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The prognosis of over 90% of infant acute lymphoblastic leukemia (ALL) remains poor because of harboring the mixed-lineage leukemia gene (

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Minimal residual disease (MRD) is commonly assessed in bone marrow (BM) aspirate. However, sample quality can impair the MRD measurement, leading to underestimated residual cells and to false negative results. To define a reliable and reproducible method for the assessment of BM hemodilution, several flow cytometry (FC) strategies for hemodilution evaluation have been compared. For each BM sample, cells populations with a well-known distribution in BM and peripheral blood - e.g., mast cells (MC), immature (IG) and mature granulocytes (N) - have been studied by FC and quantified alongside the BM differential count. The frequencies of cells populations were correlated to the IGN ratio, highlighting a mild correlation with MCs and erythroblasts (R0.25 and R0.38 respectively, with p-value0.0006 and 0.0000052), whereas no significant correlation was found with B or T-cells. The mild correlation between IGN, erythroblasts and MCs supported the combined use of these parameters to evaluate BM hemodilution, hence the optimization of the The high frequency of MRD-negative results in both HD and mHD samples implies the presence of possible false negative MRD measurements, impairing the correct assessment of patients response to therapy and highlighs the importance to evaluate BM hemodilution.

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma.

Autologous T cells expressing the Chimeric Antigen Receptor (CAR) have been approved as advanced therapy medicinal products (ATMPs) against several hematological malignancies. However, the generation of patient-specific CAR-T products delays treatment and precludes standardization. Allogeneic

UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T cell progenitors. Since relapsed T-ALL is associated with a poor prognosis improving initial treatment of patients is essential to avoid resistant selection of T-ALL. During initiation, development, metastasis and even in response to chemotherapy, tumor cells face strong metabolic challenges. In this study, we identify mitochondrial UnCoupling Protein 2 (UCP2) as a tricarboxylic acid (TCA) cycle metabolite transporter controlling glutamine metabolism associated with T-ALL cell proliferation. In T-ALL cell lines, we show that UCP2 expression is controlled by glutamine metabolism and is essential for their proliferation. Our data show that T-ALL cell lines differ in their substrate dependency and their energetic metabolism (glycolysis and oxidative). Thus, while UCP2 silencing decreases cell proliferation in all leukemia cells, it also alters mitochondrial respiration of T-ALL cells relying on glutamine-dependent oxidative metabolism by rewiring their cellular metabolism to glycolysis. In this context, the function of UCP2 in the metabolite export of malate enables appropriate TCA cycle to provide building blocks such as lipids for cell growth and mitochondrial respiration. Therefore, interfering with UCP2 function can be considered as an interesting strategy to decrease metabolic efficiency and proliferation rate of leukemia cells.

Tyrosine Kinase Inhibitors for Pediatric Leukemia History and Current Status.

Tyrosine kinase inhibitors (TKIs) block the activity of tyrosine kinases by competitive inhibition of ATP at the catalytic tyrosine kinase binding site and inhibit oncogenic signaling. One important target of TKIs is BCR-ABL1, which is constitutively activated in leukemia cells. In this review, we briefly describe the development of TKIs from the first generation to the third generation, and summarize their use in the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia in children. We highlight several future directions in the development of TKIs for pediatric leukemia therapy. In conclusion, we focus on chronic myeloid leukemia and acute lymphoblastic leukemia as the examples of pediatric blood cancer that significantly benefit from TKIs-based target therapy. Further development of TKIs will allow us to better manage pediatric leukemia.

Mapping the genetic features of T-ALL cases through simplified NGS approach.

Despite the irruption of massive sequencing technologies in clinical routine, the genetic diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) continues to be based on traditional techniques. The integration of old and new technologies with diagnostic and prognostic purposes represents a major challenge. A High-Throughput Sequencing (HTS) approach was applied to analyze the genetic landscape of two patients diagnosed with T-ALL and one early T cell precursor acute leukemia. Orthogonal standard techniques were used to confirm the findings of NGS analysis. By using a single test, a complete genetic map including 2 previously unreported missense mutations in BCL11B gene are reported. Cooperating oncogenic lesions including CDKN2AB deletions, SIL-TAL1 rearrangement and FLT3 amplification were also captured by using a single test. HTS is a useful approach that allows simultaneously analyzing mutations, CNVs and the clonal repertoire in T-ALL patients. This approach may simplify the genetic assessment of ALL.

The impact of early PEG-asparaginase discontinuation in young adults with ALL a post hoc analysis of the CALGB 10403 study.

Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, a similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup Cancer and Leukemia Group B (CALGB) 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as <4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range, 1-6), with 57 (32%) patients with ED. The ED patients were older (median, 26 vs 23 years P .023). Survival was apparently lower for ED patients compared with those receiving ≥4 doses, but this finding was not statistically significant (hazard ratio HR, 1.82 95% confidence interval CI, 0.97-3.43 P .06), with corresponding 5-year overall survival (OS) rates of 66% and 80%, respectively. In patients with standard-risk ALL, the ED of PEG-asparaginase adversely influenced OS (HR, 2.3 95% CI, 1.02-5.22 P .04) with a trend toward inferior event-free survival (EFS) (HR, 1.84 95% CI, 0.92-3.67 P .08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P .64) or EFS (P .32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, andor high white blood cell count at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL.

Cost-effectiveness Analysis of Tisagenlecleucel Versus Blinatumomab in Children and Young Adults with Acute Lymphoblastic Leukemia Partitioned Survival Model to Assess the Impact of an Outcome-Based Payment Arrangement.

This research assesses the impact of an outcome-based payment arrangement (OBA) linking complete remission (CR) to survival as a means of maintaining cost-effectiveness for a chimeric antigen receptor T cell (CAR-T) therapy in young patients with acute lymphoblastic leukemia (ALL). A partitioned survival model (PSM) was used to model the cost-effectiveness of tisagenlecleucel versus blinatumomab in ALL from the Australian healthcare system perspective. A decision tree modeled different OBAs by funneling patients into a series of PSMs based on response. Outcomes were informed by individual patient data, while costs followed Australian treatment practices. Costs and quality-adjusted life years (QALYs) were combined to calculate a single incremental cost-effectiveness ratio (ICER), reported in US dollars (2022) at a discount rate of 5% on costs and outcomes. For the base case, incremental costs and benefit were $379,595 and 4.27 QALYs, giving an ICER of $88,979. The ICER was most sensitive to discount rate ($57,660-$75,081), cure point ($62,718-$116,206) and extrapolation method ($76,018-$94,049). OBAs had a modest effect on the ICER when response rates varied. A responder-only payment was the most effective arrangement for maintaining the ICER ($88,249-$89,434), although this option was associated with the greatest financial uncertainty. A split payment arrangement (payment on infusion followed by payment on response) reduced variability in the ICER ($82,650-$99,154) compared with a single, upfront payment ($77,599-$107,273). OBAs had a modest impact on reducing cost-effectiveness uncertainty. The value of OBAs should be weighed against the additional resources needed to administer such arrangements, and importantly overall cost to government.

Central nervous system involvement in childhood acute lymphoblastic leukemia challenges and solutions.

Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2-3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear - we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase III trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.

Hyperdiploidy the longest known, most prevalent, and most enigmatic form of acute lymphoblastic leukemia in children.

Hyperdiploidy is the largest genetic entity B-cell precursor acute lymphoblastic leukemia in children. The diagnostic hallmark of its two variants that will be discussed in detail herein is a chromosome count between 52 and 67, respectively. The classical HD form consists of heterozygous di-, tri-, and tetrasomies, whereas the nonclassical one (usually viewed as duplicated hyperhaploid) contains only disomies and tetrasomies. Despite their apparently different clinical behavior, we show that these two sub-forms can in principle be produced by the same chromosomal maldistribution mechanism. Moreover, their respective array, gene expression, and mutation patterns also indicate that they are biologically more similar than hitherto appreciated. Even though in-depth analyses of the genomic intricacies of classical HD leukemias are indispensable for the elucidation of the disease process, the ensuing results play at present surprisingly little role in treatment stratification, a fact that can be attributed to the overall good prognoses and low relapse rates of the concerned patients and, consequently, their excellent treatment outcome. Irrespective of this underutilization, however, the detailed genetic characterization of HD leukemias may, especially in planned treatment reduction trials, eventually become important for further treatment stratification, patient management, and the clinical elucidation of outcome data. It should therefore become an integral part of all upcoming treatment studies.

Clinical features and outcomes of children admitted to the pediatric intensive care unit due to posterior reversible encephalopathy syndrome.

The aim of this study is to analyze the clinical features, neuroimaging findings and outcomes of the children admitted to our tertiary pediatric intensive care unit (PICU) due to posterior reversible encephalopathy syndrome (PRES). This was a retrospective study where the hospital records of children admitted to PICU due to PRES between January 1, 2011 and January 1, 2021 were reviewed. We enrolled 14 patients with a median age of 8 years (IQR 2.2-14.2) to study. Eight (57 %) patients were male. All patients had comorbid illnesses such as hemophagocytic lymphohistiocytosis in 3, Β-cell acute lymphoblastic leukemia in 2, and different diagnosis in other patients as one one. Three patients had cardiac arrest, 9 patients had seizures, 5 patients had SE, 12 patients had altered mental status, 8 patients had hypertensive crisis, 1 patient had visual impairment. Thirteen patients had occipital involvement, 11 had parietal involvement, 4 had temporal involvement, 1 had thalamic involvement, 2 had cerebellar involvement, 1 had involvement of the corpus callosum, 1 had brainstem involvement, 1 had hippocampus involvement and 1 had involvement of the basal ganglia. Fourteen patients had supratentorial involvement while 3 had infratentorial involvement. Electroencephalogram was performed for 7 patients, out of which 6 revealed encephalopathy. Median PICU LOS was 19.5 days (IQR 13.2-49.2, minimum 2 - maximum 84 days). Five patients had neurologic sequelae. Four (28.5 %) patients died and ten patients survived. Co-occurence of hypertension and seizures should prompt consideration of PRES and urgent neuroimaging, particularly in patients on immunosuppressants or chemotherapeutics. Hypertension should be addressed aggressively in patients with PRES. Electroencephalographic monitoring should be performed if there is suspicion of SE or nonconvulsive SE. Despite its usually good prognosis, PRES can cause serious morbidity and mortality with delay in diagnosis or treatment.

Comparative analysis of the variability of the human leukocyte antigen peptide-binding pockets in patients with acute leukaemia.

The association between acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) and the human leukocyte antigens (HLA) has rarely been studied in terms of diversity of peptide-binding pockets. The objective of this study was to analyse whether motifs of HLA class I and class II peptide-binding pockets andor their amino acid positions were differentially associated with ALL and AML. We included 849 patients from the EurocordEuropean Blood and Marrow Transplant registry. The HLA peptide-binding pockets whose amino acid variability was analysed were B and F for HLA class I, P4, P6, and P9 for HLA-DRB1, and P4 and P9 for HLA-DQB1. The motif RFDRAY in P4 of HLA-DRB11601020305 alleles and the motif YYVSY in P9 of HLA-DQB105020405 alleles, were statistically associated with ALL (corrected p value p

Three-year results from phase I of ZUMA-4 KTE-X19 in pediatric relapsedrefractory acute lymphoblastic leukemia.

Here we present the 3-year results of ZUMA-4, a phase III multicenter study evaluating the safety and efficacy of KTEX19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatricadolescent patients with relapsedrefractory B-cell acute lymphoblastic leukemia. Phase I explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities. Thirty-one patients were enrolled KTE-X19 was administered to 24 patients (median age 13.5 years, range 3-20 median follow-up 36.1 months). No dose-limiting toxicities were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33% in all treated patients, 75% in patients given the dose of 2×106 CAR T cellskg, 27% in patients given the dose of 1×106 cellskg in the 68 mL formulation, and 22% in patients given the dose of 1×106 cellskg in the 40 mL formulation the percentages of patients experiencing grade ≥3 neurologic events were 21%, 25%, 27%, and 11% respectively. Overall complete remission rates (including complete remission with incomplete hematologic recovery) were 67% in all treated patients, 75% in patients given 2×106 CAR T cellskg, 64% in patients given 1×106 cellskg in the 68 mL formulation, and 67% in patients given 1×106 cellskg in the 40 mL formulation. Overall minimal residual diseasenegativity rates were 100% among responders 88% of responders underwent subsequent allogeneic stem-cell transplantation. In the 1×106 (40 mL) group (recommended phase II dose), the median duration of remission censored at allogeneic stem-cell transplantation and median overall survival were not reached. Pediatricadolescent patients with relapsedrefractory B-cell acute lymphoblastic leukemia achieved high minimal residual disease-negative remission rates with a manageable safety profile after a single dose of KTE-X19. Phase II of the study is ongoing at the dose of 1×106 CAR T cellskg in the 40 mL formulation. ClinicalTrials.gov NCT02625480.

Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation a study of the SFGM-TC.

Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic stem cell transplantation (allo-HCT) still represents a major concern with poor outcomes. The aim of this study is to compare the efficacy and safety of blinatumomab and donor lymphocyte infusion (DLI) versus blinatumomab alone in this setting. This is a multicenter retrospective study from centers of SFGM-TC. All transplanted patients who received blinatumomab salvage therapy were included. Patients who received DLI from 1 month before to 100 days after the starting of blinatumomab were included in the blina-DLI group. Seventy-two patients were included. Medium follow-up was 38 months. Fifty received blinatumomab alone and 22 the association blinatumomab-DLI. Two-year overall survival (OS) was 31% in the blinatumomab group and 43% in the blinatumomab-DLI group (p 0.31). Studying DLI as a time dependent variable, PFS did not significantly differ between the 2 groups (HR0.7, 95% CI 0.4-1.5). In multivariate analysis, DLI was not a prognostic factor for OS, progression-free survival and progressionrelapse incidence. Adverse events and graft-versus-disease rates were comparable in the 2 groups. In conclusion, adding DLI between 1 month before and 100 days after start of blinatumomab is safe and does not seem to improve outcomes in B-ALL patients who relapsed after allo-HCT.

Acute undifferentiated leukemia limited to neck lymph nodes and a large mediastinal mass.

In the 2016 update of the World Health Organization (WHO) classification of myeloid neoplasms, acute undifferentiated leukemia (AUL) was defined by a lack of lineage-specific markers. AUL has very poor prognosis and no established therapies due to its rarity. We report a case of a 31-year-old man with AUL who showed complete molecular response to an acute lymphoblastic leukemia (ALL)-based regimen and received allogeneic hematopoietic stem cell transplantation. The patients blast cells were CD7-positive and localized to lymph nodes in the neck and to a large mediastinal mass there was also rearrangement of the T-cell receptor delta locus. Although the tumor showed characteristics of T-cell lymphoblastic lymphoma, it was categorized as AUL based on WHO classification. This case suggests that a high-intensity conditioning regimen could be effective for rare cases of AUL that present only in the extramedullary mass, and chemotherapy for AUL should be selected based on the characteristics of the blasts.

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic.

Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Prospective cohort study in 109 institutions in 41 countries. children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkins lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. All-cause mortality was 3.4% (n712084) at 30-day follow-up, 5.7% (n1131969) at 90-day follow-up and 13.0% (n2061581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68) p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61) p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03) p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86) p0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91) p0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84) p0.029) was associated with 30-day mortality. Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer.

The First Case of Adult Granular Acute Lymphoblastic Leukemia with

Granular acute lymphoblastic leukemia (ALL) is defined by the presence of intracytoplasmic granules in lymphoblastic blasts, mimicking acute myeloblastic leukemia. The disease is extremely rare in adults, and hence, the characteristics thereof are poorly understood. We report a case of a 70-year-old man diagnosed with granular ALL. Bone marrow examination showed blasts with azurophilic granules in the cytoplasm, but immunophenotyping showed B-ALL with aberrant expression of myeloid antigens CD13 and CD33. Karyotyping revealed monosomy 7, and targeted NGS showed

Organochlorine pesticides may induce leukemia by methylation of CDKN2B and MGMT promoters and histone modifications.

Epigenetics is the science of altering gene expression without changing nucleotide sequences and may be induced by various environmental factors, including pesticides. The aim of this study was to investigate certain epigenetic changes including the methylation of CDKN2B, CDKN2A, and MGMT gene promoters and histone modifications of H3K9ac, H4K16ac, H4K20me3, and H3K4me3, as well as their association with the levels of organochlorine pesticides (OCPs) in children with acute lymphoblastic leukemia (ALL). The evaluation of OCP levels, promoter methylation, gene expression, and expression of histone modifications was performed by gas chromatography (GC), methylation-specific polymerase chain reaction (MS-PCR), reverse transcription PCR (RT-PCR), and western blotting, respectively. The results indicated that 76.2 % of CDKN2B promoters and 85.1 % of MGMT promoters were hypermethylated in children with ALL compared to healthy children. In addition, the relative expression of CDKN2B, MGMT, H4K16ac, and H3K4me3 showed a significant decrease in children with ALL compared to healthy children. Levels of OCPs in children with ALL were significantly higher than in healthy children. Furthermore, the results revealed that the rise in the OCP levels was associated with an increase in methylation at the promoter level of CDKN2B and MGMT as well as a decrease in the relative expression of H4K16ac and H3K4me3. Therefore, it can be concluded that exposure to OCPs is associated with the induction of epigenetic changes at the level of DNA and histones, which may lead to leukemia.

Factors Affecting the Cancer Immunotherapeutic Efficacy of T Cell Bispecific Antibodies and Strategies for Improvement.

T-cell bispecific antibodies (T-BsAbs) are a new class of cancer immunotherapy drugs that can simultaneously bind to tumor-associated antigens on target cells and to the CD3 subunit of the T-cell receptor (TCR) on T cells. In the last decade, numerous T-BsAbs have been developed for the treatment of both hematological malignancies and solid tumors. Among them, blinatumomab has been successfully used to treat CD19 positive malignancies and has been approved by the FDA as standard care for acute lymphoblastic leukemia (ALL). However, in many clinical scenarios, the efficacy of T-BsAbs remains unsatisfactory. To further improve T-BsAb therapy, it will be crucial to better understand the factors affecting treatment efficacy and the nature of the T-BsAb-induced immune response. Herein, we first review the studies on the potential mechanisms by which T-BsAbs activate T-cells and how they elicit efficient target killing despite suboptimal costimulatory support. We focus on analyzing reports from clinical trials and preclinical studies, and summarize the factors that have been identified to impact the efficacy of T-BsAbs. Lastly, we review current and propose new approaches to improve the clinical efficacy of T-BsAbs.

Haploidentical Versus Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Adult Patients With RelapsedRefractory Acute Lymphoblastic Leukemia A Study From the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

The results of haploidentical stem cell transplantation (haploHCT) for patients with acute lymphoblastic leukemia (ALL) transplanted in active disease remain largely unknown. We retrospectively analyzed adult patients with RR ALL who underwent haploHCT or matched sibling donor (MSD-HCT) as a first transplantation between 2012 and 2020. The analysis comprised 274 patients, 94 had a haploHCT, and 180 had an MSD-HCT. The median follow-up was 32 months. The median age was 33 (range 18-76) and 37 (18-76) years in the haplo- and MSD-HCT groups, respectively. Post-transplant cyclophosphamide (PTCy) was used in 88% of haploHCT and in 4% of the MSD-HCT group. Graft-versus-host disease grade III-IV was higher in haploHCT than in the MSD-HCT group (18% versus 9%

CNS Involvement at Initial Diagnosis and Risk of Relapse After Allogeneic HCT for Acute Lymphoblastic Leukemia in First Complete Remission.

Outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult acute lymphoblastic leukemia (ALL) have improved over time. Studies have shown that total body irradiation (TBI) is the preferable type of myeloablative conditioning (MAC). However, outcomes based on central nervous system (CNS) involvement, namely CNS-positive versus CNS-negative, have not been compared. Here, we evaluated outcomes of 547 patients (CNS-positive 96, CNS-negative 451) who were allografted in the first complete remission (CR1) between 2009 and 2019. Primary endpoint was leukemia-free survival (LFS). Median follow-up was not different between the CNS-positive and CNS-negative groups (79 versus 67.2 months,

Elevated BaxBcl-2 Ratio A Cytotoxic Mode of Action of Kermanian Propolis Against an Acute Lymphoblastic Leukemia Cell Line, NALM-6.

Currently, alternative cancer remedies, especially herbal-derived medicines, have attracted great interest. Propolis, a honeybee-produced naturopathic formulation, is an available, affordable, and safe example of such remedies with different content according to its geographic location. Findings regarding the protective properties of this resinous substance across numerous pathological conditions are promising. Although the anti-tumor effects of propolis from different origins have been explored to some degree, yet there is no study on the effects of Kermanian propolis in the treatment of hematologic malignancies. Accordingly, the objective of the present experiment was to divulge the anti-tumor potential of this bioactive substance both as monotherapy and in combination with doxorubicin against an acute lymphoblastic leukemia cell line (NALM-6).The viability of cells treated with Kermanian propolis (5-500 μgmL) and doxorubicin (5-100 μgmL) was analyzed during 72 h. Based on the MTT results, the best incubation time, IC50 concentrations, and finally the cytotoxicity of the combination therapy were ascertained. Next, the apoptotic rate and expression of apoptosis-related genes (Bcl-2 and Bax) were assessed in mono and combination therapies using flow cytometry and real-time PCR assays, respectively. Kermanian propolis and doxorubicin have impressive tumor-suppressing activity in a dose-dependent manner (IC

Feasibility of Delivering High-Dose Methotrexate in Adolescent and Adult All Patients A Retrospective Study.

Double Philadelphia Chromosomes- A Rare, Yet an Important Cytogenetic Phenomenon of Prognostic Significance in De Novo Acute Lymphoblastic Leukemia.

Presence of additional copies of Philadelphia chromosome (Ph) is characteristic of chronic myeloid leukemia in blast crisis, very rarely observed in de novo acute lymphoblastic leukemia (ALL). Ph positive (Phve) ALL and CML in lymphoid blast crisis (CML-LBC) are biologically different with divergent clinical course. Double Phve ALL has little data available as to its incidence and prognostic significance. We studied five cases of Phve precursor B-cell ALL having an extra copy of Ph chromosome with regard to their clinical and laboratory features. An extensive review of literature was done on prognostic significance and molecular aspects of double Ph in ALL. The study confirms that double Ph was a rare phenomenon in precursor B-cell ALL. It is observed that molecular basis of double Ph positive ALL is less understood compared to CML in blast crisis. The study highlights fundamental role of cytogenetic and molecular studies in diagnosis and management of these patients. Long-term follow-up studies on a larger group of patients are required to understand the prognostic impact of extra Ph in Phve ALL, which is usually resistant to standard chemotherapeutic regimen and often requiring bone marrow transplantation. The online version contains supplementary material available at 10.1007s12288-022-01525-1.

The role of E3 ubiquitin ligase WWP2 and the regulation of PARP1 by ubiquitinated degradation in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) has been a huge threat for peoples health and finding effective target therapy is urgent and important. WWP2, as one of E3 ubiquitin ligase, is involved in many biological processes by specifically binding to substrates. PARP1 plays a role in cell apoptosis and is considered as a therapeutic target of certain cancers. In this study, we firstly found that WWP2 expressed higher in newly diagnosed ALL patients comparing with complete remission (CR) ALL patients and normal control people, and WWP2 in relapse ALL patients expressed higher than normal control people. WWP2 expression was related with the FAB subtype of ALL and the proportion of blast cells in bone marrow blood tested by flow cytometry. We demonstrated knockout WWP2 inhibited the ALL growth and enhanced apoptosis induced by Dox in vitro and vivo for the first time. WWP2 negatively regulated and interacted with PARP1 and WWP2 mechanically degraded PARP1 through polyubiquitin-proteasome pathway in ALL. These findings suggested WWP2 played a role in ALL development as well as growth and apoptosis, and also displayed a regulatory pathway of PARP1, which provided a new potential therapeutic target for the treatment of ALL.

Outcomes of Childhood Noninfant Acute Lymphoblastic Leukemia With 11q23

We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23 Data were retrospectively retrieved from 629 patients with 11q23 A specific 11q23 Compared with historical data, prognosis of patients with noninfant 11q23

Characterization of Leukemic Resistance to CD19-Targeted CAR T-cell Therapy through Deep Genomic Sequencing.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been a clinical breakthrough for pediatric B-cell acute lymphoblastic leukemia (B-ALL), and loss of the CD19 target antigen on leukemic cells represents a major mechanism of relapse. Previous studies have observed CD19 mutations specific to CD19- relapses, and we sought to clarify and strengthen this relationship using deep whole-exome sequencing in leukemic cells expanded in a patient-derived xenograft. By assessing pre-treatment and relapse cells from 13 patients treated with CAR T-cell therapy, 8 of whom developed CD19- relapse and 5 of whom developed CD19 relapse, we demonstrate that relapse-specific single-nucleotide variants and small indels with high allele frequency combined with deletions in the CD19 gene in a manner specific to those patients with CD19- relapse. Before CAR T-cell infusion, one patient was found to harbor a pre-existing CD19 deletion in the context of genomic instability, which likely represented the first hit leading to the patients subsequent CD19- relapse. Across patients, preexisting mutations and genomic instability were not significant predictors of subsequent CD19- relapse across patients, with sample size as a potential limiting factor. Together, our results clarify and strengthen the relationship between genomic events and CD19- relapse, demonstrating this intriguing mechanism of resistance to a targeted cancer immunotherapy.

Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk RelapsedRefractory ALL.

A phase III study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsedrefractory B-cell acute lymphoblastic leukemia (ALL). In phase I, we tested sequentially two cell populations for CAR transduction (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tnmem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II. The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tnmem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22-72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 1617 with Ph-like ALL and 1315 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR 0.16 95% confidence interval, 0.05-0.48 P 0.001). Tnmem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD. See related commentary by El Marabti and Abdel-Wahab, p. 694.

Outcomes of allogeneic haematopoietic stem cell transplantation with intensity-modulated total body irradiation by helical tomotherapy a 2-year prospective follow-up study.

Intensity-modulated radiation therapy (IMRT) helps achieve good radiation dose conformity and precise dose evaluation. We conducted a single-centre prospective study to assess the safety and feasibility of total body irradiation with IMRT (IMRT-TBI) using helical tomotherapy in allogeneic haematopoietic stem cell transplantation (allo-HSCT). Thirty-nine adult patients with haematological malignancy (acute lymphoblastic leukaemia The mean doses for the lungs and kidneys were 7.50 and 9.11 Gy, respectively. The mean maximum dose for the lens (rightleft) was 5.755.87 Gy. The 2-year overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 69, 64, 18 and 18%, respectively. Thirty-six patients developed early adverse events (AEs) (including four patients with Grade 34 toxicities), most of which were reversible oral mucositis and may partially have been related to IMRT-TBI. However, the incidence of toxicity was comparable to conventional TBI-based conditioning transplantation. None of the patients developed primary graft failure, or Grade III-IV acute graft-versus-host disease (GVHD). In late complications, chronic kidney disease was observed in six patients, a lower incidence compared to conventional TBI-based conditioning transplantation. No radiation pneumonitis or cataracts were observed in any of the patients. IMRT-TBI is safe and feasible for haematological malignancies with acceptable clinical outcomes.KEY MESSAGESIMRT-TBI-helical tomotherapy aids in accurate dose calculation and conformity.It could be used without any considerable increase in the rate of TBI-related AEs.Allo-HSCT with IMRT-TBI may be an alternative to conventional TBI for clinical use.

A digital platform for the design of patient-centric supply chains.

Chimeric Antigen Receptor (CAR) T cell therapies have received increasing attention, showing promising results in the treatment of acute lymphoblastic leukaemia and aggressive B cell lymphoma. Unlike typical cancer treatments, autologous CAR T cell therapies are patient-specific this makes them a unique therapeutic to manufacture and distribute. In this work, we focus on the development of a computer modelling tool to assist the design and assessment of supply chain structures that can reliably and cost-efficiently deliver autologous CAR T cell therapies. We focus on four demand scales (200, 500, 1000 and 2000 patients annually) and we assess the tools capabilities with respect to the design of responsive supply chain candidate solutions while minimising cost.

JAK Not Just Another Kinase.

The JAKSTAT axis is implicated in cancer, inflammation, and immunity. Numerous cytokinesgrowth factors affect JAKSTAT signaling. JAKs (JAK1, JAK2, JAK3, and TYK2) noncovalently associate with cytokine receptors, mediate receptor tyrosine phosphorylation, and recruit ≥1 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus to function as transcription factors. Signaling is attenuated by specific suppressor of cytokine signaling proteins, creating a negative feedback loop. Both germline mutations and polymorphisms of JAK family members correlate with specific diseases Systemic lupus erythematosus (TYK2 polymorphisms) severe combined immunodeficiency (JAK3 mutations) pediatric acute lymphoblastic leukemia (TYK2 mutations) and hereditary thrombocytosis (JAK2 mutations). Somatic gain-of-function JAK mutations mainly occur in hematologic malignancies, with the activating JAK2 V617F being a myeloproliferative disorder hallmark it is also seen in clonal hematopoiesis of indeterminate potential. Several T-cell malignancies, as well as B-cell acute lymphoblastic leukemia, and acute megakaryoblastic leukemia also harbor JAK family somatic alterations. On the other hand, JAK2 copy-number loss is associated with immune checkpoint inhibitor resistance. JAK inhibitors (jakinibs) have been deployed in many conditions with JAK activation they are approved in myeloproliferative disorders, rheumatoid and psoriatic arthritis, atopic dermatitis, ulcerative colitis, graft-versus-host disease, alopecia areata, ankylosing spondylitis, and in patients hospitalized for COVID-19. Clinical trials are investigating jakinibs in multiple other autoimmuneinflammatory conditions. Furthermore, dermatologic and neurologic improvements have been observed in children with Aicardi-Goutieres syndrome (a genetic interferonopathy) treated with JAK inhibitors.

Cranial Irradiation for Childhood Cancers and Adult Risk of Meningioma.

Following cranial irradiation, there is an increased risk of developing secondary neoplasms, especially meningiomas. Despite childhood cancer survivors who have undergone cranial irradiation having an increased risk of acquiring radiation-induced meningioma (RIM), there is no widely used standard guideline for meningioma screening. At a single institution, we reviewed three adult survivors of childhood cancer who were treated for RIM between 2010 and 2020. We recorded age at diagnosis for the primary lesion, the radiation dose, age at RIM diagnosis, and tumor characteristics including treatment, pathology, and outcome. Two had had T-cell acute lymphocytic leukemia and one a rhabdomyosarcoma. The age of diagnosis of the RIM ranged from 20 to 40 years, with latencies ranging from 18 to 33 years. All lesions were classified as WHO Grade I meningiomas, and only 1 patient had a subsequent recurrence. A literature search identified articles that address RIM a total of 684 cases were identified in 36 publications. Mean radiation doses ranged from 1.4 gray to 70 gray. Mean age of diagnosis for secondary meningioma ranged from 8 to 53.4 years old, with latency periods ranging from 2.8 to 44 years. Given variability in the way that investigators have published their results, it is difficult to make a single recommendation for RIM screening. Using our experience and the literature, we devised two different screening protocols and calculated their expense. We recommend that data be standardized in a registry to provide greater insight into the clinical and resource allocation questions, especially as long-term survival of children with pediatric cancer into full adulthood becomes more commonplace worldwide.

Detecting Sarcopenic Obesity in Survivors of Pediatric Acute Lymphoblastic Leukemia An Exploration of Body Mass Index and Triponderal Mass Index as Potential Surrogate Markers.

Survivors of pediatric acute lymphoblastic leukemia (ALL) often have altered body composition secondary to treatment effects, including sarcopenic obesity (SO), which increases the risk of both metabolic complications and frailty. SO is difficult to detect without using advanced imaging techniques to which access is often limited. To explore whether common clinical indices can reliably identify the presence of SO in a cohort of long-term survivors of ALL, the discriminatory capacity of body mass index (BMI) or triponderal mass index (TMI, kgm 3 ) for detecting SO was assessed. Thresholds of BMI and TMI associated with overweight or obesity status had poor sensitivity (<50%) and specificity for detecting SO. Total misclassification rates at these thresholds exceeded 50% and positive likelihood ratios were nonsignificant. Notably, TMI is more strongly correlated with elevated adiposity than is BMI in this survivor population ( R2 0.73 vs. 0.57), suggesting further exploration is warranted. Our study is limited by the sample size, precluding detailed regression analysis. This study highlights the challenges of identifying SO in survivors of pediatric ALL using common clinical indices. Prospective evaluation of additional potential surrogate markers in survivors, in conjunction with the component features of SO, should be a key focus of future research.

Autologous Recovery With Chromosomal Abnormalities After Unrelated Umbilical Cord Blood Transplantation With Myeloablative Conditioning in a Case of Pediatric Acute Lymphoblastic Leukemia.

Detailed case reports of autologous recovery of hematopoiesis after hematopoietic stem cell transplantation with myeloablative conditioning are scarce. We present a rare case of a 3-year-old male with relapsed KMT2A -rearranged acute lymphoblastic leukemia who experienced autologous recovery following secondary engraftment failure after cord blood transplantation with myeloablative conditioning. Similar to prior reports, we detected unusual chromosomal abnormalities, which differed at each bone marrow examination. He remains alive without relapse of acute lymphoblastic leukemia 8 months after cord blood transplantation. As the rate of recurrence or late occurrence of secondary malignant neoplasm remains unclear, careful follow-up is required, especially in pediatric patients.

Distinct clonal identities of B-ALLs arising after lenolidomide therapy for multiple myeloma.

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogeneticsfluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogeneticsFISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MMB-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

RaScALL Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL).

RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km, capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient samples. Results were validated using 100 patient samples from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% of reported cases in the study cohort (n 164) and 95% of samples (n 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n 12) and IKZF1 p.N159Y (n 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance.

Mutation of the TP53 gene in acute lymphoblastic leukemia does not affect survival outcomes after haploidentical hematopoietic stem cell transplantation.

Previous studies have demonstrated that TP53 mutation is correlated with insufficient therapy response and unfavorable prognosis in acute lymphoblastic leukemia (ALL). Few studies have investigated the impact of TP53 mutation in ALL patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We completed a retrospective study of 65 ALL patients with available TP53 status who underwent haplo-HSCT. They were divided into a TP53 mutation group (TP53

Circulating cell-free DNA for target quantification in hematologic malignancies Validation of a protocol to overcome pre-analytical biases.

Circulating tumor DNA (ctDNA) has become the most investigated analyte in blood. It is shed from the tumor into the circulation and represents a subset of the total cell-free DNA (cfDNA) pool released into the peripheral blood. In order to define if ctDNA could represent a useful tool to monitor hematologic malignancies, we analyzed 81 plasma samples from patients affected by different diseases. The results showed that (i) the comparison between two different extraction methods Qiagen (Hilden, Germany) and Promega (Madison, WI) showed no significant differences in cfDNA yield, though the first recovered higher amounts of larger DNA fragments (ii) cfDNA concentrations showed a notable inter-patient variability and differed among diseases acute lymphoblastic leukemia and chronic myeloid leukemia released higher amounts of cfDNA than chronic lymphocytic leukemia, and diffuse large B-cell lymphoma released higher cfDNA quantities than localized and advanced follicular lymphoma (iii) focusing on the tumor fraction of cfDNA, the quantity of ctDNA released was insufficient for an adequate target quantification for minimal residual disease monitoring (iv) an amplification system proved to be free of analytical biases and efficient in increasing ctDNA amounts at diagnosis and in follow-up samples as shown by droplet digital PCR target quantification. The protocol has been validated by quality control rounds involving external laboratories. To conclusively document the feasibility of a ctDNA-based monitoring of patients with hematologic malignancies, more post-treatment samples need to be evaluated. This will open new possibilities for ctDNA use in the clinical practice.

Loop CD20CD19 CAR-T cells eradicate B-cell malignancies efficiently.

CD19 chimeric antigen receptor (CAR) T cells have shown robust efficacy in relapsed and refractory acute lymphoblastic leukemia (RR ALL), but compromising result in chronic lymphoblastic leukemia (CLL) and non-Hodgkins lymphoma (NHL). CD19 relapse and the lack of CAR-T cell persistence which result in treatment failure are considerable obstacles to overcome. CAR-T targeting CD20 is an option for salvaging CD19 CAR-T failure. Previous studies have established variant structures of bispecific CAR-T which could avoid antigen-loss and immune escape. Here, we constructed tandem and loop CAR structures targeting both CD19 and CD20 antigen. Bispecific CAR-T cells could eliminate either CD19 or CD20 negative lymphoma cells, suggesting they exhibited dual antigen targeting of CD19 and CD20. By comparing the efficiency of four bispecific CAR modified T cells, it was found that loop2019 CAR was the best structure among them to eradicate lymphoma cell lines and patients primary lymphoma or CLL cells in a very low dose in vitro and prolong the survival time dramatically in lymphoma xenograft mice model. These data highlighted the potential of loop2019 CAR-T in clinical treatment.

A prospective, open-label, randomised, parallel design study of 4 generic formulations of intramuscular L-asparaginase in childhood precursor B-cell acute lymphoblastic leukaemia (ALL).

L-asparaginase is an essential medicine for childhood ALL. The quality of generic L-asparaginase available in India is a matter of concern. We compared four commonly used generic formulations of L-asparaginase in India. We conducted a prospective, open-label, randomised trial of four generic formulations of asparaginase for the treatment of patients with newly diagnosed intermediate-risk B-ALL. Patients were randomly assigned in a 1111 ratio to receive generic asparaginase at a dose of at 10,000 IUm 2 on days 9, 12, 15, and 18 of a 35-day cycle (Induction treatment). The primary end points were to determine the difference in the asparaginase activity and asparagine depletion. Historical patients who received L-asparaginase Medac (innovator) served as controls. A total of 48 patients underwent randomization 12 patients each in the four arms. Failure to achieve predefined activity threshold of 100 IUL was observed in 940 samples of Generic A (22·5%), 2340 of Generic B (57·5%), and 4344 (98%) each of Generic C and D. All 27 samples from seven historical patients who were administered Medac had activity gt 100 IUL. The average activity was significantly higher for Genericm A, 154 (70·3, 285·4) IUL followed by Generic B 84·5(44·2, 289·1) IUL, Generic C 45(14·4, 58·4) IUL, and Generic D 20·4(13, 35) IUL. Only 6 patients had asparaginase activity gt 100 IUL on each of the four occasions (Generic A 5 Generic B 1), and none of them developed Anti-Asparaginase Antibodies (AAA). On the other hand, AAA was observed in 1236 patients who had at least one level lt 100 IUL (P lt 0·05) Generic A 35, Generic B 39, Generic D (411), and Generic C (511). Generic A and B had better trough asparaginase activity compared to Generic D and C. Overall, generic formulations had lower asparaginase activity which raises serious clinical concerns regarding their quality. Until strict regulatory enforcement improves the quality of these generics, dose adaptive approaches coupled with therapeutic drug monitoring need to be considered.

High frequency of heat shock protein 27 overexpression is a highly effective, high-coverage marker for minimal residual disease detection in children with B-cell acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Minimal residual disease (MRD) detection is the most powerful prognostic tool for monitoring treatment efficacy and predicting clinical outcomes. We aimed to identify key leukemia-associated markers, the proportions of differential expression in patients, and the most effective marker combination for MRD detection by flow cytometry. Bone marrow samples were collected from 132 pediatric patients with newly diagnosed (n 115) or relapsed (n 17) B-cell precursor (BCP)-ALL. We used CD19, CD10, CD34, CD45 as backbone markers to identify immature B cells and analyzed the differential expression of 18 leukemia-associated markers using seven-color multiparameter flow cytometry. Leukemic cells in all 132 patients expressed leukemia-associated markers. The most commonly overexpressed marker was heat shock protein 27 (Hsp27) (108 patients, 81%), followed by CD73 (102 patients, 77%) and CD123 (80 patients, 60%). CD38 was underexpressed in 64 patients (48%). Hsp27 overexpression persisted in 50 out of 57 follow-up MRD bone marrow samples (87%) and was associated with older age at diagnosis. Hsp27 overexpression was not associated with MRD levels or genetic abnormalities including hyperdiploidy, t(1221)ETV6-RUNX1, t(119)TCF3-PBX1, t(922)BCR-ABL1, or 11q23KMT2A rearrangements. Four remaining leukemia-associated markers (Hsp27, CD73, CD58, CD24) after in silico deletion from the original panel could collectively detect leukemia-associated cell profiles in 100% of cases in this cohort and 98% of cases in a validation cohort. Hsp27 combined with CD73, CD58, CD24, and backbone markers allows monitoring MRD in virtually all patients with BCP-ALL.

Red Blood Cell Deformability and Distribution Width in Patients with Hematologic Neoplasms.

Despite increasing evidence that red blood cell (RBC) deformability is impaired in pathologic conditions, little research has been done on RBC deformability in hematologic diseases. The authors measured RBC deformability in patients with various hematologic diseases, including hematologic malignancies. A total of 568 patients who underwent bone marrow (BM) examination for initial diagnosis were enrolled. We collected the subjects age, gender, diagnosis of BM examination, and complete blood count results. The RBC deformability, which was quantified by an elongation index, was measured by a microfluidic ektacytometer. RBC deformability was lower in primary myelofibrosis, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) from least to greatest. When the correlation between red blood cell distribution width (RDW) and RBC deformability was analyzed for 370 subjects in hematologic neoplasms, the correlation coefficient of RDW was -0.2974 (p < 0.01). When comparing MDS and aplastic anemia (AA), the deformability of MDS was significantly lower than that of AA. RBC deformability was decreased in leukemic diseases such as AML, MDS, CML, and ALL compared to control, and RDW showed a negative correlation with deformability. RBC deformability may be used as a complementary differential diagnostic test for MDS and AA.

Ophthalmic Manifestations of Newly Diagnosed Acute Leukemia Patients in a Tunisian Cohort.

To describe ocular manifestations of acute leukemia in a Tunisian cohort and to assess the associations between ophthalmic findings and epidemiological, clinical, and biological features of the disease. A prospective study included patients newly diagnosed with acute leukemia referred to our clinics between January 2019 and July 2020. All patients underwent a complete ophthalmic evaluation and spectral-domain optical coherence tomography (SD-OCT) at presentation, then every two months during one year. We defined two groups Group 1 included patients with leukemic ophthalmopathy and group 2 included patients with normal ophthalmic examination. Forty-six patients were enrolled. The mean age of patients was 32.1±15.3 years. The sex ratio MF was 1.55 (28 male patients and 18 females). Twenty-nine patients (63%) had acute myeloid leukemia (AML), and 17 (37%) had acute lymphoblastic leukemia (ALL). The average follow-up was 9.1 months (range 3-12 months). We observed ophthalmic manifestations in 28 patients (61%). Among them, 17 (61%) had vision-threatening complications. The posterior segment was the most common site of ocular involvement (82% of group1). Primary leukemic infiltration (Disc edema, ptosis, exophthalmos) was present in 13 eyes (14.1%). Twenty-seven eyes (29.3%) had secondary involvement lesions (Subconjunctival hemorrhage, periorbital ecchymosis, retinalsub-hyaloid hemorrhage, dilatedtortuous veins). Twenty-one eyes (22.8%) showed other ocular manifestations which etiopathogenesis is not yet fully understood (White-centred hemorrhages, cotton-wool spots, serous retinal detachment, hemorrhagic pigment epithelial detachment). Leukemic retinopathy was significantly more frequent in adults (2339 and 17 in adult and pediatric groups, respectively p0.003). Patients suffering from AML were more likely to have secondary ocular involvement (2029 and 717 in AML and ALL patients, respectively p0.047). Retinal hemorrhages were statistically associated with anemia and thrombocytopenia (p0.041 and p0.034 respectively). Leukemic ophthalmopathy seems to be frequent and may lead to severe visual impairment. An ophthalmic assessment complemented with SD-OCT has paramount importance in all newly diagnosed acute leukemic patients.

The risk factors and early predictive model of hematotoxicity after CD19 chimeric antigen receptor T cell therapy.

Hematotoxicity is the most common long-term adverse event after chimeric antigen receptor T cell (CAR-T) therapy. Here, a total of 71 patients with relapsed or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL) or large B-cell lymphoma (LBCL) were used to develop an early hematotoxicity predictive model and verify the accuracy of this model. The incidences of early hematotoxicity at 3 month following CAR-T infusion in B-ALL and LBCL were 45.5% and 38.5%, respectively. Multivariate analyses revealed that the severity of cytokine release syndrome (CRS) was an independent risk factor affecting early hematotoxicity. The analysis between the peak cytokine levels and early hematotoxicity suggested that tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were closely associated with early hematotoxicity. Then, an early predictive model of hematotoxicity was constructed based on the peak contents of TNF-α and CRP. This model could diagnose early hematotoxicity with positive predictive values of 87.7% and 85.0% in training and validation cohorts, respectively. Lastly, we constructed the nomogram for clinical practice to predict the risk of early hematotoxicity, which performed well compared with the observed probability. This early predictive model is instrumental in the risk stratification of CAR-T recipients with hematotoxicity and early intervention for high-risk patients.

Real world outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation-A single institution experience.

Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) has been associated with a worse prognosis compared to Ph negative ALL. Tyrosine kinase inhibitor (TKI) therapy has led to an improvement in response rates and survival, thus becoming a critical component of therapy. We performed a retrospective cohort study of Ph ALL patients treated at the University of Michigan who received TKI therapy pre- and post-allogeneic hematopoietic stem cell transplant (HSCT) from April 2007 to November 2019. The study included 40 patients with Ph ALL (47.5% female) with a median age of 54 (24-69) years. Median event-free survival (EFS) was not reached, with a 5-year EFS of 61%. Median overall survival (OS) was not reached, with a 5-year OS of 71%. There was no difference in 2-year EFS or OS for patients on pre-transplant imatinib or dasatinib (p 0.16, 0.09, respectively), though definitive conclusions are challenging as post-transplant TKI therapy was variable. The incidence of any grade acute graft-versus-host disease (GVHD) was 62.5% (2540) and any grade chronic GVHD was 77.5% (3140). Complete molecular remission (CMR) was achieved in 57.5% of patients pre-transplant with no significant difference when stratified by induction TKI (p 1). Achievement of CMR pre-HSCT showed a trend towards improved 2-year EFS (p0.0198) but did not significantly change 2-year OS (p 1). Patients receiving 1

PI3K Targeting in Non-solid Cancer.

Despite the therapeutic progress, relapse remains a major problem in the treatment of acute lymphoblastic leukemia (ALL). Most leukemia cells that survive chemotherapy are found in the bone marrow (BM), thus resistance to chemotherapy and other treatments may be partially attributed to pro-survival signaling to leukemic cells mediated by leukemia cell-microenvironment interactions. Adhesion of leukemia cells to BM stromal cells may lead to cell adhesion-mediated drug resistance (CAM-DR) mediating intracellular signaling changes that support survival of leukemia cells. In ALL and chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3KAKT signaling pathway has been shown to be critical in CAM-DR. PI3K targeting inhibitors have been approved for CLL and have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K signaling for normal hematopoietic and leukemia cells and summarize preclinical inhibitors of PI3K in ALL.

An interactive mass spectrometry atlas of histone posttranslational modifications in T-cell acute leukemia.

The holistic nature of omics studies makes them ideally suited to generate hypotheses on health and disease. Sequencing-based genomics and mass spectrometry (MS)-based proteomics are linked through epigenetic regulation mechanisms. However, epigenomics is currently mainly focused on DNA methylation status using sequencing technologies, while studying histone posttranslational modifications (hPTMs) using MS is lagging, partly because reuse of raw data is impractical. Yet, targeting hPTMs using epidrugs is an established promising research avenue in cancer treatment. Therefore, we here present the most comprehensive MS-based preprocessed hPTM atlas to date, including 21 T-cell acute lymphoblastic leukemia (T-ALL) cell lines. We present the data in an intuitive and browsable single licensed Progenesis QIP project and provide all essential quality metrics, allowing users to assess the quality of the data, edit individual peptides, try novel annotation algorithms and export both peptide and protein data for downstream analyses, exemplified by the PeptidoformViz tool. This data resource sets the stage for generalizing MS-based histone analysis and provides the first reusable histone dataset for epidrug development.

Gamma-secretase inhibitor does not induce cytotoxicity in adult T-cell leukemia cell lines despite NOTCH1 expression.

Activated mutations in NOTCH1 are drivers of T-cell type acute lymphoblastic leukemialymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemialymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. We analyzed the expression of NOTCH1 in six ATL- and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 (i.e., the cleaved form of NOTCH1) together with GSI on cell proliferation. Activated NOTCH1 found in ATL- and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of Tax expression (HTLV-1-coded protein). Whole-exome sequencing revealed that activated NOTCH1 mutations were undetectable in six ATL- and HTLV-1-infected cell lines, regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines. These findings suggested that NOTCH1 protein is constitutively activated but is likely a passenger during NOTCH1-mutation-negative ATL cell proliferation.

Differential Diagnosis of Hematologic and Solid Tumors Using Targeted Transcriptome and Artificial Intelligence.

Diagnosis and classification of tumors is increasingly dependent on biomarkers. RNA expression profiling using next-generation sequencing provides reliable and reproducible information on the biology of cancer. This study investigated targeted transcriptome and artificial intelligence for differential diagnosis of hematologic and solid tumors. RNA samples from hematologic neoplasms (N 2606), solid tumors (N 2038), normal bone marrow (N 782), and lymph node control (N 24) were sequenced using next-generation sequencing using a targeted 1408-gene panel. Twenty subtypes of hematologic neoplasms and 24 subtypes of solid tumors were identified. Machine learning was used for diagnosis between two classes. Geometric mean naïve Bayesian classifier was used for differential diagnosis across 45 diagnostic entities with assigned rankings. Machine learning showed high accuracy in distinguishing between two diagnoses, with area under the curve varying between 1 and 0.841. Geometric mean naïve Bayesian algorithm was trained using 3045 samples and tested on 1415 samples, and showed correct first-choice diagnosis in 100%, 88%, 85%, 82%, 88%, 72%, and 72% of acute lymphoblastic leukemia, acute myeloid leukemia, diffuse large B-cell lymphoma, colorectal cancer, lung cancer, chronic lymphocytic leukemia, and follicular lymphoma cases, respectively. The data indicate that targeted transcriptome combined with artificial intelligence are highly useful for diagnosis and classification of various cancers. Mutation profiles and clinical information can improve these algorithms and minimize errors in diagnoses.

PAX5 P80R-mutated B-cell acute lymphoblastic leukemia with transformation to histiocytic sarcoma clonal evolution assessment using NGS-based immunoglobulin clonality and mutation analysis.

Clonality assessment by the detection of immunoglobulin (IG) gene rearrangements is an important method to determine whether two concurrent or subsequent lymphoid malignancies in one patient are clonally related. Here, we report the detailed clonality analysis in a patient with a diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) followed by a histiocytic sarcoma (HS), in which we were able to study clonal evolution by applying next generation sequencing (NGS) to identify IG rearrangements and gene mutations. Using the sequence information of the NGS-based IG clonality analysis, multiple related subclones could be distinguished in the PAX5 P80R-mutated B-ALL. Notably, only one of these subclones evolved into HS after acquiring a RAF1 mutation. This case demonstrates that NGS-based IG clonality assessment and mutation analysis provide clear added value for clonal comparison and thereby improves clinicobiological understanding.

DNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia.

Aberrant DNA methylation constitutes a key feature of pediatric acute lymphoblastic leukemia at diagnosis, however its role as a predisposing or early contributor to leukemia development remains unknown. Here, we evaluate DNA methylation at birth in 41 leukemia-discordant monozygotic twin pairs using the Illumina EPIC array on archived neonatal blood spots to identify epigenetic variation associated with development of pediatric acute lymphoblastic leukemia, independent of genetic influence. Through conditional logistic regression we identify 240 significant probes and 10 regions associated with the discordant onset of leukemia. We identify a significant negative coefficient bias, indicating DNA hypomethylation in cases, across the array and enhanced in open sea, shelfshore, and gene body regions compared to promoter and CpG island regions. Here, we show an association between global DNA hypomethylation and future development of pediatric acute lymphoblastic leukemia across disease-discordant genetically identical twins, implying DNA hypomethylation may contribute more generally to leukemia risk.

Clinical characteristics and prognosis of seizures in 75 children with acute lymphoblastic leukemia.

To investigate the clinical characteristics, treatment, and prognosis of seizures in children with acute lymphoblastic leukemia (ALL) during chemotherapy. Children with ALL with seizures during chemotherapy admitted to the Department of Pediatrics, Peking University Peoples Hospital from January 2010 to March 2022 were retrospectively analyzed. Clinical data including the incidence of seizure, time at seizure onset, causes, management, and prognosis were collected retrospectively. A total of 932 children with ALL were admitted during the study period, of whom, 75 (8%) were complicated with seizures during the period of chemotherapy. There were 40 males and 35 females, with a median age of 7.5 (1-17) years, and 43 cases (57.3%) occurred within the first 2 months of chemotherapy. The underlying diseases were reversible posterior encephalopathy syndrome ( Seizures are relatively common in children with ALL, most commonly due to reversible posterior encephalopathy syndrome, methotrexate-related neurotoxicity, and cerebral hemorrhage. Seizures occurred within 2 months of chemotherapy in most cases. Neuroimaging and EEG should be performed as soon as possible after the first seizure onset to identify the etiology and to improve the treatment regimen. Some cases developed symptomatic epilepsy, with a satisfactory outcome of seizure remission mostly after concurrent antiseizure medication therapy. 探讨急性淋巴细胞白血病患儿化疗过程中出现癫痫发作的临床特点、治疗和预后。 回顾性分析2010年1月至2022年3月北京大学人民医院儿科收治的化疗过程中合并癫痫发作的急性淋巴细胞白血病患儿, 总结癫痫发作的发病率、发病时间、病因、治疗和预后。 研究期间共收治急性淋巴细胞白血病患儿932例, 其中75例(8%)在化疗过程中合并癫痫发作症状, 男40例, 女35例, 中位年龄7.5岁(117岁)。43例(57.3%)患儿的癫痫发作发生在开始化疗的前2个月内, 直接原因分别为可逆性后部脑病综合征(15例)、脑出血(10例, 其中1例合并静脉窦血栓形成)、鞘内注射或全身应用氨甲蝶呤(11例)、脑脓肿(真菌性3例, 细菌性4例)、病毒性脑炎(2例)、热性惊厥(7例)、低钠血症(7例)、低钙血症(2例) 14例患儿的癫痫发作病因不明。64例患儿在癫痫发作后行头颅影像学检查, 其中37例(57.8%)异常 44例行脑电图检查, 其中24例(54.4%)异常。55例患儿经规律化疗后骨髓持续缓解, 8例行造血干细胞移植, 9例死亡, 3例失访。18例(24%)患儿诊断为症状性癫痫, 多数予抗癫痫发作药物控制良好, 2例为药物难治性癫痫。 癫痫发作在急性淋巴细胞白血病患儿中不少见, 最常见的病因为可逆性后部脑病综合征、氨甲蝶呤相关性神经毒性、脑出血。癫痫发作大多发生在化疗开始的2个月内 在首次癫痫发作后, 应尽快完善神经影像学和脑电图检查以协助明确病因及指导治疗 部分病例可发展为症状性癫痫, 大多数预后良好, 个别为药物难治性癫痫。

Two pediatric oncologic cases of hypereosinophilic syndrome and review of the literature.

Persistent peripheral blood hypereosinophilia may cause tissue damage, leading to hypereosinophilic syndrome (HES) with end-organ dysfunction. Here we discuss two unique pediatric cases of primary hypereosinophilic syndrome with oncologic etiologies to highlight the importance of early recognition, workup and treatment of HES. CASE 1 A previously healthy 7-year-old male presented with acute myocardial infarction and transient ischemic attack and found to have significant hyperleukocytosis with a total white blood count of 131 000 and hypereosinophilia with an absolute eosinophil count of 99 560. He was ultimately diagnosed with precursor B-cell acute lymphoblastic leukemia with immunoglobulin heavy chain gene rearrangement. He completed standard treatment without significant complications and remains in remission at about 2 years off therapy. He is in overall good health and has normal cardiac function. CASE 2 A 13-year-old female was referred for iron deficiency and reported a history of severe anxiety, shortness of breath and anorexia. She had experienced fatigue and dizziness associated with frequent panic attacks and shortness of breath with strenuous activity since the age of five. Serial laboratory investigations revealed persistent hypereosinophilia (AEC 4000-6000μl). Additional workup revealed elevated vitamin B12 (>2000 pgml normal range 243-894) and tryptase (16.4 ngml normal range ≤10.9). The FIP1L1-PDGFRA gene fusion was detected by fluorescence in situ hybridization (FISH) on peripheral blood, diagnostic for myeloidlymphoid neoplasm with eosinophilia. Evaluation for end-organ damage associated with persistent hypereosinophilia included an echocardiogram which revealed severe restrictive cardiomyopathy with pulmonary hypertension. Monotherapy with imatinib was initiated, after which she achieved a rapid hematologic response and remains in molecular remission, though she continues to have persistent asymptomatic severe pulmonary hypertension in the setting of severe diastolic dysfunction. Persistent hyperosinophilia can be a silent cause of significant and often irreversible tissue damage and should therefore always prompt workup for both primary and secondary causes.

NGS better discriminates true MRD positivity for the risk stratification of childhood ALL treated on an MRD-based protocol.

We compared minimalmeasurable residual disease (MRD) levels evaluated by routinely used real-time quantitative polymerase chain reaction (qPCR) patient-specific assays and by next-generation sequencing (NGS) approach in 780 immunoglobulin (IG) and T-cell receptor (TR) markers in 432 children with B-cell precursor acute lymphoblastic leukemia treated on the AIEOP-BFM ALL 2009 protocol. Our aim was to compare the MRD-based risk stratification at the end of induction. The results were concordant in 639 of 780 (81.9%) of these markers 37 of 780 (4.7%) markers were detected only by NGS. In 104 of 780 (13.3%) markers positive only by qPCR, a large fraction (23104 22.1%) was detected also by NGS, however, owing to the presence of identical IGTR rearrangements in unrelated samples, we classified those as nonspecificfalse-positive. Risk group stratification based on the MRD results by qPCR and NGS at the end of induction was concordant in 76% of the patients 19% of the patients would be assigned to a lower risk group by NGS, largely owing to the elimination of false-positive qPCR results, and 5% of patients would be assigned to a higher risk group by NGS. NGS MRD is highly concordant with qPCR while providing more specific results and can be an alternative in the front line of MRD evaluation in forthcoming MRD-based protocols.

Lisaftoclax in Combination with Alrizomadlin Overcomes Venetoclax Resistance in Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Preclinical Studies.

Despite approval of B-cell lymphoma (BCL)-2 inhibitor venetoclax for certain hematologic malignancies, its broader clinical benefit is curtailed by resistance. Our study aimed to determine if treatment with novel anticancer agents targeting BCL-2 and mouse double minute 2 (MDM2) could overcome venetoclax resistance in preclinical models. Venetoclax-sensitive and venetoclax-resistant acute myeloid leukemia (AML) and acute lymphoblastic leukemia cells and xenograft models were used to evaluate antitumor effects and underlying mechanisms associated with combined BCL-2 inhibitor lisaftoclax (APG-2575) and MDM2 inhibitor alrizomadlin (APG-115). The combination exhibited synergistic antiproliferative and apoptogenic activities in TP53 wild-type AML cell lines in vitro. This synergy was further exemplified by deep antitumor responses and prolonged survival in AML cell line-derived and patient-derived xenograft models. Interestingly, the combination treatment resensitized (to apoptosis) venetoclax-resistant cellular and mouse models established via chronic drug exposure or genetically engineered with clinically relevant BCL-2 gene mutations. Synergistic effects in reducing cellular viability and proliferation were also demonstrated in primary samples of patients with venetoclax-resistant AML treated with lisaftoclax and alrizomadlin ex vivo. Mechanistically, alrizomadlin likely primes cancer cells to BCL-2 inhibition-induced cellular apoptosis by downregulating expression of antiapoptotic proteins myeloid cell leukemia-1 and BCL-extra-large and upregulating pro-death BCL-2-associated X protein. Lisaftoclax in combination with alrizomadlin overcomes venetoclax resistance mediated by various mechanisms, including BCL-2 mutations. In addition, we posit further, putative molecular mechanisms. Our data rationalize clinical development of this treatment combination in patients with diseases that are insensitive or resistant to venetoclax.

Modeling of the Acute Lymphoblastic Leukemia Detection by Convolutional Neural Networks (CNNs).

The techniques differed in many of the literature on the detection of Acute Lymphocytic Leukemia from the blood smear pictures, as the cases of infection in the world and the Kingdom of Saudi Arabia were increasing and the causes of this disease were not known, especially for children, which is a serious and fatal disease. Through this work we seek to contribute to discover the blood cells affected by Acute Lymphocytic Leukem and to find an effective and fast method and to have the correct diagnosis as the time factor is important in the diagnosis and the initiation of treatment. which is based on one of the deep learning techniques that specialize in very deep networks, the use of one of the CNNs is VGG16. Detection scheme is implemented by pre-processing, feature extraction, model building, fine tuning method, classification are executed. By using VGG16 pre-trained, and using SVM and MLP classification algorithms in Machine Learning. Our results are evaluated based on criteria such as Accuracy, Precision, Recall, and F1-Score. The accuracy results for SVM classifier MLP of 77% accuracy at 0.001 learning rate and the accuracy for SVM classifier 75% at 0.005 learning rate. Whereas, the best accuracy result for VGG16 model was 92.27% at 0.003 learning rate. The best validation accuracy result was 85.62% at 0.001 learning rate.

Disseminated intravascular coagulation in a cohort of adult acute leukemia patients a single center experience.

We aimed to detect the incidence of disseminated intravascular coagulation (DIC) in patients with acute leukemia (AL) and find out its association with types of AL and patients clinical and pathological parameters. In this prospective study, 59 newly diagnosed adults with AL were clinically examined and screened for DIC presentation time. Coagulation tests, including prothrombin time, activated partial thromboplastin time, fibrinogen level, D-dimer, antithrombin, and protein C and protein S levels were all assessed. The International Society for Thrombosis and Hemostasis scoring system was adopted to diagnose overt DIC. The age of the studied patients ranged from 15 to 81 years with a median of 41 years male to female ratio was 1.11. acute myeloid leukemia (AML) constituted 64.4% of the total cases (38 patients). DIC was detected in 28 patients (47.5%) its incidence was higher in AML than in acute lymphoblastic leukemia (ALL) (52.6% vs. 38.1%). Overt DIC was significantly associated with bleeding manifestations, duration of symptoms, and leukocytosis ( P -values 0.050, 0.044, and 0.003, respectively). Bleeding events were encountered in 50.8% of patients (25 AML and 5 ALL patients). Bleeding was associated significantly with leukocytosis, thrombocytopenia, and low fibrinogen level. Thrombosis was found in two patients (3.4%) at presentation. Overt DIC was common in patients with AL at presentation, mostly in AML. Routine testing for coagulopathy in newly diagnosed AL patients will possibly aid in improving the overall patients survival.

Infectious events in pediatric patients with acute lymphoblastic leukemialymphoma undergoing evaluation for fever without severe neutropenia.

Infections cause significant treatment-related morbidity during pediatric acute lymphoblastic leukemialymphoma (ALLLLy) therapy. Fevers during periods without severe neutropenia are common, but etiologies are not well-described. This study sought to describe the bloodstream infection (BSI) and non-BSI risk in children undergoing therapy for ALLLLy. Demographic and clinical data were abstracted for febrile episodes without severe neutropenia at two childrens hospitals. Treatment courses were stratified by intensity. Multivariate logistic regression evaluated characteristics associated with infection. There were 1591 febrile episodes experienced by 524 patients. Of these, 536 (34%) episodes had ≥1 infection BSI occurred in 30 (1.9%) episodes. No BSIs occurred in episodes with a recent procedural sedation or cytarabine exposure. Presence of hypotension, chillsrigors, higher temperature, and infant phenotype were independently associated with BSI (p < .05). Of the 572 non-BSIs, the most common was upper respiratory infection (URI) (n 381, 67%). Compared to episodes without infection, URI symptoms, higher temperature, absolute neutrophil count 500-999μl, and evaluation during a low-intensity treatment course were more likely to be associated with a non-BSI (p < .05) and inpatient status was less likely to be associated with a non-BSI (p < .05). The BSI rate in pediatric patients with ALLLLy and fever without severe neutropenia is low, but one-third of the time, patients have a non-BSI. Future research should test if the need for empiric antibiotics can be tailored based on the associations identified in this study.

Optimizing thiopurine therapy in children with acute lymphoblastic leukemia A promising MINT sequencing strategy and therapeutic DNA-TG monitoring.

Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on

Practical aspects of chimeric antigen receptor T-cell administration From commercial to point-of-care manufacturing.

Chimeric antigen receptor T-cells targeting the CD19 antigen have achieved impressive results in patients with relapsedrefractory (RR) B-cell malignancies, leading to their approval in the European Union and other jurisdictions. In Spain, the 100% academic anti-CD19 CART-cell product varnimcabtagene autoleucel (var-cel, ARI-0001 cells) has been extraordinarily approved under the Hospital Exemption clause for the treatment of patients older than 25 years of age with RR acute lymphoblastic leukaemia. Var-cel has also been granted PRIority MEdicines designation by the European Medicines Agency for the same indication. In this review we reveal some practical aspects related to the preparation and administration of academic point-of-care CART-cell products, using var-cel as an example, and put them into the context of commercial products.

Extramedullary Relapse of Acute Lymphoblastic Leukemia Involving the Parotid Gland A Case Report and Literature Review.

While extramedullary relapse of leukemia could occur, the parotid gland is a rare site of recurrence. Extramedullary relapse involving the parotid gland could be mistaken for other diseases. Moreover, the diagnosis of this disease is often delayed due to its rarity. Herein, we present a case of extramedullary relapse of acute lymphoblastic leukemia involving the parotid gland. 백혈병의 골수 외 재발이 발생할 수 있지만 이하선은 드문 재발 부위이다. 이하선을 포함하는 골수 외 재발은 다른 질환과 혼동될 수 있으며 종종 질환의 희귀성으로 인해 진단이 지연될 수 있다. 이에 저자들은 재발성 급성 림프아구성 백혈병 환자에서 이하선의 급성 림프아구성 백혈병의 골수 외 재발 사례와 영상 소견을 보고한다.

Hematopoietic stem cell transplantation from HLA-matched sibling donors in children with acute lymphoblastic leukemia A report from the Childrens Cancer Hospital Egypt.

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used for high-risk acute lymphoblastic leukemia (ALL) patients in their first complete remission (CR1), and for relapsed patients in second complete remission (CR2). We retrospectively analyzed data for 67 children with ALL, from a cancer center in a lowmiddle income country, who had undergone HSCT from human leukocyte antigen (HLA)-matched sibling donors (MSDs) using myeloablative conditioning (MAC) regimens, between 2007 and 2020, describing the survival outcome and relapse probability after achieving CR1 and CR2 and determining outcome differences in relation to indications for HSCT in patients transplanted in CR1. All patients had achieved a negative minimal residual disease prior to transplant (<0.01%). Forty-six patients (68.7%) were in CR1 25 had adverse cytogenetics, including 18 patients with Philadelphia chromosome-positive ALL (Ph-positive ALL), and 21 had poor induction response. The 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) for the whole cohort were 56.1% (95% CI, 42.8%-69.4%), 49% (95% CI, 35.7%-62.3%) and 33.5% (95% CI, 21.7%-45.8%), respectively with better EFS and CIR for CR1 transplants compared to CR2 transplants (P0.02 and P0.03, respectively). Patients with Ph-positive ALL had better 5-year OS, EFS and non-relapse mortality (NRM) compared with other CR1 transplants (P0.015, P0.009 and P0.028, respectively). Hematopoietic stem cell transplantation from MSD for ALL in CR1 group had superior outcomes compared to CR2 group and was apparently a curable option for Ph-positive ALL without an increased risk of non-relapse mortality. Poorer survival rates and higher relapse probabilities were associated with HSCT conducted to patients who had a poor response to induction therapy or suffered a relapse.

Transcriptomic Analysis of Conserved Telomere Maintenance Component 1 (CTC1) and Its Association with Leukemia.

Telomere length (TEL) regulation is important for genome stability and is governed by the coordinated role of shelterin proteins, telomerase (TERT), and CST (CTC1OBFC1TEN1) complex. Previous studies have shown the association of telomerase expression with the risk of acute lymphoblastic leukemia (ALL). However, no data are available for CST association with the ALL. The current pilot study was designed to evaluate the CST expression levels in ALL. In total, 350 subjects were recruited, including 250 ALL cases and 100 controls. The subjects were stratified by age and categorized into pediatrics (1-18 years) and adults (19-54 years). TEL and expression patterns of CTC1, OBFC1, and TERT genes were determined by qPCR. The univariable logistic regression analysis was performed to determine the association of gene expression with ALL, and the results were adjusted for age and sex in multivariable analyses. Pediatric and adult cases did not reflect any change in telomere lengths relative to controls. However, expression of CTC1, OBFC1, and TERT genes were induced among ALL cases. Multivariable logistic regression analyses showed association of CTC1 with ALL in pediatric β estimate (standard error (SE) -0.013 (0.007),

Normal and Aberrant TALE-Class Homeobox Gene Activities in Pro-B-Cells and B-Cell Precursor Acute Lymphoblastic Leukemia.

Homeobox genes encode transcription factors regulating basic developmental processes. They are arranged according to sequence similarities of their conserved homeobox in 11 classes, including TALE. Recently, we have reported the so-called TALE-code. This gene signature describes physiological expression patterns of all active TALE-class homeobox genes in the course of hematopoiesis. The TALE-code allows the evaluation of deregulated TALE homeobox genes in leukemialymphoma. Here, we extended the TALE-code to include the stages of pro-B-cells and pre-B-cells in early B-cell development. Detailed analysis of the complete lineage of B-cell differentiation revealed expression of TALE homeobox genes IRX1 and MEIS1 exclusively in pro-B-cells. Furthermore, we identified aberrant expression of IRX2, IRX3 and MEIS1 in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) which originates from early B-cell progenitors. The data showed correlated activities of deregulated TALE-class members with particular BCP-ALL subtype markers, namely IRX2 with TCF3E2A-fusions, IRX3 with ETV6TEL-fusions, and MEIS1 with KMT2AMLL-fusions. These correlations were also detected in BCP-ALL cell lines which served as experimental models. We performed siRNA-mediated knockdown experiments and reporter gene assays to analyze regulatory connections. The results showed mutual activation of IRX1 and TCF3. In contrast, IRX2 directly repressed wild-type TCF3 while the fusion gene TCF3PBX1 lost the binding site for IRX2 and remained unaltered. IRX3 mutually activated fusion gene ETV6RUNX1 while activating itself by aberrantly expressed transcription factor KLF15. Finally, KMT2A activated MEIS1 which in turn supported the expression of IRX3. In summary, we revealed normal TALE homeobox gene expression in early B-cell development and identified aberrant activities of IRX2, IRX3 and MEIS1 in particular subtypes of BCP-ALL. Thus, these TALE homeobox genes may serve as novel diagnostic markers and therapeutic targets.

Genomic Landscape of Mixed-Phenotype Acute Leukemia.

Mixed-phenotype leukemia (MPAL) is a type of acute leukemia in which the blast population shows mixed features of myeloid, T-lymphoid, andor B-lymphoid differentiation. MPALs are rare and carry a poor prognosis, thus, often pose both a diagnostic and therapeutic challenge. Conventionally, the diagnosis of MPAL requires either a single blast population with a lineage-defining phenotypic expression of multiple lineages (myeloid, B-cell andor T-cell) (biphenotypic) or two distinct blast populations that each independently satisfy criteria for designation as AML, B-ALL, andor T-ALL (bilineage). Given the rarity of MPAL, minimal studies have been performed to describe the genomic landscape of these neoplasms. IRB approval was obtained. Central MCC database was searched for any patient with a diagnosis of acute undifferentiated leukemia (AUL), acute leukemia of ambiguous lineage (ALAL), and MPAL. All patient diagnoses were manually reviewed by a hematopathologist to confirm the diagnosis of MPAL. Genomic and molecular data were collated from the EMR and bioinformatically from MCC genomics repositories. Twenty-eight patients with MPAL were identified. Thirteen were female and 15 were male. Average age was 56 years old (range 28-81). Ten cases were biclonal and 18 were biphenotypic. Diagnoses were as follows Bmyeloid (

Modern Management Options for Ph ALL.

Impressive advances have been achieved in the management of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) since the initial concurrent use of imatinib and standard chemotherapy. The attenuation of chemotherapy has proven to be equally effective and less toxic, the use of third generation TKI upfront has improved the frequency of complete molecular response and the survival rate, and the combination of tyrosine kinase inhibitors with immunotherapy has further increased the rate of molecular response to 70-80% after consolidation, which has been translated into a survival rate of 75-90% in recent trials. As a result of these improvements, the role of allogeneic hematopoietic stem cell transplantation is being redefined. The methodology of measurable residual disease assessment and the detection of ABL1 mutations are also improving and will contribute to a more precise selection of the treatment for newly diagnosed and relapsed or refractory (RR) patients. Finally, new compounds combined with immunotherapeutic approaches, including cellular therapy, are being used as rescue therapy and will hopefully be included in first line therapy in the near future. This article will review and update the modern management of patients with Ph ALL.

JAKBCL2 inhibition acts synergistically with LSD1 inhibitors to selectively target ETP-ALL.

ETP-ALL (Early T cell Progenitor Acute Lymphoblastic Leukemia) represents a high-risk subtype of T cell acute lymphocytic leukemia (T-ALL). Therapeutically, ETP-ALL patients frequently relapse after conventional chemotherapy highlighting the need for alternative therapeutic approaches. Using our ZEB2

UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM) a phase 1, dose-escalation trial.

The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16-70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10 Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8-24·8). Median age was 37 years (IQR 28-45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level) one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8-24·8), overall response rate was 48% (95% CI 28-69 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2-2·8), and overall survival was 13·4 months (95% CI 4·8-23·0). UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia. Servier.

Cost-Utility Analysis of Pegaspargase for the Treatment of Acute Lymphoblastic Leukemia in Greece.

Acute lymphoblastic leukemia (ALL) is an acute, rapidly progressing and life-threatening form of cancer involving immature lymphocytes called lymphoblasts. ALL is the most common subtype of leukemia in children and adolescents. The aim of the present study was to assess the cost-utility of pegaspargase versus L-asparaginase, both followed by Erwinase in the therapy sequence, as a treatment option for pediatric, adolescent, and adult patients with ALL in Greece. A published cost-utility model comprising a decision tree and a state-transition Markov model was adapted from a public payer perspective to compare a pegaspargase treatment sequence with an L-asparaginase sequence. Efficacy and safety data, as well as utility values, were extracted from the published literature. Direct costs pertaining to drug acquisition, administration, and management of hypersensitivity were considered in the analysis (€2020). Model-extrapolated outcomes included quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICER). All future outcomes were discounted at 3.5% per annum. Sensitivity analyses were used to explore the impact of changing input data. The analysis showed that the pegaspargase sequence was estimated to produce 0.05 additional QALYs (18.12 vs. 18.07) and lower cost of - €1698 compared with L-asparaginase, indicating that the pegaspargase sequence was a dominant treatment strategy (improved outcomes with reduced costs) compared with L-asparaginase. Deterministic sensitivity analysis confirmed the cost-effective profile of pegaspargase. At the defined willingness-to-pay threshold of €54,000QALY gained, probabilistic sensitivity analysis showed that pegaspargase had a 100% probability of being cost effective relative to the L-asparaginase sequence. The pegaspargase sequence was found to be less costly and more effective (in terms of QALYs) in relation to the L-asparaginase sequence, representing a dominant strategic option for Greek public payers in ALL.

Secondary donor-derived CD19 CAR-T therapy is safe and efficacious in acute lymphoblastic leukemia with extramedullary relapse after first autologous CAR-T therapy.

Despite the advancement of treatments, adults with relapsedrefractory (RR) B-lineage acute lymphoblastic leukemia (B-ALL) have poor prognosis, with an expected five-year overall survival (OS) rate of 10%‒20% (Nguyen et al., 2008 Oriol et al., 2010). Extramedullary relapse of B-ALL is regarded as a high-risk factor generally associated with poor survival, occurring in about 15% to 20% of all relapsed patients (Ding et al., 2017 Sun et al., 2018). The central nervous system (CNS) and the testes are the most common sites of extramedullary relapse of B-ALL. In addition, extramedullary leukemia can appear in the skin, eyes, breasts, bones, muscles, and abdominal organs. The prognosis of relapsed extramedullary B-ALL after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor (Spyridonidis et al., 2012 Dahlberg et al., 2019). Conventional chemotherapy or radiation is often ineffective in such patients. At present, there are no optimal treatment strategies for treating extramedullary leukemia after allo-HSCT.

An easy-to-use nomogram predicting overall survival of adult acute lymphoblastic leukemia.

Adult acute lymphoblastic leukemia (ALL) is heterogeneous both biologically and clinically. The outcomes of ALL have been improved with the application of children-like regimens and novel agents including immune therapy in young adults. The refractory to therapy and relapse of ALL have occurred in most adult cases. Factors affecting the prognosis of ALL include age and white blood cell (WBC) count at diagnosis. The clinical implications of genetic biomarkers, including chromosome translocation and gene mutation, have been explored in ALL. The interactions of these factors on the prediction of prognosis have not been evaluated in adult ALL. A prognostic model based on clinical and genetic abnormalities is necessary for clinical practice in the management of adult ALL. The newly diagnosed adult ALL patients were divided into the training and the validation cohort at 73 ratio. Factors associated with overall survival (OS) were assessed by univariatemultivariate Cox regression analyses and a signature score was assigned to each independent factor. A nomogram based on the signature score was developed and validated. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to assess the performance of the nomogram model. This study included a total of 229 newly diagnosed ALL patients. Five independent variables including age, WBC, bone marrow (BM) blasts, MLL rearrangement, and ICT gene mutations (carried any positive mutation of IKZF1, CREBBP and TP53) were identified as independent adverse factors for OS evaluated by the univariate, Kaplan-Meier survival and multivariate Cox regression analyses. A prognostic nomogram was built based on these factors. The areas under the ROC curve and calibration curve showed good accuracy between the predicted and observed values. The DCA curve showed that the performance of our model was superior to current risk factors. A nomogram was developed and validated based on the clinical and laboratory factors in newly diagnosed ALL patients. This model is effective to predict the overall survival of adult ALL. It is a simple and easy-to-use model that could efficiently predict the prognosis of adult ALL and is useful for decision making of treatment.

Case Report Successful engraftment of allogeneic hematopoietic stem cells using CAR-T cell therapy as the conditioning regimen in RR Ph

Consolidative allogeneic hematopoietic stem cells (allo-HSCs) after chimeric antigen receptor T cells (CAR-T) therapy is an emerging modality in hematologic malignancies. Knowledge about the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR-T therapy without a conditioning regimen is limited. We report a patient with relapsedrefractory (RR) Ph We report the successful engraftment of allogeneic HSCs using CAR-T cell therapy as a conditioning regimen for RR B-ALL patients.

Thiotepa, busulfan and fludarabine conditioning-regimen is a promising approach for older adult patients with acute lymphoblastic leukemia treated with allogeneic stem cell transplantation.

For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity.

Correction Development of a Therapeutic Video Game With the MDA Framework to Decrease Anxiety in Preschool-Aged Children With Acute Lymphoblastic Leukemia Mixed Methods Approach.

This corrects the article DOI 10.219637079..

Incidence of adverse effects in patients receiving ponatinib with concomitant azole antifungals.

Ponatinib plus Hyper-CVAD yields a five-year overall survival of 73% in patients with Philadelphia-positive acute lymphoblastic leukemia. Ponatinib dose intensity is associated with increased incidence of adverse effects (AEs), including vascular events. Ponatinib combined with azole antifungals may further increase the risk of AEs due to increased ponatinib exposure. We reviewed 53 patients who received ponatinib with intensive (

Oral Mercaptopurine Adherence in Pediatric Acute Lymphoblastic Leukemia A Survey Study From the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium.

Phase I trial of myeloablative conditioning with 3-day total marrow and lymphoid irradiation for leukemia.

This prospective phase I trial aimed to determine the recommended dose of 3-day total marrow and lymphoid irradiation (TMLI) for a myeloablative conditioning regimen by increasing the dose per fraction. The primary end-point of this single-institution dose escalation study was the recommended TMLI dose based on the frequency of dose-limiting toxicity (DLT) ≤100 days posthematopoietic stem cell transplantation (HSCT) a 3 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (141618 Gy in six fractions over 3 days) were set. The treatment protocol began at 14 Gy. Dose-limiting toxicities were defined as grade 3 or 4 nonhematological toxicities. Nine patients, with a median age of 42 years (range, 35-48), eight with acute lymphoblastic leukemia and one with chronic myeloblastic leukemia, received TMLI followed by unrelated bone marrow transplant. The median follow-up period after HSCT was 575 days (range, 253-1037). Three patients were enrolled for each dose level. No patient showed DLT within 100 days of HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. All patients achieved neutrophil engraftment at a median of 19 days (range, 14-25). One-year overall and disease-free survival rates were 83.3% and 57.1%, respectively. Three patients experienced relapse, and no nonrelapse mortality was documented during the observation period. One patient died due to disease relapse 306 days post-HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. The efficacy evaluation of this regimen is currently being planned in a phase II study.

Radiation and leukaemia Which leukaemias and what doses

The cause(s) of most cases of leukaemia is unknown. Save for several rare inherited disorders the most convincingly-identified causes of leukaemia are exposures to ionizing radiations, to some chemicals and to some anti-cancer drugs. Data implicating ionizing radiations as a cause of leukaemias come from several sources including persons exposed to the atomic bomb explosions in Japan, persons receiving radiation therapy for cancer and other disorders, persons occupationally exposed to radiation such as radiologists and nuclear facility workers, cigarette smokers, and others. Although ionizing radiations can be a cause of almost all types of leukaemias, some are especially sensitive to induction such as acute and chronic myeloid leukaemias (AML and CML) and acute lymphoblastic leukaemia (ALL). Whether chronic lymphocytic leukaemia can be caused by radiation exposure is controversial. The mechanism(s) by which ionizing radiations cause leukaemia differs for different leukaemia types. I discuss these issues and close with a hypothesis which might explain why haematopoietic stem cells are localized to the bone marrow.

Acute kidney injury after CAR-T cell infusion.

Chimeric antigen receptor T (CAR-T)-cell, an adaptive immune therapy is approved for patients with acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Its use and subsequent toxicities are expected to rise in the coming years. The main toxicities are cytokine release syndrome, hemophagocytic lymphohistiocytosis and immune effector cell associated neurotoxicity syndrome. Cytokine release syndrome is observed in up to 40% of patients. Almost 20% of patient suffer from acute kidney injury after CAR-T cell infusion. Associated factors are high-grade cytokine release syndrome, a prior autologous or allogeneic stem cell transplantation andrequirement of intensive care unit. Several mechanisms may contribute to the occurrence of acute kidney injury after CAR-T infusion hypoperfusion during cytokine release syndrome, cytokine injury, T cell infiltration, tumor lysis syndrome and sepsis-induced injury. Kidney injury is associated with substantial increase in morbi-mortality.

Central nervous system infection by Bacillus cereus a case report and literature review.

Bacillus cereus is a ubiquitous pathogen that usually produces self-limiting gastrointestinal symptoms. However, in susceptible patients, it can lead to central nervous system infections which are potentially fatal. We present the case of a 10-year-old male under chemotherapy treatment for acute lymphoblastic leukemia. During the induction period he developed a brain abscess due to B. cereus which was diagnosed through imaging tests and direct detection in the cerebrospinal fluid. His evolution was favorable with antibiotic treatment. So far, 26 other cases of central nervous system infections due to B. cereus have been described in literature, and besides being infrequent, they are a diagnostic challenge. However, in preterm infants, patients with hematological malignancies or central nervous system surgery, early suspicion should be established to start an appropriate antibiotic treatment and improve prognosis. Infección del sistema nervioso central por Bacillus cereus descripción de un caso y revisión de la bibliografía. Introducción. Bacillus cereus es un patógeno ubicuo que, habitualmente, produce síntomas gastrointestinales autolimitados. Sin embargo, en pacientes susceptibles, puede dar lugar a infecciones del sistema nervioso central potencialmente mortales. Desarrollo. Presentamos el caso de un varón de 10 años en tratamiento quimioterápico por leucemia linfoblástica aguda. Durante el período de inducción desarrolló un absceso cerebral por B. cereus que fue diagnosticado mediante pruebas de imagen y detección directa en el líquido cefalorraquídeo. Su evolución fue favorable con tratamiento antibiótico. Conclusiones. Hasta ahora se han descrito en la bibliografía otros 26 casos de infección del sistema nervioso central por B. cereus, que, además de ser infrecuentes, suponen un reto diagnóstico. Sin embargo, en los recién nacidos prematuros, en pacientes con neoplasias hematológicas o con antecedentes de cirugía del sistema nervioso central, debe establecerse una sospecha temprana para iniciar un tratamiento antibiótico adecuado que mejore el pronóstico.

Cytogenetic and molecular characteristics and outcomes of adult patients with early T-cell precursor acute lymphoblastic leukemia.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently identified high-risk subgroup of T-cell ALL in children. However, there have been conflicting reports and limited data have been reported in adult patients. We retrospectively analyzed the cytogenetic and molecular characteristics and long-term survival outcomes of adult patients with ETP-ALL versus non-ETP-ALL. We analyzed 58 patients (median age, 35 years range, 18-76 years) with newly diagnosed T-cell ALL who received a uniform remission induction and consolidation chemotherapy with suitable samples for genetic analyses. If a donor was available, all patients were recommended allogeneic hematopoietic cell transplantation (allo-HCT) for post-remission therapy. Out of 58 patients, 21 (36.2%) had ETP-ALL. Patients with ETP-ALL were older and had a higher proportion of complex karyotype than non-ETP-ALL. Additionally, more DNMT3A mutations were detected in ETP-ALL, whereas FBXW7 mutations and CDKN2ACDKN2B deletions were found nearly exclusively in non-ETP-ALL. The overall complete remission (CR) rates were not different between ETP-ALL (95.2%) and non-ETP-ALL (81.1%) and subsequent allo-HCT proceeding rates in CR1 were 61.9% for ETP-ALL and 43.2% for non-ETP-ALL, respectively. The overall prognosis of patients with T-ALL was poor that estimated 5-year overall survival (OS) was 33.3% for ETP-ALL and 29.5% for non-ETP-ALL. In a subgroup analysis of patients treated with allo-HCT in CR1 (n 29), 5-year OS was 53.8% for ETP-ALL and 55.4% for non-ETP-ALL. Our data showed molecular characteristics of ETP-ALL and non-ETP-ALL and revealed that intensive chemotherapy followed by allo-HCT for post-remission therapy can contribute to preserved survival outcome of adult patients with ETP-ALL.

Measuring disparities in event-free survival among children with acute lymphoblastic leukemia in an academic institute in Oklahoma, 2005-2019.

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. While there have been successes in the treatment of leukemia, less information is available on reasons for disparities in event-free survival (EFS) among underserved populations. We partnered with a childrens hospital at an academic institution to abstract data from the institutions cancer registry, the state cancer registry, and electronic medical records on cancer diagnosis, treatment, and outcomes for children with ALL (n 275) diagnosed from 2005 to 2019 prior to age 20. We evaluated the relation between 1) raceethnicity, 2) distance to the childrens hospital, and 3) area deprivation with EFS, defined as time from diagnosis to relapse, death, or the end of the study period. We evaluated differences in EFS using Kaplan-Meier analysis with the log-rank test. We used the Cox Proportional Hazards Model for multivariable survival analyses. Most children were diagnosed with ALL under five years of age (45%) and with Pre-B ALL (87%). Twelve percent of children experienced a relapse and 5% died during induction or remission. EFS at 5 years was 82%. Non-Hispanic (NH) Black children had worse, though imprecise, EFS compared to NH White children (Adjusted Hazard Ratio 2.07, 95% CI 0.80, 5.38). Children residing in areas with higher deprivation had a higher adjusted hazard of poor outcomes compared to the least deprived areas, though estimates were imprecise (2nd quartile HR 1.51, 3rd quartile 1.85, 4th quartile 1.62). We observed no association between distance to the childrens hospital and EFS. We observed poorer EFS for NH Black children and children residing in areas with high deprivation, though the estimates were not statistically significant. Our next steps include further evaluating socioeconomic factors in both rural and urban children to identify disparities in outcomes for children with ALL and other childhood cancers.

Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsedrefractory acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed andor refractory ALL. Patients aged 1-21 years (n 24) received 4-week induction therapy with carfilzomib at dose levels of 27 mgm Following dose escalation of carfilzomib, the recommended phase 2 carfilzomib dose was identified as 56 mgm These data support the use of carfilzomib in pediatric patients with relapsed andor refractory ALL.

Targeting FLT3-specific chimeric antigen receptor T cells for acute lymphoblastic leukemia with KMT2A rearrangement.

CD19-specific chimeric antigen receptor T (CAR T) immunotherapy is used to treat B-cell malignancies. However, antigen-escape mediated relapse following CAR T therapy has emerged as a major concern. In some relapsed cases, especially KMT2A rearrangement-positive B-acute lymphoblastic leukemia (KMT2A-r B-ALL), most of the B-cell antigens are lost via lineage conversion to the myeloid phenotype, rendering multi-B-cell-antigen-targeted CAR T cell therapy ineffective. Fms-related tyrosine kinase-3 (FLT3) is highly expressed in KMT2A-r B-ALL therefore, in this study, we aimed to evaluate the antitumor efficacy of CAR T cells targeting both CD19 and FLT3 in KMT2A-r B-ALL cells. We developed piggyBac transposon-mediated CAR T cells targeting CD19, FLT3, or both (dual) and generated CD19-negative KMT2A-r B-ALL models through CRISPR-induced CD19 gene-knockout (KO). FLT3 CAR T cells showed antitumor efficacy against CD19-KO KMT2A-r B-ALL cells both in vitro and in vivo dual-targeted CAR T cells showed cytotoxicity against wild-type (WT) and CD19-KO KMT2A-r B-ALL cells, whereas CD19 CAR T cells demonstrated cytotoxicity only against WT KMT2A-r B-ALL cells in vitro. Therefore, targeting FLT3-specific CAR T cells would be a promising strategy for KMT2A-r B-ALL cells even with CD19-negative relapsed cases.

Cell adhesion molecule CD99 in cancer immunotherapy.

The CD99 antigen is a transmembrane protein expressed in a broad variety of tissues, particularly in hematopoietic cells, thymus, endothelial cells, etc. It participates in several crucial biological processes including cell adhesion, migration, death, differentiation and inflammation. CD99 has been shown oncogenic or tumor suppressor roles in different types of cancer. Therefore, it has been used as a biomarker and therapeutic target for several types of cancer. Moreover, it has also been reported to be involved in several critical immune processes, such as T cell activation and differentiation, dendritic cell differentiation, and so on. Hence, CD99 may have potential values in cancer immunotherapy. Anti-CD99 antibodies have been shown therapeutic effects on certain types of cancer, especially on Ewing sarcoma and T cell acute lymphoblastic leukemia (ALL). This review summarizes the recent progresses of CD99 in cancer research and targeting therapies, especially in cancer immunotherapy, which may help researchers understand the crucial roles of CD99 in cancer development and design new therapeutic strategies.

Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity.

Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph) leukemia. We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). Peripheral blood mononuclear cells from 53 Ph patients on TKIs and 15 control patients without Ph leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up 26 months Q1-Q3 5-37 months). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.

Structural, Optical, Antibacterial, and Anticancer Properties of Cerium Oxide Nanoparticles Prepared by Green Synthesis Using

Currently, new advancements in the area of nanotechnology opened up new prospects in the field of medicine that could provide us with a solution for numerous medical complications. Although a several varieties of nanoparticles is being explored to be used as nanomedicines, cerium oxide nanoparticles (CeO

A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia quiescent phenotype and unique transcriptomic profile.

In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p<0.05) with 70.6% down-regulated in NBDG-low cells. Hierarchical clustering of DETs showed distinct segregation of NBDG-low from NBDG-med and NBDG-high groups with marked transcription expression alterations in the NBDG-low group consistent with cancer survival. In conclusion, A unique subpopulation of cells with low glucose uptake (NBDG-low) in B-ALL was discovered. These cells, despite their quiescence characteristics, once transplanted in mice, showed potent leukemia initiating capacity. Although NBDG-med cells also initiated leukemia, gene expression profiling revealed a distinct signature that clearly distinguishes NBDG-low cells from NBDG-med and the rest of the leukemia populations. These results suggest that NBDG-low cells may represent quiescent LSCs. These cells can be activated in the appropriate environment

T-cell Acute Lymphoblastic Leukemia in an Infant A Case Report and Review of Literature.

A high index of suspicion of acute leukemia in infants presenting with atypical clinical and laboratory features is of paramount importance to avoid the delay in diagnosis, and treatment of this rare, yet extremely aggressive entity. We report a case of a 10 months infant presenting with a one-month history of fever and restlessness along with complete blood count (CBC) findings of bicytopenia, borderline leukocytosis, leucoerythroblastic picture, and reactive lymphocytes. Considering infection, the patient was kept on antibiotics and symptomatic treatment. However, the persistence of findings led to bone marrow aspirate which revealed T-cell acute lymphoblastic leukemia (T-ALL) on flow cytometry. Infant ALL is almost B cell phenotype and T-ALL is hardly ever reported. Knowledge and recognition of these cases can help to improve awareness regarding consideration of this rare phenotype of leukemia irrespective of clinical presentation and age of the patient. Key Words Acute lymphoblastic leukemia, Infant leukemia, Flow cytometry.

Unrelated cord blood transplantation vs. HLA-matched sibling transplantation for adults with B-cell acute lymphoblastic leukemia in complete remission superior OS for patients with long-term survival.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for adult acute lymphoblastic leukemia (ALL). For patients who lack a human leukocyte antigen (HLA)-matched sibling donor, unrelated cord blood (UCB) is an alternative graft option. Previous studies have focused mainly on all T- and B-cell ALL (B-ALL) patients, while data related specifically to adult B-ALL patients after UCB transplantation (UCBT) are scarce. We retrospectively compared the outcomes of UCBT and HLA-matched sibling transplantation (MST) in the treatment of adult B-ALL patients in complete remission (CR) at our center. From June 2006 to December 2020, 156 adult B-ALL patients who achieved CR before transplantation were enrolled. The main clinical outcomes of UCBT and MST were analyzed. Hematopoietic recovery was significantly faster in MST recipients than in UCBT recipients. Higher incidences of grades II-IV and III-IV acute graft-versus host disease (aGVHD) were found in UCBT recipients (P < 0.001 and 0.03), while a lower incidence of extensive chronic GVHD (cGVHD) was found in UCBT recipients (P < 0.001). The cumulative incidences of 2-year non-relapse mortality (NRM), 2-year relapse, 5-year disease-free survival (DFS) and 5-year GVHD-free relapse-free survival (GRFS) were comparable between MST and UCBT recipients. The overall survival (OS) during the first 700 days was similar between the MST and UCBT groups, while the OS of patients with a survival time of more than 700 days in the UCBT group was better than that in the MST group according to multivariate analysis (P 0.03). Our study shows that when treating adult B-ALL patients in CR, UCBT can achieve comparable effects as MST, may provide superior OS for patients with long-term survival, and should be considered a good alternative.

Effect of Philadelphia Chromosome Karyotype and Allogeneic Hematopoietic Stem Cell Transplantation on Patients with Acute Lymphoblastic Leukemia.

AbstractObjective To explore the effect of Philadelphia chromosome karyotype (Ph) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the treatment of acute lymphoblastic leukemia (ALL). The data of 429 patients with all from January 2012 to December 2020 were retrospectively analyzed. According to the results of cytogenetic karyotype analysis, they were divided into Ph Among the 429 patients, 6 (1.40%) died during induction therapy, 60 (13.99%) had no response, 363 (84.62%) achieved complete remission (CR) and 287 (66.90%) achieved minimal residual disease negative (MRD-). There was no significant difference in short-term efficacy (CR%, CR1%, MRD-%) among Ph Karyotype (Ph 费城染色体核型和异基因造血干细胞移植对急性淋巴细胞白血病患者疗效的影响. 探究费城染色体核型（Ph）和异基因造血干细胞移植（allo-HSCT）对急性淋巴细胞白血病（ALL）患者疗效的影响. 回顾性分析2012年1月－2020年12月血液科429例ALL患者的资料，根据细胞遗传学核型分析结果将患者分为Ph 在429例ALL患者中，6例（1.40%）在诱导治疗期间死亡，60例（13.99%）无反应，最终达到完全缓解（CR）共363例（84.62%），达到微小残留病灶阴性（MRD-）共有287例（66.90%）。Ph 核型（Ph

Analysis of 42 cases of childhood superior vena cava syndrome associated with mediastinal malignancy.

Report of Chinese Childrens Cancer Group acute lymphoblastic leukemia 2015 multicenter study.

Double filtration plasmapheresis for hypertriglyceridemic acute pancreatitis caused by fat overload syndrome.

Severe hypertriglyceridemia (HTG) can cause acute pancreatitis (AP). We report a patient with acute lymphoblastic leukaemia who received long-term intravenous parenteral nutrition solution without monitoring of the serum triglyceride (TG) level, which resulted in fat overload syndrome and HTG-AP. Double filtration plasmapheresis was performed to eliminate the TGs and treat the AP.

Clinical and Prognostic Impact of Copy Number Alterations and Associated Risk Profiles in a Cohort of Pediatric B-cell Precursor Acute Lymphoblastic Leukemia Cases Treated Under ICiCLe Protocol.

Copy number alteration (CNA) status and CNA risk profiles of

Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood

Infant acute lymphoblastic leukemia (ALL) with

Lessons to cancer from studies of leukemia and hematopoiesis.

The starting point to describing the origin and nature of any cancer must be knowledge about how the normal counterpart tissue develops. New principles to the nature of hematopoietic stem cells have arisen in recent years. In particular, hematopoietic stem cells can choose a cell lineage directly from a spectrum of the end-cell options, and are, therefore, a heterogeneous population of lineage affiliatedbiased cells. These cells remain versatile because the developmental trajectories of hematopoietic stem and progenitor cells are broad. From studies of human acute myeloid leukemia, leukemia is also a hierarchy of maturing or partially maturing cells that are sustained by leukemia stem cells at the apex. This cellular hierarchy model has been extended to a wide variety of human solid tumors, by the identification of cancer stem cells, and is termed the cancer stem cell model. At least, two genomic insults are needed for cancer, as seen from studies of human childhood acute lymphoblastic leukemia. There are signature mutations for some leukemias and some relate to a transcription factor that guides the cell lineage of developing hematopoietic stemprogenitor cells. Similarly, some oncogenes restrict the fate of leukemia stem cells and their offspring to a single maturation pathway. In this case, a loss of intrinsic stem cell versatility seems to be a property of leukemia stem cells. To provide more effective cures for leukemia, there is the need to find ways to eliminate leukemia stem cells.

IL-7 Comprehensive review.

IL-7 is a member of the family of cytokines with four anti-parallel α helixes that bind Type I cytokine receptors. It is produced by stromal cells and is required for development and homeostatic survival of lymphoid cells. Interleukin 7 (IL7) human IL7 gene ID 3574 on ch 8 murine Il7 gene ID 16,196 on ch 3. Precursor contains a signal sequence, mature human IL-7 peptide 152aa, predicted 17.4kd peptide, glycosylated resulting in 25kd. Crystal structure httpwww.rcsb.orgstructure3DI2. REGULATION OF IL-7 PRODUCTION Major producers are stromal cells in thymus, bone marrow and lymphoid organs but also reported in other tissues. Production is primarily constitutive but reported to be affected by IFNγ and other factors. IL-7 RECEPTORS Two chains IL-7Rα (IL-7R) and γc (IL-2RG). Human IL-7R gene ID 3575 on ch 5 human IL2RG gene ID 3561 on ch X mouse IL-7R gene ID 16,197 on ch 15 murine Il2rg gene ID 16,186 on ch X. Member of γc family of receptors for cytokines IL-2, -4, -9, -15, and -21. Primarily expressed on lymphocytes but reports of other cell types. Expression in T-cells downregulated by IL-7. Low expression on Tregs, no expression on mature B-cells. Crystal structure httpwww.rcsb.orgstructure3DI2. IL-7 RECEPTOR SIGNAL TRANSDUCTION PATHWAYS Major signals through JAK1, JAK3 to STAT5 and through non-canonical STAT3, STAT1, PI3KAKT and MEKERK pathways. BIOLOGICAL ACTIVITY OF IL-7 Required for survival of immature thymocytes, naïve T-cells, memory T-cells, pro-B-cells and innate lymphocytes. Pharmacological treatment with IL-7 induces expansion of naïve and memory T-cells and pro-B-cells. ABNORMALITIES OF THE IL-7 PATHWAY IN DISEASE Deficiencies in the IL-7 pathway in humans and mice result in severe combined immunodeficiency due to lymphopenia. Excessive signaling of the pathway in mice drives autoimmune diseases and in humans is associated with autoimmune syndromes including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, atopic dermatitis and asthma. Mutations in the IL-7 receptor pathway drive acute lymphoblastic leukemia. IL-7 has been evaluated in patients with cancer and shown to expand lymphocytes. It accelerated lymphocyte recovery after hematopoietic stem cell transfer, and increased lymphocyte counts in AIDS patients and sepsis patients. Monoclonal antibodies blocking the IL-7 receptor are being evaluated in autoimmune diseases. Cytotoxic monoclonals are being evaluated in acute lymphoblastic leukemia. Drugs blocking the signal transduction pathway are being tested in autoimmunity and acute lymphoblastic leukemia.

Outcomes of blinatumomab based therapy in children with relapsed, persistent, or refractory acute lymphoblastic leukemia a multicenter study focusing on predictors of response and post-treatment immunoglobulin production.

The management of RefractoryRelapsed B-cell Acute Lymphoblastic Leukemia (RR ALL) remains challenging. Incorporating blinatumomab in RR ALL treatment has shown encouraging results. We describe the outcome and predictors of response in children receiving blinatumomab as a bridge to definitive therapy. Immunoglobulin (Ig) G and viral serology before and after therapy were evaluated. Thirty-three patients that failed standard first-line treatments due to relapsed ALL (

Evaluation of neuropathic pain with diverse pathophysiologies in childhood cancers.

Neuropathic pain (NP) is caused by damage or disease affecting the somatosensory nervous system. The aim of this study was to evaluate the clinical characteristics, pathophysiologies, and treatments applied in pediatric cancer patients with NP. Patients with cancer having NP between 5 and 18 years of age who were followed up in the pediatric oncology clinic of Okmeydani Training and Research Hospital between January 2015 and April 2019 were included in this study. NP was described as tingling, burning, and stinging. Patients with acute lymphoblastic leukemia and brain tumors were excluded from the study. A number of pediatric cancer patients were also recorded. Patients age, gender, cancer diagnosis, NP characteristics and causes, treatments, and response to those treatments were investigated retrospectively and groups of NP according to their pathophysiological mechanism were established. NP was found in 26 (16%) of 160 patients followed up for childhood cancers. The average age was 11.8±4 years. Ten of the patients (38.4%) were female, and 16 (61.5%) were male. Osteosarcoma was the most common diagnosis in 10 (38%) patients. The most common cause of NP was compression of a nerverootspinal cord in 9 (35%) patients and the second most common was related with limb-sparing surgery. NP was found to be associated with chemotherapy (CT) in 5 (19%) patients, mostly with vincristine. Gabapentin was administered in a total of 22 (85%) patients for treatment. Opioid administration was more common as the disease stage progressed (p<0.05). A good or partial response to treatment was achieved in 19 (73%) patients. NP can occur in childhood cancers and is related to the cancer itself, CT, surgical treatment, and disseminated disease. Although there is no standard protocol, gabapentin and, for advanced-stage patients, opioids are the most commonly used treatment options.