2826 metabolites were identified. Among them, 38 metabolites were identified by univariate analysis, and 7 metabolites that were altered by conditioning therapy were identified by multivariate analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for pathway enrichment analysis. Among the enriched KEGG pathways, the 3 significantly altered metabolic pathways were pyrimidine metabolism phenylalanine, tyrosine, and tryptophan biosynthesis and phenylalanine metabolism. In addition, L-phenylalanine was significantly correlated with blood urea nitrogen (BUN), and palmitoylcarnitine was correlated with aspartate aminotransferase (AST). In summary, consolidation therapy significantly affected pyrimidine- and phenylalanine-associated metabolic pathways in pediatric ALL patients. These findings may provide an insight into the role of metabolic profiling in consolidation treatment and as a potential for pediatric ALL patients.

Effect of chemotherapy (with and without radiotherapy) on the intelligence of children and adolescents treated for acute lymphoblastic leukemia a meta-analysis.

This meta-analysis assesses cognitive functioning in children with acute lymphoblastic leukemia post-treatment who were treated with either chemotherapy-only (CT-only) or in combination with radiation therapy (CTRT). The databases Pubmed and PsychInfo were searched between 1-1-2000 and 31-12-2021. Data were analyzed using Comprehensive Meta-Analysis (version 2). Mean weighted intelligence after treatment was 100.2 (number of studies n 51, 95% CI 98.8-101.5). For CT-only, it was 100.8 (95% CI 99.5-102.2) and for CTRT 97.8 (95% CI 95.9-100.2). Compared to recruited healthy controls, treated children had on average lower IQ scores (n 23, mean difference -7.8, 95% CI -10.7 to -5.0, p < 0.001). When looking only at studies using controls recruited from the patients family, results remained significant (n 5, mean difference -6.0, 95% CI -8.6 to -3.5, p 0.001). Meta-regressions aimed at identifying predictors of IQ after treatment failed to find an effect for sex or age. We could demonstrate an effect of time between diagnosis and IQ measurement for the CTRT treated patient (B -0.26, 95% CI -0.40 to -0.1, p 0.002). IQ scores of patients treated with CT-only or CTRT treatment regimens did not differ from the normative population. However, compared to recruited control groups, patients showed lower mean IQ scores. The Flynn effect andor selection effects may play a role in this discrepancy. Considering time since diagnosis may have a significant impact on IQ, at least in CTRT treated patients, long-term clinical follow-up of neurocognitive development may be prudent to detect possible (late) neurocognitive effects.

Phlegmonous gastritis associated with invasive Pseudomonas aeruginosa infection.

We report the case of a 49 years-old female that was hospitalized due to a recent diagnosis of acute lymphoblastic leukemia. As a consequence of induction chemotherapy (CALGB 10403 scheme), she developed severe neutropenia (0.04 103ul). On day 6 of chemotherapy, she complained of epigastric pain, fever, coffee ground emesis, and melena.

Comparison of characteristics and outcomes on ETP-ALLLBL and non-ETP ALL patients receiving allogeneic hematopoietic stem cell transplantation.

This study aims to compare the characteristics of early T-cell precursor acute lymphoblastic leukemialymphoma (ETP-ALLLBL) and non-ETP ALL patients and the outcomes of these patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 57 patients with T-cell acute lymphoblastic leukemialymphoma receiving allo-HSCT at our center between January 2016 and March 2022 were enrolled in the study. Twenty-eight patients were diagnosed as ETP-ALLLBL (2857, 49.12%) in the cohort. The baseline characteristic was not significantly different between the two groups. The median time for myeloid engraftment was 14 days (ranged from 11 to 21) The prognosis of patients with ETP-ALLLBL was similar to non-ETP ALL patients when they received allo-HSCT.

Erratum Patient-specific assays based on whole-genome sequencing data to measure residual disease in children with acute lymphoblastic leukemia A proof of concept study.

This corrects the article DOI 10.3389fonc.2022.899325..

Post-Hematopoietic Cell Transplantation Relapsed Acute Lymphoblastic Leukemia Current Challenges and Future Directions.

Allogeneic hematopoietic cell transplantation (allo-HCT) represents an important and potentially curative treatment option for adult patients with acute lymphoblastic leukemia. Relapse continues to remain the most important factor influencing overall survival post allo-HCT. We discuss early identification, clinical manifestations, and management of relapsed disease. Routine evaluation of measurable residual disease (MRD) and change in donor chimerism play a crucial role in early detection. Pivotal clinical trials have led to FDA approval of multiple novel agents like blinatumomab and inotuzumab. Combining targeted therapy with cellular immunotherapy serves as the backbone for prolonging overall survival in these patients. Donor lymphocyte infusions have traditionally been used in relapsed disease with suboptimal outcomes. This review provides insight into use of cellular therapy in MRD positivity and decreasing donor chimerism. It also discusses various modalities of combining cellular therapy with novel agents and discussing the impact of chimeric antigen receptor T-cell therapy in the setting of post allo-HCT relapse both as consolidative therapy and as a bridge to second transplant.

Cardiac involvement in a patient with B-cell lymphoblastic lymphomaacute lymphoblastic leukemia and a history of allogeneic hematopoietic stem cell transplantation and CAR T-cell therapy A case report.

Cardiac involvement in hematological malignancies is uncommon, with only a few cases reported to date, and it often leads to a poor prognosis. Here, we report a case of a 42-year-old woman with a history of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell lymphoblastic lymphomaacute lymphoblastic leukemia in whom cardiac mass and myocardial infiltration were detected. Prior to this presentation, massive pericardial effusion had occurred 6 months after CAR T-cell therapy, which was improved

Health utility of children with acute lymphoblastic leukemia in China.

Acute lymphoblastic leukemia is the most common cancer in children. As the 5-year survival rate has been improved to over 80%, more emphasis is now placed on reducing therapy toxicities and enhancing health-related quality of life (HRQoL) of patients during treatment. Our objective was to measure health utility of pediatric acute lymphoblastic leukemia (pALL) patients in China, examine utility weights of different treatment phases and influencing factors of health utility, as well as identify which aspects of HRQoL were most impaired. A cross-sectional study was conducted in Shanghai Childrens Medical Center (SCMC) Affiliated to Shanghai Jiao Tong University School of Medicine in China from April to November 2021. Primary caregivers of 247 patients completed the assessment by CHU9D-CHN and health utility scores were computed for all the patients and stratified by treatment phases. Various multivariable models were constructed and the best was chosen to identify independent factors associated with utility scores. Factors affecting the most impaired dimensions were also examined. The overall mean (SD) health utility score was 0.79 (±0.17) and significantly increased from induction (0.73 ±0.19, This is the first study that measured health utility of children with pALL in China. Mean health utility scores increased from induction to maintenance. These provided important utility estimates that help inform future health economic models. The phrasing of School workhomework in CHU9D-CHN could be further improved. More efforts are needed to design and implement specific interventions targeting at the dimension able to join in activities for enhancing HRQoL of children with pALL in China.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to compare outcomes of tyrosine kinase inhibitor (TKI) maintenance therapy with or without allogeneic hematopoietic stem cell transplantation (HSCT) in Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) in first remission (CR1). A literature search was performed on PubMed, Cochrane, and Clinical trials.gov. After screening 1720 articles, 12 studies were included. Proportions and odds ratios (OR) with 95% confidence intervals (CI) were computed. I

Post-Transplantation Sinusoidal Obstruction Syndrome in Adult Patients with B Cell Acute Lymphoblastic Leukemia Treated with Pretransplantation Inotuzumab.

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication that can be observed after allogeneic hematopoietic cell transplantation (HCT). Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody-drug conjugate that has demonstrated high efficacy in relapsedrefractory (RR) acute lymphoblastic leukemia (ALL) but is associated with an increased risk of SOS in HCT recipients. Here we aimed to examine the incidence and outcomes of SOS in 47 adult patients with RR ALL who received inotuzumab therapy and subsequently underwent HCT at our institution. All patients received prophylactic therapy with ursodiol, and continuous low-dose heparin also was administered to patients receiving myeloablative conditioning (MAC). SOS occurred in 12 patients (26%) post-HCT, at a median onset of 11 days (range, 3 to 41 days). SOS was graded as very severe in 50% (n 6), severe in 25% (n 3), and mild in 25% (n 3). All patients diagnosed with SOS received treatment with defibrotide for a median of 21 days (range, 3 to 34 days), with resolution of SOS occurring in 8 patients (67%). Mortality from SOS was 33% (n 4) and occurred at a median of 10 days from diagnosis (range, 3 to 31 days) in patients graded as very severe (n 3) or severe (n 1). There were no significant differences between patients who developed SOS and those who did not develop SOS in the median time from the last dose of inotuzumab to transplantation (46 days versus 53 days P .37), use of an MAC regimen (42% versus 49% P .75), number of lines of therapy prior to inotuzumab (P .79), median number of administered cycles of inotuzumab (2 versus 2 P .14), or receipt of inotuzumab as the last therapy prior to HCT (67% versus 66% P 1.0). Sirolimus-based graft-versus-host disease (GVHD) prophylaxis was used more frequently in the SOS group (75% versus 29% P < .01), but there was no between-group difference in the peak sirolimus level (P .81) or the median time to peak sirolimus level (7 days versus 3.5 days P .39). In univariable analysis, only the use of sirolimus-based GVHD prophylaxis was significantly associated with an increased risk of SOS (hazard ratio HR, 7.50 95% confidence interval CI, 1.7 to 33.6 P < .01). In the SOS group, the 100-day mortality rate was 33% (n 4), and median overall survival (OS) post-HCT was 4.3 months (range, 0.2 to 57.2 months). In the group without SOS, the 100-day mortality rate was 14% (n 5) and the median OS post-HCT was 10.7 months (range, .52 to 39.6 months). In this study cohort, SOS was prevalent in HCT recipients who had been treated with inotuzumab prior to transplantation, and sirolimus-based GVHD prophylaxis was a risk factor for SOS in inotuzumab recipients.

CircFBXW7 in patients with T-cell ALL depletion sustains MYC and NOTCH activation and leukemia cell viability.

Circular RNAs (circRNAs) are emerging as new players in leukemogenic mechanisms. In patients with T-cell Acute Lymphoblastic Leukemia (T-ALL), the recent report of a remarkable dysregulation of circRNAs incited further functional investigation. Here we focus on circFBXW7, highly expressed in T-cells, with a notably high abundance of the circular compared to linear transcript of FBXW7. Two T-ALL patient cohorts profiled with RNA-seq were analyzed in comparison with five populations of developing thymocytes as normal counterpart, quantifying circRNA and gene expression. CircFBXW7 expression was very heterogeneous in T-ALL patients allowing their stratification in two groups with low and high expression of this circRNA, not correlated with FBXW7 mutation status and T-ALL molecular subgroups. With a loss-of-function study in T-ALL in vitro, we demonstrate that circFBXW7 depletion increases leukemic cell viability and proliferation. Microarray profiling highlighted the effect of the circFBXW7 silencing on gene expression, with activation of pro-proliferative pathways, supporting a tumor suppressor role of circFBXW7 in T-ALL. Further, MYC and intracellular NOTCH1 protein levels, as well as expression of MYC target and NOTCH signaling genes were elevated after circFBXW7 depletion, suggesting an inhibitory role of circFBXW7 in these oncogenic axes. Plus, low circFBXW7 levels were associated with a particular gene expression profile in T-ALL patients, which was remarkably mirrored by the effects of circFBXW7 loss-of-function in vitro. CircFBXW7 depletion notably emerges as a new factor enhancing a proliferative phenotype and the activation of the MYC signaling pathway, key players in this aggressive malignancy.

Expression of Long Non-Coding RNA H19 in Acute Lymphoblastic Leukemia.

OObjective Long non-coding RNA (lncRNA) H19 has essential roles in growth, migration, invasion, and metastasis of most cancers. H19 dysregulation is present in a large number of solid tumors and leukemia. However, the expression level of H19 in acute lymphoblastic leukemia (ALL) has not been elucidated yet. The current study aimed to explore This experimental study was conducted in bone marrow (BM) samples collected from 25 patients with newly diagnosed ALL. In addition, we cultured the RPMI-8402, Jurkat, Ramos, and Daudi cell lines and assessed the effects of internal (hypoxia) and external (chemotherapy medications L-asparaginase ASP and vincristine VCR) factors on h19 expression. The expressions of There was significantly increased Our findings suggest that

New association between splicing factor-coding gene polymorphisms and the risk of acute lymphoblastic leukemia in southern Chinese children A five-center case-control study.

The role of splicing factor-coding gene polymorphisms in pediatric acute lymphoblastic leukemia (ALL) susceptibility is still unclear. A case-control designed model was used to estimate the overall risk of pediatric ALL and five single nucleotide polymorphisms (SNPs) of splicing factor-coding genes in 808 cases and 1,340 controls, which were genotyped using a TaqMan assay. Stratified analysis was performed to explore the association of rs2233911 genotype and pediatric ALL susceptibility. The influence of splicing factor arginineserine-rich 1 (SFRS1) polymorphisms on the sensitivity to different chemotherapeutic regimens based on minimal residual disease (MRD) levels was analyzed. The haplotype analysis was adopted to evaluate the association between inferred haplotypes of the splicing factor-coding genes and pediatric ALL risk. Among the five analyzed SNPs, SFRS1 rs2233911 AGGG exhibited a significant association with increased pediatric ALL risk. The stratified analysis further identified the harmful effect of SFRS1 rs2233911 AGGG in specific subgroups. Moreover, rs2233911 AGGG had a protective effect on MRD in marrow of ≥0.01% 12 weeks of Chinese Children Cancer Group chemotherapeutics, but provided a harmful effect on MRD in the marrow of ≥0.01% at days 15-19 of the South China Children Leukemia Group chemotherapeutics. Haplotype analysis of these five SNPs yielded haplotypes ACGCC and ACGTC significantly correlating with increased pediatric ALL susceptibility. On the contrary, haplotypes GCATG and GTACC were linked with remarkably decreased pediatric ALL risk. SFRS1 gene polymorphism was associated with increased pediatric ALL risk and indicated that rs2233911 AGGG might be a potential biomarker for choosing chemotherapeutics.

CAR T-Cell Immunotherapy Treating T-ALL Challenges and Opportunities.

T-cell acute lymphoblastic leukemia (T-ALL), a form of T-cell malignancy, is a typically aggressive hematological malignancy with high rates of disease relapse and a poor prognosis. Current guidelines do not recommend any specific treatments for these patients, and only allogeneic stem cell transplant, which is associated with potential risks and toxicities, is a curative therapy. Recent clinical trials showed that immunotherapies, including monoclonal antibodies, checkpoint inhibitors, and CAR T therapies, are successful in treating hematologic malignancies. CAR T cells, which specifically target the B-cell surface antigen CD19, have demonstrated remarkable efficacy in the treatment of B-cell acute leukemia, and some progress has been made in the treatment of other hematologic malignancies. However, the development of CAR T-cell immunotherapy targeting T-cell malignancies appears more challenging due to the potential risks of fratricide, T-cell aplasia, immunosuppression, and product contamination. In this review, we discuss the current status of and challenges related to CAR T-cell immunotherapy for T-ALL and review potential strategies to overcome these limitations.

Notch Partners in the Long Journey of T-ALL Pathogenesis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease that arises from the oncogenic transformation of developing T cells during T-lymphopoiesis. Although T-ALL prognosis has improved markedly in recent years, relapsing and refractory patients with dismal outcomes still represent a major clinical issue. Consequently, understanding the pathological mechanisms that lead to the appearance of this malignancy and developing novel and more effective targeted therapies is an urgent need. Since the discovery in 2004 that a major proportion of T-ALL patients carry activating mutations that turn

Combined BCL-2 and PI3KAKT Pathway Inhibition in

Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with

Do CAR-T and Allogeneic Stem Cell Transplant Both Have a Place in Lymphoid Neoplasms

Allogeneic stem cell transplantation (allo-SCT) represented the first immunotherapy to treat hematologic malignancies it has been considered as a cure for the disease and never as an approach to extend the life of patients. The success of allo-SCT derives both from the ability to treat patients with intensive chemoradiotherapy and from the potent graft-versus-leukemia effects mediated by donor immunity. Although considerable progress has been made in the last years, significant barriers still remain in the form of disease relapse, graft-versus-host disease, infectious complications, and regimen-related toxicities. Moreover, the treatment of hematologic malignancies, particularly acute lymphoblastic leukemia and certain forms of lymphomas, has been revolutionized by the commercial introduction of genetically modified autologous T-lymphocyte therapy (CAR-T). Our review discusses current standards and the shifting paradigms in the indications for allo-SCT and the role of CAR-T cell therapy for lymphoid neoplasms.

A Novel Form of Arginine-Chitosan as Nanoparticles Efficient for siRNA Delivery into Mouse Leukemia Cells.

The modification of chitosan (CS) has greatly expanded its application in the field of medicine. In this study, low-molecular-weight chitosan was modified with arginine (Arg) by a simple method. The identification by the Fourier transform infrared spectra (FTIR) showed that Arg was successfully covalently attached to the CS. Interestingly, Arg-CS was identified as nanoparticles by atomic force microscopy (AFM) and transmission electron microscopy (TEM), whose particle size was 75.76 ± 12.07 nm based on Dynamic Light Scattering (DLS) characterization. Then, whether the prepared Arg-CS nanoparticles could encapsulate and deliver siRNA safely was investigated. Arg-CS was found to be able to encapsulate siRNAs in vitro via electrostatic interaction with siRNA the Arg-CSsiRNA complex was safe for L1210 leukemia cells. Therefore, modification of chitosan by Arg produces novel nanoparticles to deliver siRNA into leukemia cells. This is the first time to identify Arg-CS as nanoparticles and explore their ability to deliver

Prognostic Role of CD200 in Acute Lymphoblastic Leukemia Patients.

Overexpression of CD200 in ALL patients indicates that it may be useful in the characterization of leukemia initiating cells (LIC). We aim at investigating the expression pattern of CD200 on leukemic B cells and the correlation of CD200 expression with various clinical and laboratory findings in 62 newly diagnosed acute lymphoblastic leukemia patients. All patients were subjected to full history taking, a thorough clinical examination, and laboratory investigations, which included complete blood count (CBC), BM aspiration, immunophenotyping of blast cells, and CD200 expression. There is a higher statistically significant mean value of CD200 expression among the cases (66.15 ± 23.08) than the control group (0.37 ± 0.2) ( This study showed that CD200 expression was expressed in 100% of the patients. Correlations between CD200 expression and different laboratory data of patients revealed that there was an impact of CD200 on different diagnostic findings. After the follow-up of the patients, we found that the use of PRISM function of the software could add value to the detection of minimal residual disease.

Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo.

The anticancer activity of Curaxin CBL0137, a DNA-binding small molecule with chromatin remodulating effect, has been demonstrated in different cancers. Herein, a comparative evaluation of CBL0137 activity was performed in respect to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia and multiple myeloma (MM) cultured in vitro. MTT assay showed AML and MM higher sensitivity to CBL0137s cytostatic effect comparatively to other hematological malignancy cells. Flow cytometry cell cycle analysis revealed an increase in subG1 and G2M populations after CBL0137 cell treatment, but the prevalent type of arrest varied. Apoptosis activation by CBL0137 measured by Annexin-VPI dual staining was more active in AML and MM cells. RT2 PCR array showed that changes caused by CBL0137 in signaling pathways involved in cancer pathogenesis were more intensive in AML and MM cells. On the murine model of AML WEHI-3, CBL0137 showed significant anticancer effects in vivo, which were evaluated by corresponding changes in spleen and liver. Thus, more pronounced anticancer effects of CBL0137 in vitro were observed in respect to AML and MM. Experiments in vivo also indicated the perspective of CBL0137 use for AML treatment. This in accordance with the frontline treatment approach in AML using epigenetic drugs.

Dexamethasone-Induced Fatty Acid Oxidation and AutophagyMitophagy Are Essential for T-ALL Glucocorticoid Resistance.

ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study analyzed the effects of Dex, one of the main GCs used in ALL treatment, on two T-ALL cell lines resistant Jurkat and unselected CCRF-CEM, representing a mixture of sensitive and resistant clones. In addition to nuclear targeting, we observed a massive accumulation of Dex in mitochondria. Dex-treated leukemic cells suffered metabolic reprogramming from glycolysis and glutaminolysis towards lipolysis and increased FAO, along with increased membrane polarization and ROS production. Dex provoked mitochondrial fragmentation and induced autophagymitophagy. Mitophagy preceded cell death in susceptible populations of CCRF-CEM cells while serving as a pro-survival mechanism in resistant Jurkat. Accordingly, preventing FAO or autophagy greatly increased the Dex cytotoxicity and overcame GC resistance. Dex acted synergistically with mitochondria-targeted drugs, curcumin, and cannabidiol. Collectively, our data suggest that GCs treatment should not be neglected even in apparently GC-resistant clinical cases. Co-administration of drugs targeting mitochondria, FAO, or autophagy can help to overcome GC resistance.

The Importance of Selected Dysregulated microRNAs in Diagnosis and Prognosis of Childhood B-Cell Precursor Acute Lymphoblastic Leukemia.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a frequent type of childhood hematological malignancy. The disease is classified into several subtypes according to genetic abnormalities. MicroRNAs (miRNAs) are involved in pathological processes (e.g., proliferation, apoptosis, differentiation). A miRNA is a group of short non-coding RNAs with relevant regulatory effects on gene expression achieved by suppression of the translation or degradation of messenger RNA (mRNA). These molecules act as tumor suppressors andor oncogenes in the pathogenesis of pediatric leukemias. The characteristic features of miRNAs are their stable form and the possibility of secretion to the circulatory system. The role of miRNA in BCP-ALL pathogenesis is still emerging, but several studies have suggested using miRNA expression profiles as biomarkers for diagnosis, prognosis, and response to therapy in leukemia. The dysregulation of some miRNAs involved in childhood acute lymphoid leukemia, such as miR-155, miR-200c, miR-100, miR-181a, miR125b, and miR146a is discussed, showing their possible employment as therapeutic targets. In the current review, the capabilities of miRNAs in non-invasive diagnostics and their prognostic potential as biomarkers are presented.

Optimizing Molecular Minimal Residual Disease Analysis in Adult Acute Lymphoblastic Leukemia.

Minimalmeasurable residual disease (MRD) evaluation has resulted in a fundamental instrument to guide patient management in acute lymphoblastic leukemia (ALL). From a methodological standpoint, MRD is defined as any approach aimed at detecting and possibly quantifying residual neoplastic cells beyond the sensitivity level of cytomorphology. The molecular methods to study MRD in ALL are polymerase chain reaction (PCR) amplification-based approaches and are the most standardized techniques. However, there are some limitations, and emerging technologies, such as digital droplet PCR (ddPCR) and next-generation sequencing (NGS), seem to have advantages that could improve MRD analysis in ALL patients. Furthermore, other blood components, namely cell-free DNA (cfDNA), appear promising and are also being investigated for their potential role in monitoring tumor burden and response to treatment in hematologic malignancies. Based on the review of the literature and on our own data, we hereby discuss how emerging molecular technologies are helping to refine the molecular monitoring of MRD in ALL and may help to overcome some of the limitations of standard approaches, providing a benefit for the care of patients.

Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia.

A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q del(6q) as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3PBX1 and ETV6RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID

Prevalence and risk factors of disseminated intravascular coagulation in childhood acute lymphoblastic leukemia.

Few studies have examined disseminated intravascular coagulation (DIC) in childhood acute lymphoblastic leukemia (ALL). Our aims were to evaluate the prevalence, risk factors and outcomes of DIC at ALL presentation and during induction chemotherapy. The medical records of ALL patients aged <15 years were retrospectively reviewed. Logistic regression analysis was used to identify risk factors. The Kaplan-Meier method was used to depict survival. Of the 312 patients, 48 (15.4%) and 76 (24.4%) had DIC at presentation and during induction chemotherapy, respectively. Risk factors for DIC at presentation (OR and 95% CI) were antibiotics prior to admission 2.34 (1.17-4.89), white blood cell count ≥100 × 10 Antibiotics prior to admission, hyperleukocytosis, thrombocytopenia and high NCI risk were risk factors of DIC at presentation. Antibiotics prior to admission, high peripheral blasts and transaminitis were risk factors of DIC during induction chemotherapy. There are only two studies, both published before 2000, evaluating risk factors of DIC in pediatric ALL patients without reporting outcomes. DIC was associated with lower remission and survival rates in pediatric ALL patients. We identified the risk factors of DIC at presentation as antibiotics prior to admission, hyperleukocytosis, thrombocytopenia and high NCI risk. The risk factors of DIC during induction chemotherapy were antibiotics prior to admission, high peripheral blasts and aspartate transaminitis. Pediatric ALL patients who have the aforementioned risk factors should be closely monitored for DIC secondary to infection, and early treatment with appropriate antimicrobial agents is recommended.

6-mercaptopurine (6-MP) is a key component in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). Recent next-generation sequencing analysis of childhood ALL clarified the emergence of the relapse-specific mutations of the

Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer.

For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking. Within the Childrens Oncology Group and the Dana Farber Cancer Institutes Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mgm From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed cumulative doxorubicin dose 297 ± 91 mgm Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.

Adherence to Oral Chemotherapy in Acute Lymphoblastic Leukemia during Maintenance Therapy in Children, Adolescents, and Young Adults A Systematic Review.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. Treatment is long and involves 2-3 years of a prolonged maintenance phase composed of oral chemotherapies. Adherence to these medications is critical to achieving good outcomes. However, adherence is difficult to determine, as there is currently no consensus on measures of adherence or criteria to determine nonadherence. Furthermore, there have been few studies in pediatric B-ALL describing factors associated with nonadherence. Thus, we performed a systematic review of literature on oral chemotherapy adherence during maintenance therapy in ALL following PRISMA guidelines. Published studies demonstrated various objective and subjective methods of assessing adherence without generalizable definitions of nonadherence. However, the results of these studies suggested that nonadherence to oral maintenance chemotherapy was associated with increased risk of relapse. Future studies of B-ALL therapy should utilize a uniform assessment of adherence and definitions of nonadherence to better determine the impact of nonadherence on B-ALL outcomes and identify predictors of nonadherence that could yield targets for adherence improving interventions.

CMV reactivation after allogeneic HCT is associated with a reduced risk of relapse in acute lymphoblastic leukemia.

Cytomegalovirus reactivation (CMVR) after allogeneic hematopoietic cell transplantation (HCT) is a frequent complication related to survival outcomes, but the impact of CMVR on relapse is still unclear, especially in acute lymphoblastic leukemia (ALL). In this nationwide retrospective study, we included patients with acute myeloid leukemia (AML) and ALL in first or second complete remission who underwent their first HCT using pre-emptive strategy for CMVR. Because ninety percent of cases with CMVR had occurred by day 64 and ninety percent of cases with grades II to IV acute GVHD had occurred by day 58, a landmark point was set at day 65. In the landmark analyses, 3793 patients with AML and 2213 patients with ALL who survived without relapse for at least 65 days were analyzed. In the multivariate analyses, CMVR was associated with a lower incidence of relapse in both AML (hazard ratio HR, 0.81 95% confidence interval CI, 0.69-0.95 P 0.009) and ALL (HR, 0.81 95% CI, 0.66-0.99 P 0.045). These findings were confirmed when we treated CMVR as a time-dependent covariate. Moreover, our study suggested that the protective effect of CMVR on relapse was independent of acute GVHD. A post-hoc subgroup analysis that combined AML and ALL showed that CMVR had a mild anti-leukemia effect without effect modification in contrast to the impact of CMVR on NRM. Our findings may provide important implications for the strategy used for CMV prophylaxis after HCT.

Pattern of brexucabtagene autoleucel-related neurotoxicity on magnetic resonance imaging of the brain in a patient with relapsedrefractory B-cell acute lymphoblastic leukemia and prior leptomeningeal disease.

Immune effector cell-associated neurotoxicity syndrome (ICANS) secondary to chimeric antigen receptor T-cell therapy is common in adult patients with relapsedrefractory (RR) B-cell acute lymphoblastic leukemia (ALL), but imaging findings during neurologic toxicity and their meaning have yet to be systematically described in this patient population. Brexucabtagene autoleucel (brexu-cel) is a CD19-directed autologous T-cell immunotherapy for the treatment of adult patients with RR B-cell ALL that can enter the central nervous system. We present a case of an adult patient with RR B-cell ALL and prior leptomeningeal disease who developed neurologic toxicity and new findings on magnetic resonance imaging of the brain while receiving brexu-cel. We interpret the patients neuroimaging studies within clinical context to differentiate ICANS from active treatment of residual leukemia.

Bimodal Age Distribution in Cancer Incidence.

Cancer is caused by accumulation of genetic changes which include activation of protooncogenes and loss of tumor suppressor genes. The age-specific incidence of cancer in general increases with advancing age. However, some cancers exhibit a bimodal distribution. Commonly recognized cancers with bimodal age distribution include acute lymphoblastic leukemia, osteosarcoma, Hodgkins lymphoma, germ cell tumors and breast cancer. Delayed infection hypothesis has been used to provide explanation for the early childhood peak in leukemias and lymphomas, whereas the peak at an older age is associated with accumulation of protooncogenes and weakened immune system. Further genetic analysis and histopathological variations point to distinctly different cancers, varying genetically and histologically, which are often combined under a single category of cancers. Tumor characteristics and age distribution of these cancers varies also by population groups and has further implications on cancer screening methods. Although significant advances have been made to explain the bimodal nature of such cancers, the specific genetic mechanisms for each age distribution remain to be elucidated. Further distinction among the different cancer subtypes may lead to improvements in individual risk assessments, prevention and enhancement of treatment strategies.

Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia.

Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies. Using current techniques, accurate detection of such aberrations can be challenging, due to the rapidly expanding list of key genetic abnormalities. Whole genome sequencing (WGS) has the potential to improve genetic testing, but requires comprehensive validation. We performed WGS on 210 childhood B-ALL samples annotated with clinical and genetic data. We devised a molecular classification system to subtype these patients based on identification of key genetic changes in tumour-normal and tumour-only analyses. This approach detected 294 subtype-defining genetic abnormalities in 96% (202210) patients. Novel genetic variants, including fusions involving genes in the MAP kinase pathway, were identified. WGS results were concordant with standard-of-care methods and whole transcriptome sequencing (WTS). We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6RUNX1-like subtypes. Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r) a good-risk B-ALL subtype with high survival rates. Overall, we have validated that WGS provides a standalone, reliable genetic test to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for the risk-directed treatment stratification, while simultaneously performing as a research tool to identify novel disease biomarkers.

Clinical significance of EVI-1 gene expression and aberrations in patient with de-novo acute myeloid and acute lymphoid leukemia.

Acute leukemia is a common health problem in adults and children, however its exact molecular etiology is still unclear. The expression of EVI-1 was assessed in the bone marrow of 178 de-novo acute leukemia patients (101 AML, 71 ALL and 6 MPAL), compared to 40 control subjects. EVI-1 gene aberrations were also assessed in 69 AML patients using Fluorescence in situ hybridization (FISH) technique. The expression of EVI-1 was significantly lower in ALL patients compared to control 0.177 (0.002-15.189) vs 0.953 (0.179-1.68) respectively, P 0.009. There was no significant difference between AML patients and control group 0.150 (0.0-641) vs 0.953 (0.179-1.68) respectively, P 0.082. The sensitivity, specificity, AUC of EVI-1 in ALL were (80.3 %, 60 % and 0.778 respectively, P 0.009), and (67.3 %, 60 %, 0.667 respectively P 0.082) in AML patients. One patient showed EVI-1 gene rearrangement in a complex karyotype and four patients showed EVI-1 amplification in hyperdiploid karyotypes. All patients with BCR-ABL fusion were EVI-1 over-expressers (P 0.010). AML patients with EVI-1 low expression were positively associated with t(821)(q22q22)RUNX1RUNX1T1 fusion, favorable recurrent translocation, and low genetic risk (P 0.037, P 0.023, and P 0.013 respectively). There was a significant association between low EVI-1 expression and prolonged overall survival (OS) in AML patients, while there was no significant association with the disease-free survival (DFS) (P 0.048 and P 0.419). There was no significant impact of EVI-1 expression on OS and DFS rates in ALL patients. EVI-1 expression could be a helpful diagnostic, prognostic, and predictive biomarker for acute leukemia especially in AML.

Exploring the pharmacological mechanisms of Shuanghuanglian against T-cell acute lymphoblastic leukaemia through network pharmacology combined with molecular docking and experimental validation.

Due to the poor prognosis of T-cell acute lymphoblastic leukaemia (T-ALL), there is an urgent need to identify safer and more cost-effective drugs. This study evaluated the antitumour activity of Shuanghuanglian (SHL) on T-ALL cells and elucidated the mechanism. Jurkat and Molt4 cells were treated with SHL (0.1, 0.2 and 0.4 mgmL) for 24 and 48 h. The controls were treated with RPMI 1640 containing 10% foetal bovine serum. Cell viability was evaluated through Cell Counting Kit-8 assay. Patterns of death and signalling pathway alterations caused by SHL were identified by network pharmacology combined with GO enrichment analysis and then were verified by Hoechst 33342 staining, Annexin V-FITCPI staining and Western blotting. Interactions of the active ingredients with targets were analysed by molecular docking. The IC

Lineage switch of acute myeloid leukemia to T-Cell acute lymphoblastic leukemia - A unique case report.

Lineage switch is term described when leukemic cells on relapse exhibit a new phenotype, where losses of one lineage defining markers with simultaneous gain of another lineage defining markers occur. Relapse of acute leukemia is although a very common event, lineage switch occurs and reported very rarely in such cases. The pathogenesis involved in this phenomenon remains unclear however plasticity of hematopoietic progenitor affected by intrinsic and extrinsic environmental cues can be a possible explanation. In most of the cases at the time of relapse conversion of B-acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) occurs. Here, we presented an unusual case of 10 year old boy with AML switched to T-ALL upon relapse, which is very rare and not well documented till date in literature. The diagnosis was further supported by morphologic, cytochemistry and flowcytometric immunophenotyping (FCM-IPT). Prognosis and survival of such cases remains poor even by the use of standard chemotherapy.

Influence of E-cadherin methylation on prognosis in children with acute lymphoblastic leukemia.

To study the significance of E-cadherin and the association between E-cadherin methylation status and prognosis in children with acute lymphoblastic leukemia (ALL) by examining the mRNA and protein expression of E-cadherin and its gene methylation status in bone marrow mononuclear cells of children with ALL. The samples of 5 mL bone marrow blood were collected from 42 children with ALL who were diagnosed for the first time at diagnosis (pre-treatment group) and on day 33 of induction chemotherapy (post-treatment group). RT-qPCR, Western blot, and methylation-specific PCR were used to measure the mRNA and protein expression of E-cadherin and the methylation level of the The mRNA and protein expression levels of E-cadherin in the post-treatment group were significantly higher than those in the pre-treatment group ( E-cadherin expression is associated with the development of ALL in children, and its decreased expression and increased methylation level may indicate a poor prognosis.

Clinical features and prognosis of high hyperdiploid childhood acute lymphoblastic leukemia a multicenter retrospective analysis in Fujian Province, China.

To study the clinical features and prognosis of high hyperdiploid (HHD) childhood acute lymphoblastic leukemia (ALL). A retrospective analysis was performed on the medical data of 1 414 children who were newly diagnosed with ALL and were admitted to five hospitals in Fujian Province of China from April 2011 to December 2020. According to karyotype, they were divided into two groups HHD ( Among the 1 414 children with ALL, 172 (12.16%) had HHD. Compared with the non-HHD group, the HHD group had significantly lower proportions of children with risk factors for poor prognosis at diagnosis (age of onset ≥10 years or <1 year, white blood cell count ≥50×10 The ALL children with HHD have few risk factors for poor prognosis at diagnosis and often have good prognosis. The number of chromosomes and trisomy of specific chromosomes are associated with prognosis in these children.

TIM3, a human acute myeloid leukemia stem cell marker, does not enrich for leukemia-initiating stem cells in B-cell acute lymphoblastic leukemia.

Not available.

The Successful Implementation of a Modified Pediatric Acute Lymphoblastic Leukemia Protocol to Treat an Elderly Patient With T-cell Lymphoblastic Leukemia A Case Report.

Acute lymphoblastic leukemia (ALL) is a group of hematological malignancies most commonly seen in pediatrics. The disease process localizes in lymphoid organs, the central nervous system, the mediastinum, and bone marrow (BM). The clinical features of T-cell acute lymphoblastic leukemia (T-ALL) in adults include evidence of generalized lymphadenopathy, hepatosplenomegaly, immunosuppression, and hypercalcemia. There is limited research on the efficacy of using modified pediatric treatment regimens in the elderly over the age of 60 with ALL this case report aims to illustrate the successful treatment of a 67-year-old male patient diagnosed with T-ALL, using a modified Childrens Oncology Group (COG) protocol. Through this, it has been shown to be an effective, safe, and efficacious treatment option for our patient.

Comprehensive molecular understanding of pediatric acute myeloid leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with various genetic abnormalities. Recent advances in genetic analysis have enabled the identification of causative genes in > 90% of pediatric AML cases. Fusion genes such as RUNX1RUNX1T1, CBFBMYH11, and KMT2AMLLT3 are frequently detected in > 70% of pediatric AML cases, whereas FLT3-internal tandem duplication, CEBPA-bZip, and NPM1 mutations are detected in approximately 5-15% of cases, respectively. Conversely, mutations in DNMT3A, TET2, and IDH, which are common in adults, are extremely rare in pediatric AML. The genetic characteristics of pediatric AML are slightly different from those of adult AML. For accurate risk stratification and treatment intensity, genome analysis should be performed in a simple, fast, and inexpensive manner and the results should be returned to patients in real time. As with acute lymphoblastic leukemia, the presence or absence of minimal residual disease is an important factor in determining the success of treatment against AML, and it is important to predict prognosis and formulate treatment strategies considering the genetic abnormalities. For the development and clinical application of new molecularly targeted therapies based on identified genetic abnormalities, it is necessary to explore when and in which combinations drugs will be most effective.

FAT1 expression in T-cell acute lymphoblastic leukemia (T-ALL) modulates proliferation and WNT signaling.

FAT atypical cadherin 1 (FAT1), a transmembrane protein, is frequently mutated in various cancer types and has been described as context-dependent tumor suppressor or oncogene. The FAT1 gene is mutated in 12-16% of T-cell acute leukemia (T-ALL) and aberrantly expressed in about 54% of T-ALL cases contrasted with absent expression in normal T-cells. Here, we characterized FAT1 expression and profiled the methylation status from T-ALL patients. In our T-ALL cohort, 53% of patient samples were FAT1 positive (FAT1pos) compared to only 16% FAT1 positivity in early T-ALL patient samples. Aberrant expression of FAT1 was strongly associated with FAT1 promotor hypomethylation, yet a subset, mainly consisting of TLX1-driven T-ALL patient samples showed methylation-independent high FAT1 expression. Genes correlating with FAT1 expression revealed enrichment in WNT signaling genes representing the most enriched single pathway. FAT1 knockdown or knockout led to impaired proliferation and downregulation of WNT pathway target genes (CCND1, MYC, LEF1), while FAT1 overexpressing conveyed a proliferative advantage. To conclude, we characterized a subtype pattern of FAT1 gene expression in adult T-ALL patients correlating with promotor methylation status. FAT1 dependent proliferation and WNT signaling discloses an impact on deeper understanding of T-ALL leukemogenesis as a fundament for prospective therapeutic strategies.

Isolated central nervous system relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia during ponatinib maintenance therapy.

A 65-year-old man was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia with no initial central nervous system (CNS) involvement. Complete remission was achieved after the induction therapy. However, during consolidation therapy, he developed septic shock and pneumocystis pneumonia, leading to interruption in chemotherapy and allogeneic transplantation. Subsequently, he achieved complete molecular remission and ponatinib maintenance therapy was initiated. Two years later, he developed left leg paralysis and was diagnosed with isolated CNS relapse however, radiation therapy improved CNS lesions and paralysis. Thus, ponatinib maintenance therapy alone is inadequate in preventing CNS relapse in patients who have not completed systemic chemotherapy for CNS relapse prevention.

Microphysiological Drug-Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia.

Despite increasing survival rates of pediatric leukemia patients over the past decades, the outcome of some leukemia subtypes has remained dismal. Drug sensitivity and resistance testing on patient-derived leukemia samples provide important information to tailor treatments for high-risk patients. However, currently used well-based drug screening platforms have limitations in predicting the effects of prodrugs, a class of therapeutics that require metabolic activation to become effective. To address this issue, a microphysiological drug-testing platform is developed that enables co-culturing of patient-derived leukemia cells, human bone marrow mesenchymal stromal cells, and human liver microtissues within the same microfluidic platform. This platform also enables to control the physical interaction between the diverse cell types. Herein, it is made possible to recapitulate hepatic prodrug activation of ifosfamide in their platform, which is very difficult in traditional well-based assays. By testing the susceptibility of primary patient-derived leukemia samples to the prodrug ifosfamide, sample-specific sensitivities to ifosfamide in primary leukemia samples are identified. The microfluidic platform is found to enable the recapitulation of physiologically relevant conditions and the testing of prodrugs including short-lived and unstable metabolites. The platform holds great potential for clinical translation and precision chemotherapy selection.

Harnessing the MYB-dependent TAL1 5super-enhancer for targeted therapy in T-ALL.

The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5super-enhancer (5SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy.

Experience Caring for an Acute Lymphoblastic Leukemia Patient With COVID-19 in the ICU.

This article describes the authors experience providing care in the ICU to a patient with acute lymphoblastic leukemia who had contracted COVID-19. The period of care spanned from June 29 to July 12, 2021. Data were collected during direct care, observations, and interviews and using medical record reviews. During the course of care, supportive care, bundle care, and other infection control measures were provided. The patient was monitored and tracked regularly for infection-related indicators, which successfully mitigated the impact of the infection and prevented secondary bacterial infections. Respiratory care measures such as assistance with Q3H awake prone positioning on the bed were provided. Also, the safety and smoothness of the ventilator pipeline and catheter when prone were confirmed and the setting of the ventilator was adjusted based on the blood oxygen concentration and gas analysis. These measures improved the patients oxygenation, allowing their successful removal from the ventilator. Delayed chemotherapy affects the survival rate of patients with acute lymphoblastic leukemia as well as improves their physical and emotional status. Using patient-centered communication skills, empathizing with the patients negative feelings, encouraging and assisting their participation in self-care, and helping facilitate prescribed hematologist-oncologist care, the author helped increase the patients perceived self-control and positive attitudes and effectively alleviated their hopelessness regarding their current situation. Several recommendations arise from this care experience. Social media apps may be used to create virtual support groups for patients comprising significant relatives and friends to better support patients in quarantine. Also, a health education brochure addressing the latest COVID-19 disease, treatment, and care information may be given to patients with COVID-19 upon hospital admission to reduce their uncertainties and improve their self-care awareness to maximize their ability to successfully navigate the long quarantine treatment process. 照顧一位急性淋巴性白血病確診COVID-19病人之加護經驗. 本文為照護一位急性淋巴性白血病病人確診COVID-19之加護經驗。照護期間為2021年6月29日至7月12日，以直接照護、觀察、訪談及病歷查閱等方式收集資料，確認個案有感染、氣體交換障礙及無望感之健康問題。照護期間，提供支持性及組合式照護等感染控制措施，定期監測及追蹤感染相關指標，成功緩解現存感染及預防繼發性細菌感染；協助個案執行清醒俯臥治療，確認俯臥時呼吸器管路及導管之安全性及暢通性、依據血氧濃度及氣體分析調整呼吸器設定等呼吸照護措施，使個案氧合情形獲得改善並成功脫離呼吸器；延誤化療除影響急性淋巴性白血病存活率，更對病人身心造成巨大衝擊，利用以病人為中心溝通技巧，同理負向感受，鼓勵及協助參與自我照顧，協助照會血液腫瘤科醫師，提供清楚資訊，增進其自我控制感及正向態度，有效緩解個案對現況之無望感受。經由此照護經驗，建議利用社群軟體協助建立重要關係人群組，使隔離中的病人得到更好的家庭支持，建議於清醒COVID-19病人入院治療時，給予「COVID-19最新治療與照護資訊」相關的衛教手冊，透過清楚詳細的資訊，減輕此類病人的不確定感、增進自我照護認知，以順利度過漫長的隔離治療過程。.

Outcomes of Philadelphia Positive Acute Lymphoblastic Leukemia in Adolescent and Young Adults.

Background Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) accounts for 25% of acute lymphoblastic leukemia cases in the adolescent and young adult (AYA) age subgroup. It is associated with poor outcomes and is considered a standard indication for allogeneic stem cell transplant (Allo-SCT). Improved outcomes have been reported with addition of tyrosine kinase inhibitors (TKIs) to chemotherapy in children and the role of Allo-SCT is now being debated in the first remission. Complete response (CR) at three months is associated with improved survival even without Allo-SCT in first CR. In this study, we have analyzed disease-free survival (DFS), overall survival (OS), and factors affecting survival outcomes of Ph ALL in the AYA subgroup, in resource-limited settings treated with chemotherapy and TKIs. Materials and methods This is a retrospective, multicenter cohort study of Ph ALL AYA patients, aged 18-40 years, and registered between January 2015 and December 2020. Primary objectives are to calculate disease-free survival (DFS) and overall survival (OS). Secondary objectives are to identify prognostic factors affecting response rates and outcomes. List of cases was obtained from hospital information system (HIS) and data were collected from patient case notes and electronic medical records. Data analysis was done utilizing the SPSS statistical program (Armonk, NY IBM Corp.). Results Forty-nine patients were identified with Ph ALL with a median age of 23 years (range 18-40 years) and a male-to-female ratio of 2.51. None of the patients had central nervous system (CNS) disease. White cell count was >30,000 per mm

COVID-19 infection during blinatumomab therapy Is safety a dilemma

Patients with acute lymphoblastic leukemia may be particularly vulnerable to SARS-CoV-2 infection and severe illness. The mainstay of current treatment is the use of blinatumomab in patients with refractory or relapsed B-cell precursor acute lymphoblastic leukemia. We discuss the case of a patient with relapsed acute lymphoblastic leukemia who became positive for SARS-CoV-2 during blinatumomab therapy. There are no formal recommendations on the decision to continue, withhold, or delay blinatumomab treatment in these patients. More studies exploring this issue are warranted, as SARS-CoV-2 is expected to be here to stay.

The prognostic significance of

The prognostic significance of cytokine receptor like factor 2 (

SOHO State of the Art Updates and Next Questions Optimal Timing of Blinatumomab for the Treatment of B-Acute Lymphoblastic Leukemia.

Blinatumomab is a CD19 targeting bi-specific T-cell engager antibody construct developed for the treatment of CD19 expressing B-cell malignancies. Numerous adult and pediatric B-ALL clinical trials have demonstrated blinatumomabs efficacy in the relapse setting as well as in patients with residual disease after upfront chemotherapy. The safety profile of blinatumomab is also favorable, making it a feasible option for most patients. Several key questions remain, including the role of blinatumomab as a replacement for toxic elements of standard chemotherapy regimens in the upfront setting, its role as a bridge to hematopoietic stem cell transplantation, or whether previous blinatumomab impacts the efficacy of subsequent CAR-T cell therapy.

Title Obesogenic microbial signatures and the development of obesity in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer with survival exceeding 90% for standard-risk groups. A debilitating side-effect of treatment is the development of overweightobesity (OWOB), which develops in approximately 40% of children by the end of treatment. The microbiome has been associated with the development of OWOB. We examined fluctuations in the microbiome with the development of OWOB during the first six months of treatment at diagnosis, and two subsequent timepoints (N 62). Shotgun metagenomic sequencing was performed on Illumina Nextseq system, and taxa and functional pathways were extracted from sequences using kraken2 and humann2, respectively. An association of increased presence of several species (e.g., Klebsiella pneumoniae, Escherichia coli) was observed in children with OWOB, while lean-promoting species (Veillonella, Haemophilus, and Akkermansia) were increased in children who maintained a normal weight. Pathway analysis revealed purine nucleotide biosynthesis, sugar nucleotide biosynthesis, and enzyme cofactor biosynthesis were positively correlated with Bacteroides spp. among children with OWOB. We identified several taxa and functional pathways that may confer increased risk for the development of OWOB. The associations observed in this pilot are preliminary and warrant further research in the microbiome and the development of OWOB in childhood ALL.

Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy.

Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19

MiR-128-3p as blood based liquid biopsy biomarker in childhood acute lymphoblastic leukemia.

Minimal residual disease (MRD) is one of the most valuable independent prognostic factors in acute lymphoblastic leukemia (ALL). Bone marrow (BM) aspiration, however, is an invasive process. Previous studies have shown that microRNAs (miR) and extracellular vesicle (EV)-related miRs show different expression profiles at the presence of malignant cells compared to healthy controls. In our previous project, we have reported that two miRs previously described to be overexpressed in blasts were significantly decreased over the first week of the therapy of patients with ALL in the platelet free plasma fraction (PFP) of peripheral blood samples (PB). The aim of the current study was to assess the relation between day 15 flow cytometry (FC) MRD and expression of miR-128-3p and miR-222-3p miRs in exosome-enriched fraction (EEF) of PFP to evaluate whether their expression in EEF correlates with day 15 FC MRD more precisely. PB was collected from 13 patients diagnosed with pediatric pre-B ALL at 4 time points. Expression of miR-128-3p and miR-222-3p was measured by qPCR in PFP and EEF. Positive correlation was found between changes of miR-128-3p expression in EEF or PFP by day 8 of chemotherapy and day 15 FC MRD (r Our results show that circulating miRs are potential biomarkers of ALL MRD, asmiR-128-3p level both in PFP and EEF predicts day 15 FC MRD. In addition, the assessment of the EEF gave a more promising result.

Analyzing sleep status in children with acute leukemia.

Quality sleep is essential for physical and mental health. We aimed to analyze sleep disorders in children with acute leukemia and explore associated factors. General data and sleep disorders in children with acute leukemia during chemotherapy were collected by general questionnaires, Childrens Sleep Disorders Scale and the Parenting Stress Index-short form. In total, 173 valid questionnaires were collected. The total Sleep Disorder Scale score > 39 is considered a sleep disorder, while sleep disorders accounted for 45.66% (79173). In the cohort, 167 children had acute lymphoblastic leukemia, with 40.12% (67167) having sleep disorders, while six children had acute non-lymphoblastic leukemia, with 50.00% (36) having sleep disorders. Single- and multi-factor regression analyses of age, gender, number of children in the family, and time spent using electronic devices showed that factors influencing sleep disorders in these children were mainly parental scolding and adenoid hypertrophy. Children with sleep disorders had more parental stress than those without sleep disorders (P < 0.05). The high incidence of sleep disorders in children with acute leukemia is related to airway conditions and parental behaviors. Sleep disorders in children can increase parenting stress. Factors potentially affecting sleep quality should be addressed as early as possible, while parental education should be strengthened to better facilitate the physical and psychological recovery of their children.