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Chemotherapy-related hyperbilirubinemia in pediatric acute lymphoblastic leukemia a genome-wide association study from the AIEOP-BFM ALL study group.

Characterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS). Patients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during inductionconsolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial. Compared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during inductionconsolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P 0.003 85.2 ± 2% for grade 0, P < 0.001) and a higher cumulative incidence of relapse (15.6 ± 3% versus 9.0 ± 1% for grades 1-2, P 0.08 11.1 ± 1% for grade 0, P 0.007). GWAS identified a strong association of the rs6744284 variant T allele in the UGT1A gene cluster with risk of hyperbilirubinemia (allelic odds ratio (OR) 2.1, P 7 × 10 Chemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia. httpwww. gov NCT00430118.

Guest editorial recent progress in pediatric leukemia.

Recent progress in comprehensive genomic analysis and well-designed clinical trials has dramatically improved the treatment strategies for pediatric leukemia, resulting in better prognosis and reducing acute and late adverse events. This review series describes successes and challenges for the future in the management of pediatric leukemia.

Current status of producing autologous hematopoietic stem cells.

Hematopoietic stem cells (HSCs) transplantation is an established therapy for many diseases of the hematopoietic system, for example aplastic anemia, acute myeloid leukemia and acute lymphoblastic leukemia. With the development of the HSCs research, HSCs provide an attractive method for treating hereditary blood disorders and immunotherapy of cancer by introducing gene modification. Compared with allogenic HSCs transplantation, using autologous HSCs or HSCs from induced pluripotent stem cells (iPSCs) would eliminate the probability of alloimmunization and transfusion-transmitted infectious diseases. The methods for obtaining autologous HSCs include amplifying patients HSCs or inducing patients somatic cells to HSCs (graph abstract). However, the biggest problem is inducing HSCs to proliferate in vitro and maintaining their stemness at the same time. Although many tests have been made to transform iPSCs to HSCs, the artificially generated HSCs still have substantial disparity compared with physiological HSCs. This review summarized the application status and obstacles to implantation of autologous HSCs and iPSC-derived HSCs. Meanwhile, we summarized the latest research progress in HSCs amplification and iPSCs reprogramming methods, which will help to solve the problems mentioned above.

Infectious Complications and Preventative Strategies following Chimeric Antigen Receptor T-cells (CAR-T cells) Therapy for B-Cell Malignancies.

Several chimeric antigen receptor T-cell constructs (CAR-T cells) are currently approved for the treatment of B-cell malignancies, including non-Hodgkin lymphoma and acute lymphoblastic leukemia. Additionally, multiple other products are being investigated and developed for other hematological malignancies and solid cancers. Patients receiving CAR-T cells are at increased risk of infectious complications that lead to increased morbidity and inferior mortality in these patients. In this review, we discuss the literature on the incidence and types of infection in patients in the early and late-phase after CAR-T cells infusion. Additionally, we summarize the current literature on prophylaxis against viral, bacterial, and fungal infections after CAR-T cells infusion and the utility of preventative and supportive measures including intravenous immunoglobulins and myeloid growth factors.

Understanding the Etiology of Pancytopenias in the CAR T-Cell Therapy Setting What We Know and What We Dont

Chimeric antigen receptor T-cell (CAR T-cell) therapy represents an innovative and transformative therapy for patients with relapsed andor refractory (RR) hematological malignancies. CAR T-cell therapy was first approved in RR diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia, today the use of CAR T-cell therapy has expanded to multiple myeloma and other lymphoma subtypes such as follicular and mantle cell lymphoma. It is also being explored in earlier lines of therapy in DLBCL. CAR T-cell therapy is associated with a unique toxicity profile and development of cytopenias post CAR T-cell therapy has been reported in all pivotal clinical trials and is now considered a related side effect. Here, we provide an in-depth evaluation of etiologies, consequences, and current management strategies for cytopenias following CAR T-cell therapy.

An acute lymphoblastic leukemia cell-based preclinical assay revealed functional differences between commercial brands of L-asparaginase administered in Colombia.

L-asparaginase (L-ASNase) is an essential component of chemotherapy strategies due to its differential action between normal and leukemic cells. Recently, concerns about the efficiency of commercial formulations administered in developing countries have been reported, and available methods have limitations for directly determining the quality of the formulation of the medications. We developed a cell-based protocol to analyze the activity of different L-ASNase formulations used in Colombia to induce apoptosis of the NALM-6 cell line after 24, 48, and 72 hours, using flow cytometry. Then we compared results and determined the statistically significant differences. Three statistically different groups, ranging from full to no activity against leukemic cells, using 0.05, 0.5, and 5.0 IUml concentrations, were identified. Group 1 (asparaginase codified ASA2-4) exhibited very low to no activity against B-cell acute lymphoblastic leukemia (B-ALL) cells. Group 2 (ASA6) exhibited intermediate-level activity, and group 3 (ASA1 and ASA5) exhibited high activity. Differences found between the therapeutic formulations of L-ASNase distributed in Colombia raise concerns about the quality of the treatment administered to patients in low- and middle-income countries. Therefore, we recommend a preclinical evaluation of formulations of L-ASNase in order to prevent therapeutical impacts on the outcome of ALL patients.

TAL1 activation in T-Cell acute lymphoblastic leukemia A novel oncogenic 3 neoenhancer.

T-cell acute lymphocytic leukemia protein 1 (TAL1) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). Its deregulation can occur through diverse in cis-alterations, including SIL-TAL1 microdeletions, translocations with Tcell Receptor (TCR) loci and, more recently described upstream intergenic non-coding mutations. These mutations consist of recurrent focal microinsertions that create an oncogenic neo-enhancer accompanied with activating epigenetic marks. This observation laid the groundwork for an innovative paradigm, the activation of proto-oncogenes via genomic alterations of non-coding intergenic regions. However, for the majority of TAL1 expressing (TAL1) T-ALLs, the deregulation mechanism remains unresolved. We took advantage of H3K27ac and H3K4me3 ChIP-seq data of eight T-ALLs, including five TAL1 cases and identified a putative novel oncogenic neo-enhancer downstream of TAL1 in an unresolved monoallelic TAL1 case. A rare but recurrent somatic heterozygous microinsertion within this region creates a de novo binding site for MYB transcription factor (TF). Here, we demonstrate that this mutation leads to increased enhancer activity, gain of active epigenetic marks and TAL1 activation via recruitment of MYB. These results highlight the diversity of non-coding mutations that can drive oncogene activation.

Abnormal expression of

Leukemia is a neoplasm with high incidence and mortality rates. Mitotic death has been observed in tumor cells treated with chemotherapeutic agents. Ras family proteins participate in the transduction of signals involved in different processes, such as proliferation, differentiation, survival, and, paradoxically, initiation of cell death. This study investigated the effect of Human T-cell acute lymphoblastic leukemia MOLT-4 cells showed nuclear fragmentation and presence of multiple nuclei and micronuclei after transfection with either wt or mutant Transfection of human T-cell acute lymphoblastic leukemia MOLT-4 cells with either normal or mutated

Ponatinib-Induced Cerebrovascular Accident (CVA).

Ponatinib is a highly potent tyrosine kinase inhibitor shown to have excellent outcomes in the treatment of acute and chronic leukemias. Despite its high efficacy, ponatinib has been shown to carry an increased risk for cardiovascular adverse events, not attributable to a known mechanism. We present a case of a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) who developed a cerebrovascular condition while receiving maintenance therapy with the lowest treatment dose of ponatinib for a prolonged duration.

Outdoor artificial light at night, air pollution, and risk of childhood acute lymphoblastic leukemia in the California Linkage Study of Early-Onset Cancers.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0-14 years) however, the etiology remains incompletely understood. Several environmental exposures have been linked to risk of childhood ALL, including air pollution. Closely related to air pollution and human development is artificial light at night (ALAN), which is believed to disrupt circadian rhythm and impact health. We sought to evaluate outdoor ALAN and air pollution on risk of childhood ALL. The California Linkage Study of Early-Onset Cancers is a large population-based case-control in California that identifies and links cancer diagnoses from the California Cancer Registry to birth records. For each case, 50 controls with the same year of birth were obtained from birth records. A total of 2,782 ALL cases and 139,100 controls were identified during 2000-2015. ALAN was assessed with the New World Atlas of Artificial Night Sky Brightness and air pollution with an ensemble-based air pollution model of particulate matter smaller than 2.5 microns (PM

Haploidentical vs matched unrelated donors for patients with ALL donor age matters more than donor type.

Haploidentical hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis yields similar overall survival (OS) as HLA-matched-unrelated donor (MUD) HCT with conventional prophylaxis. Given prognostic implications of donor age, we investigated the impact of donor age younger (<35 years n868) vs older (>35 years n418) and donor-type haploidentical (n373) vs MUD (n913) on OS in adult patients with acute lymphoblastic leukemia (ALL). Older donor age was independently associated with significantly poor OS hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.10-1.71, p0.005 donor-type was not. Next, we directly compared the outcomes of a younger haploidentical donor (n187) vs an older MUD (n232). In this cohort, more patients in the haploidentical group had B-cell immunophenotype (89% vs 77%, respectively, p<0.001), poor cytogenetics (61% vs 51%, respectively, p0.44), Philadelphia chromosome-negative (53% vs 48%, respectively, p0.38), received bone marrow graft (42% vs 16%, respectively, p<0.001) and reduced-intensity conditioning (45% vs 23%, respectively, p<0.001). In multivariate analysis, the older MUD group was associated with a significantly higher risk of chronic GVHD HR 1.91, 95% CI 1.28-2.85, p0.002, higher non-relapse mortality (HR 2.75, 95% CI 1.51-4.99, p0.001), lower relapse (HR 0.50, 95% CI 0.31-0.82, p0.006) and poorer OS (HR 1.77, 95% CI 1.16-2.71, p0.008). Despite a higher risk of relapse, younger donor haploidentical HCT with PTCy prophylaxis may be preferred over an older MUD HCT with conventional prophylaxis in patients with ALL due to lower nonrelapse mortality and better OS. Further analysis comparing the effect of donor age in haploidentical-PTCy vs MUD-PTCy is warranted.

Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis.

Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n 591, ages 18-84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis. We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL. See related commentary by Saiki and Ogawa, p. 102. This article is highlighted in the In This Issue feature, p. 101.

Immunophenotypic characterization of acute leukemias in Bahia, Brazil.

To characterize the immunophenotypic profile of acute leukemias in the population of the state of Bahia, Brazil. This is a descriptive, retrospective study. From 2014 to 2018, 796 new cases of acute leukemia were evaluated. The data were obtained from analysis of reports and records of tests performed by flow cytometry immunophenotyping. All individuals of all age groups diagnosed as acute lymphoblastic leukemia or acute myeloid leukemia were included in the study. Demographic variables and expression of leukemia antigens were evaluated. Most cases were diagnosed as acute myeloid leukemia and 42.7% as acute lymphoblastic leukemia. Significant differences were found in expression of markers in acute leukemias when age groups were compared, as well as in demographic characteristics. B-cell acute lymphoblastic leukemia was more prevalent than cases of T-cell origin. Assessing the aberrant markers in acute myeloid leukemias, the non-acute promyelocytic leukemia group presented expression of CD7 and CD56 as the most frequent ones. In B-cell acute lymphoblastic leukemia, the most frequent aberrant markers were CD66c, CD13 and CD33. Significant differences were found as to several antigens when comparing adults and children, and these findings may contribute to future studies correlating the phenotypic profile to genetic characteristics and therapeutic response, including specific antigen therapies, which may be better targeted.

Effect of nutritional parameters on microbial production of L-Asparaginase by novel

L-Asparaginase owes considerable significance in food and pharmaceutical applications. L-Asparaginase is an antineoplastic enzyme that finds application in the treatment of Acute Lymphoblastic Leukemia (ALL) and in mitigating acrylamide (a potent carcinogen) production during baking. In this study, we aimed to optimize nutritional parameters that are significant in initiating and regulating a bioprocess system in order to maximize enzyme production from a novel isolated bacterial species

Tyrosine kinases in KMT2AMLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance.

Allele-specific polymerase chain reaction can determine the diplotype of NUDT15 variants in patients with childhood acute lymphoblastic Leukemia.

Mercaptopurine intolerance is an adverse effect of mercaptopurine administration in pediatric patients with acute lymphoblastic leukemia (ALL). NUDT15 variants have emerged as major determinants of mercaptopurine intolerance, especially in the Asian population. Two variants, c.5556insGAGTCG in exon 1 and c.415C > T in exon 3, were commonly detected in the same allele, named NUDT1512. Although rare, compound heterozygous mutations also occur, with the two variants on different alleles (NUDT1536), which may confer tolerance to considerably lesser mercaptopurine dosage. Sanger sequencing or pyrosequencing can determine the NUDT15 variants but not the phase. Here, we designed an allele-specific PCR (AS-PCR) with locked nucleic acid-modified primers. A cohort of 63 patients harboring heterozygous c.5556insGAGTCG and c.415C > T NUDT15 variations was selected for haplotyping using AS-PCR. Of the 63 patients, 60 harbored the NUDT1512 variant and three harbored compound heterozygous mutations, including two NUDT1536 and one NUDT1527 variants. These findings suggest that AS-PCR can determine NUDT15 diplotype and identify patients with compound heterozygous NUDT15 variants, which may enable precise genetic diagnosis of NUDT15. Nevertheless, a larger clinical trial is required to understand the clinical significance of NUDT1536 in pediatric patients with ALL because of its low incidence rate and challenges in detecting this variant.

Feasibility of serial neurocognitive assessment using Cogstate during and after therapy for childhood leukemia.

Neurocognitive impairment is frequently observed among survivors of childhood acute lymphoblastic leukemia (ALL) within the domains of attention, working memory, processing speed, executive functioning, and learning and memory. However, few studies have characterized the trajectory of treatment-induced changes in neurocognitive function beginning in the first months of treatment, to test whether early changes predict impairment among survivors. If correct, we hypothesize that those children who are most susceptible to early impairment would be ideal subjects for clinical trials testing interventions designed to protect against treatment-related neurocognitive decline. In this pilot study, we prospectively assessed neurocognitive functioning (attention, working memory, executive function, visual learning, and processing speed), using the Cogstate computerized battery at six time points during the 2 years of chemotherapy treatment and 1-year post-treatment (Dana-Farber Cancer Institute ALL Consortium protocol 11-001 NCT01574274). Forty-three patients with ALL consented to serial neurocognitive testing. Of the 31 participants who remained on study through the final time point, 1 year after completion of chemotherapy, 28 (90%) completed at least five of six planned Cogstate testing time points. Performance and completion checks indicated a high tolerability (≥ 88%) for all subtests. One year after completion of treatment, 10 of 29 patients (34%) exhibited neurocognitive function more than 2 standard deviations below age-matched norms on one or more Cogstate subtests. Serial collection of neurocognitive data (within a month of diagnosis with ALL, during therapy, and 1-year post-treatment) is feasible and can be informative for evaluating treatment-related neurocognitive impairment.

A rare maxillofacial manifestation of acute lymphoblastic leukemia in a 9-year-old child.

Acute lymphoblastic leukemia (ALL) is considered as the most common malignant neoplasm of childhood and the frequent cause of death from cancer before 20-years of age. The facial swelling mimicking a maxillofacial tumor is rarely associated with ALL. Clinicians should be aware of such rare manifestation of ALL. We present a case with an atypical mass in the facial region secondary to ALL, which resulted in diagnostic dilemma. Reports of such atypical swelling in patients with ALL are occasional. The swelling was aggressive and the disease had a fulminant course.

Prognostic significance of steroid response in pediatric acute lymphoblastic leukemia The CCCG-ALL-2015 study.

Whether steroid response is an independent risk factor for acute lymphoblastic leukemia (ALL) is controversial. This study aimed to investigate the relationship between response to dexamethasone and prognosis in children with ALL. We analyzed the data of 5,161 children with ALL who received treatment in accordance with the Chinese Childrens Cancer Group ALL-2015 protocol between January 1, 2015, and December 31, 2018, in China. All patients received dexamethasone for 4 days as upfront window therapy. Based on the peripheral lymphoblast count on day 5, these patients were classified into the dexamethasone good response (DGR) and dexamethasone poor response (DPR) groups. A peripheral lymphoblast count ≥1× 10 The age, white blood cell counts, prevalence of the Response to dexamethasone was associated with an early treatment response in our study. In the intermediate-risk group, dexamethasone response added a prognostic value in addition to minimal residual disease, which may direct early intervention to reduce the relapse rate.

The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia advances, challenges and future perspectives.

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging pediatric and adult haematologic disease still associated with an unsatisfactory cure rate. Unlike B-ALL, the availability of novel therapeutic options to definitively improve the life expectancy for relapsedresistant patients is poor. Indeed, the shared expression of surface targets among normal and neoplastic T-cells still limits the efficacy and may induce fratricide effects, hampering the use of innovative immunotherapeutic strategies. However, novel monoclonal antibodies, bispecific T-cell engagers (BTCEs), and chimeric antigen receptors (CAR) T-cells recently showed encouraging results and some of them are in an advanced stage of pre-clinical development or are currently under investigation in clinical trials. Here, we review this exciting scenario focusing on most relevant advances, challenges, and perspectives of the emerging landscape of immunotherapy of T-cell malignancies.

PD-1 signalling defines and protects leukaemic stem cells from T cell receptor-induced cell death in T cell acute lymphoblastic leukaemia.

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy with poor prognosis, but a decisive marker and effective treatment for leukaemia stem cells (LSCs) remain unclear. Here, using lineage tracing, limiting dilution assays and in vivo live imaging approaches, we identify rare inhibitory receptor programmed cell death 1 (PD-1)-expressing cells that reside at the apex of leukaemia hierarchy for initiation and relapse in T-ALL. Ablation of PD-1-expressing cells, deletion of PD-1 in T-ALL cells or blockade of PD-1 or PD-1 ligand 1 significantly eradicated LSCs and suppressed disease progression. Combination therapy using PD-1 blockade and chemotherapy substantially extended the survival of mice engrafted with mouse or human T-ALL cells. Mechanistically, PD-1

The pathogenesis and development of targeted drugs in acute T lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is mainly classified into acute T- and B-lymphoblastic leukaemia according to the source of its lymphocytes, thymus and bone. Among them, the incidence of adult T-cell accounts for about 25% of adult acute lymphoblastic leukaemia, but the degree of malignancy is high and the treatment rate and prognosis are poor. At this stage, there are few targeted drugs and the commonly used broad-spectrum chemotherapeutic drugs have poor efficacy and many adverse drug reactions. Understanding and investigating the pathogenesis of T-acute lymphoblastic leukaemia is very important for further developing new targeting drugs and improving existing drugs. Dysregulated signalling pathways are the main aetiological factors of T-acute lymphoblastic leukaemia. They play crucial roles in promoting tumour initiation, progression, drug design and therapy responses. This is primarily because signalling pathways are indispensable for many cellular biological processes, including tumour growth, migration, invasion, metastasis and others. As a result, small molecule inhibitors targeting the major kinase components of the signalling pathway have received a lot of attention and have been developed and evaluated in preclinical models and clinical trials. Already marketed drugs are also being repurposed in combination therapies to further improve efficacy and overcome tumour cell resistance. In this review, we have aimed to examine the latest and most classical signalling pathways in the aetiology of T-acute lymphoblastic leukaemia and shed light on potential targets for novel therapeutic agents to act on.

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL. To compare the prevalence of cCMV infection between ALL cases and matched controls. In this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mothers race and ethnicity. Data were analyzed from November to May 2022. cCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots. ALL diagnosed in children aged 0 to 14 years. A total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19). In this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

Cmpd10357 to treat B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of cancer found in children. Although the overall survival rates are now >80%, 15%-20% of pediatric patients relapse, with survival rates subsequently dropping to 5%-10%. Cmpd10357, 3-amino-5-arylamino-6-chloro-N- (diaminomethylene) pyrazine-2-carboximide, is a highly potent, cell-permeant compound recently shown to have cytotoxic effects on solid tumors, including human breast cancer and high-grade gliomas, independent of their proliferative status. Cmpd10357 demonstrated concentration-dependent cytotoxicity in two human B-ALL cell lines, JM1 and Reh, at half-maximal inhibitory concentrations (IC

Super-refractory status epilepticus during blinatumomab initiation for B-cell acute lymphoblastic leukemia.

Seizures have been reported as an adverse effect of blinatumomab, a bispecific T-cell engager monoclonal antibody, which is mainly used for the treatment of pediatric relapsedrefractory leukemia. Here, we present the first reported case of super-refractory status epilepticus in an 11-year-old boy with B-cell acute lymphoblastic leukemia (B-ALL) while receiving blinatumomab. Our patient had a complete return to baseline despite enduring encephalopathy, refractory subclinical seizures requiring prolonged therapeutic burst suppression and MRI signal changes. This case demonstrates that super-refractory status epilepticus is a possible neurotoxic adverse effect of blinatumomab treatment, which responds well to conventional protocols for acute refractory seizures. Seizures are a known side effect of blinatumomab, a relatively new immunotherapy drug, which is mainly used for the treatment of relapsed leukemia in children. Here, we present the first reported case of seizure continuing for more than 24 h despite appropriate antiseizure treatment while also receiving blinatumomab. Despite an extended period of altered mental status, new abnormalities on imaging of the brain and a medication-induced coma to treat unrelenting seizures, our patient returned completely to his healthy brain function. This case demonstrates that seizures, which are especially difficult to treat, can be associated with blinatumomab immunotherapy for pediatric refractory B-ALL however, standard-tiered seizure treatments can be effective.

TSLP as a Potential Therapy in the Treatment of CRLF2 B Cell Acute Lymphoblastic Leukemia.

Cytokine receptor-like factor 2 B-cell acute lymphoblastic leukemia (CRLF2 B-ALL) is a high-risk subtype characterized by CRLF2 overexpression with poor survival rates in children and adults. CRLF2 and interleukin-7 receptor alpha (IL-7Rα) form a receptor for the cytokine thymic stromal lymphopoietin (TSLP), which induces JAKSTAT and PI3KAKTmTOR pathway signals. Previous studies from our group showed that low TSLP doses increased STAT5, AKT, and S6 phosphorylation and contributed to CRLF2 B-ALL cell survival. Here we investigated the role of TSLP in the survival and proliferation of CRLF2 B-ALL cells in vitro and in vivo. We hypothesized that high doses of TSLP increase CRLF2 signals and contribute to increased proliferation of CRLF2 B-ALL cells in vitro and in vivo. Interestingly, we observed the opposite effect. Specifically, high doses of TSLP induced apoptosis in human CRLF2 B-ALL cell lines in vitro, prevented engraftment of CRLF2 B-ALL cells, and prolonged the survival of TSLP patient-derived-xenograft mice. Mechanistically, we showed that high doses of TSLP induced loss of its receptor and loss of CRLF2 signals in vitro. These results suggest that high doses of TSLP could be further investigated as a potential therapy for the treatment of CRLF2 B-ALL.

Centrosome Amplification Is a Potential Molecular Target in Paediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children, with most cases arising from fetal B cell precursor, termed B-ALL. Here, we use immunofluorescence analysis of B-ALL cells to identify centrosome amplification events that require the centrosome clustering pathway to successfully complete mitosis. Our data reveals that primary human B-ALL cells and immortal B-ALL cell lines from both human and mouse sources show defective bipolar spindle formation, abnormal mitotic progression, and cell death following treatment with centrosome clustering inhibitors (CCI). We demonstrate that CCI-refractory B-ALL cells exhibit markers for increased genomic instability, including DNA damage and micronuclei, as well as activation of the cyclic GMP-AMP synthase (cGAS)-nuclear factor kappa B (NF-κB) signalling pathway. Our analysis of cGAS knock-down B-ALL clones implicates cGAS in the sensitivity of B-ALL cells to CCI treatment. Due to its integral function and specificity to cancer cells, the centrosome clustering pathway presents a powerful molecular target for cancer treatment while mitigating the risk to healthy cells.

Electrochemical Biosensors in the Diagnosis of Acute and Chronic Leukemias.

Until now, morphological assessment with an optical or electronic microscope, fluorescence in situ hybridization, DNA sequencing, flow cytometry, polymerase chain reactions, and immunohistochemistry have been employed for leukemia identification. Nevertheless, despite their numerous different vantages, it is difficult to recognize leukemic cells correctly. Recently, the electrochemical evaluation with a nano-sensing interface seems an attractive alternative. Electrochemical biosensors measure the modification in the electrical characteristics of the nano-sensing interface, which is modified by the contact between a biological recognition element and the analyte objective. The implementation of nanosensors is founded not on single nanomaterials but rather on compilating these components efficiently. Biosensors able to identify the molecules of deoxyribonucleic acid are defined as DNA biosensors. Our review aimed to evaluate the literature on the possible use of electrochemical biosensors for identifying hematological neoplasms such as acute promyelocytic leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia. In particular, we focus our attention on using DNA electrochemical biosensors to evaluate leukemias.

Optical Genome Mapping for Comprehensive Assessment of Chromosomal Aberrations and Discovery of New Fusion Genes in Pediatric B-Acute Lymphoblastic Leukemia.

To assess the potential added value of Optical Genomic Mapping (OGM) for identifying chromosomal aberrations. We utilized Optical Genomic Mapping (OGM) to determine chromosomal aberrations in 46 children with B-cell Acute lymphoblastic leukemia ALL (B-ALL) and compared the results of OGM with conventional technologies. Partial detection results were verified by WGS and PCR. OGM showed a good concordance with conventional cytogenetic techniques in identifying the reproducible and pathologically significant genomic SVs. Two new fusion genes ( OGM addresses some of the limitations associated with conventional cytogenomic testing. This all-in-one process allows the detection of most major genomic risk markers in one test, which may have important meanings for the development of leukemia pathogenesis and targeted drugs.

Immunophenotype of Measurable Residual Blast Cells as an Additional Prognostic Factor in Adults with B-Cell Acute Lymphoblastic Leukemia.

Measurable residual disease (MRD) is a well-known independent prognostic factor in acute leukemias, and multicolor flow cytometry (MFC) is widely used to detect MRD. MFC is able not only to enumerate MRD accurately but also to describe an antigen expression profile of residual blast cells. However, the relationship between MRD immunophenotype and patient survival probability has not yet been studied. We determined the prognostic impact of MRD immunophenotype in adults with B-cell acute lymphoblastic leukemia (B-ALL). In a multicenter study RALL-2016 (NCT03462095), 267 patients were enrolled from 2016 to 2022. MRD was assessed at the end of induction (day 70) in 94 patients with B-ALL by six- or 10-color flow cytometry in the bone marrow specimens. The 4 year relapse-free survival (RFS) was lower in MRD-positive B-ALL patients 37% vs. 78% (

Autologous versus allogeneic hematopoietic cell transplantation for older patients with acute lymphoblastic leukemia. An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n 209) or matched unrelated donor (MUD, n 209) with autologous (auto, n 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p 0.11) while overall survival (OS) rates were 42% versus 45% (p 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p 0.22) and 25% versus 10% (p 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio HR 2.1, p 0.02) and MUD-HCT (HR 3.08, p < 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR 1.55, p 0.01) and OS (HR 1.62, p 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials.

A stem cell epigenome is associated with primary nonresponse to CD19 CAR T-cells in pediatric acute lymphoblastic leukemia.

CD19 CAR T-cell therapy (CD19-CAR) has changed the treatment landscape and outcomes for patients with pre-B cell acute lymphoblastic leukemia (B-ALL). Unfortunately, primary non-response (PNR), sustained CD19 disease and concurrent expansion of CD19-CAR, occurs in 20% of patients and is associated with adverse outcomes. Although some failures may be attributable to CD19 loss, mechanisms of CD19-independent, leukemia intrinsic resistance to CD19-CAR remain poorly understood. We hypothesized that PNR leukemias are distinct compared to primary sensitive (PS) leukemias and that these differences are present prior to treatment. We utilized a multi-omic approach to investigate this in 14 patients (7 PNR and 7 PS) enrolled in the PLAT-02 trial at Seattle Childrens Hospital. Long-read PacBio sequencing identified one PNR where 47% of CD19 transcripts had exon 2 skipping, but other samples lacked CD19 transcript abnormalities. Epigenetic profiling discovered DNA hypermethylation at genes targeted by polycomb repressive complex 2 (PRC2) in embryonic stem cells. Similarly, ATAC-seq revealed reduced accessibility at these PRC2 target genes with a gain in accessibility of regions characteristic of hematopoietic stem cells and multi-lineage progenitors in PNR. Single cell RNA-seq and CyTOF analyses identified leukemic subpopulations expressing multi-lineage markers and decreased antigen presentation in PNR. We thus describe the association of a Stem Cell Epigenome (SCE) with primary resistance to CD19-CAR therapy. Future trials incorporating these biomarkers, with addition of multi-specific CAR T-cells targeting against leukemic stem cell or myeloid antigens, andor combined epigenetic therapy to disrupt this distinct stem cell epigenome may improve outcomes of patients with B-ALL.

CD19-CAR-T cells are an effective therapy of post-transplant relapse in B- ALL patients Real-World Data from Germany.

Patients with precursor B cell acute lymphoblastic leukemia (pB-ALL) who have relapsed subsequent to allogeneic stem cell transplantation (alloHSCT), have relapsed more than once, or are resistant upfront have a dismal prognosis. CD19-targeted CAR-T cells have evolved as potent immune therapies. Tisagenlecleucel (Tisa-cel) is a commercial autologous CD19-directed CAR-T cell product. We performed a retrospective study inviting all CAR-T cell centers in Germany to participate. Eighty-one patients with pB-ALL were included. Twenty-eight days after CAR-T cell infusion, 71 patients (87.7%) were in CR, and 8 (9.9%) were in NR. At two years, the probabilities of event-free, relapse-free and overall survival were 45.3% (pEFS), 51.7% (pRFS) and 53.2% (pOS), respectively. pEFS was not different in patients without (n16, 55.0%) vs. with prior alloHSCT (n65, 43.4%). In patients treated after alloHSCT, the time to relapse after alloHSCT was a strong predictor of outcome. Patients relapsing within 6 months of alloHSCT had a disappointing pEFS (pOS) of 18.4% (16.0%) pEFS (pOS) for those relapsing later was 55.5% (74.8%). Our study provides real-world experience in pediatric, adolescent and young adult patients with ALL treated with Tisa-cel, where the majority of patients were treated after having relapsed post-alloHSCT. A total of 45.3% were rescued with a single dose of Tisa-cel. Our novel finding that ALL patients post-alloHSCT had by far a better pEFS if relapse occurred beyond 6 months might be helpful in clinical decision-making and motivates studies to uncover the reasons.

Management of acute lymphoblastic leukemia in older adults.

Acute lymphoblastic leukemia, commonly known to affect the younger population, is a disease that is affecting the elderly in an increasing amount as the human life span continues to lengthen. Traditional cytotoxic agents are intolerable to elderly individuals owing to comorbidities, weakened immune systems, and organ dysfunction. Alternative agents and regimens are needed to allow for elderly patient to tolerate full cycles of therapy while providing complete and durable remissions. With the advent of targeted agents, such as monoclonal antibodies and bispecific T-cell engagers, a number of options have proven themselves to be effective in the elderly and optimal for tolerability. Here, we review and discuss the literature addressing regimens that use new agents, such as blinatumomab, inotuzumab ozogamicin, and venetoclax, and those that use modified dosing strategies of traditional chemotherapy.

Association of ABO mismatch with the outcomes of allogeneic hematopoietic cell transplantation for acute leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT, the independent impact of donor-recipient ABO mismatching remains unclear. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified patients aged ≥18 years with AML or ALL who underwent allo-HCT between 2008 and 2018. Our objectives were to analyze the outcomes of allo-HCT based on the donor-recipient ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Among 4946 eligible patients, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had a minor ABO mismatch, 899 patients (18.1%) had a major ABO mismatch, and 276 patients (5.6%) had a bidirectional ABO mismatch. In multivariable analyses, compared to ABO matched allo-HCT, the presence of a major ABO mismatch was associated with worse overall survival (HR 1.16, 95% CI 1.05-1.29 p 0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90 p < 0.001), and higher primary graft failure (HR 1.60, 95% CI 1.12-2.30, p 0.01). Relapse, acute graft versus host disease (GVHD) grades III-IV and chronic GVHD were not significantly associated with ABO status. While donor age was not significantly associated with outcomes, older recipient age was associated with worse survival and non-relapse mortality. Our study demonstrates that donor-recipient ABO status is independently associated with survival and other post-transplantation outcomes in acute leukemia. This underscores the importance of considering the ABO status in donor selection algorithms and its impact in acute leukemia.

Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia.

Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy associated with high mortality rates (less than 30% 5-year survival). Despite advances in our understanding of the molecular mechanisms underpinning leukemogenesis, standard-of-care therapeutic approaches have not changed over the last couple of decades. Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 has shown remarkable clinical outcomes for patients with acute lymphoblastic leukemia (ALL) and is now an FDA-approved therapy. Targeting of myeloid malignancies that are CD19-negative with this promising technology remains challenging largely due to lack of alternate target antigens, complex clonal heterogeneity, and the increased recognition of an immunosuppressive bone marrow. We carefully reviewed a comprehensive list of AML targets currently being used in both proof-of-concept pre-clinical and experimental clinical settings. We analyzed the expression profile of these molecules in leukemic as well normal tissues using reliable protein databases and data reported in the literature and we provide an updated overview of the current clinical trials with CAR T-cells in AML. Our study represents a state-of-art review of the field and serves as a potential guide for selecting known AML-associated targets for adoptive cellular therapies.

Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.

Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD) however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer.

Clinical study on application of 3D Slicer software assisted domestic frameless stereotactic robot in biopsy of intracranial lesions.

Central Nervous System Status is Prognostic in T-Cell Acute Lymphoblastic Leukemia A Childrens Oncology Group Report.

To determine the prognostic significance of central nervous system (CNS) leukemic involvement in newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL), outcomes on consecutive, phase 3 Childrens Oncology Group (COG) clinical trials were examined. AALL0434 and AALL1231 tested efficacy of novel agents incorporated into augmented Berlin-Frankfurt-Münster (aBFM) therapy. In addition to testing study-specific chemotherapy through randomization, the AALL0434 regimen delivered cranial radiation (CRT) to the majority of subjects (90.8%), while AALL1231 intensified chemotherapy to eliminate CRT in 88.2% of subjects. In combined analysis of 2,164 T-ALL subjects (AALL0434 1,550 AALL1231 614), 1,564 were CNS-1 (72.3%), 441 CNS-2 (20.4%), and 159 CNS-3 (7.3%). The 4-year event-free survival (EFS) was similar for CNS-1 (85.1±1.0%) and CNS-2 (83.2±2.0%), but lower for CNS-3 (71.8±4.0%) p0.0004. Subjects with CNS-1 and CNS-2 had similar 4-year overall-survival (OS) (90.1±0.8% and 90.5±1.5%), with OS for CNS-3 (82.7±3.4%) p0.005. Despite therapeutic differences, outcomes for CNS-1 and CNS-2 were similar regardless of CRT, intensified corticosteroids or novel agents. Except for significantly superior outcomes with nelarabine on AALL0434 (4-year disease-free survival 93.1%±5.2%), EFSOS was inferior with CNS-3 status, all of whom received CRT. Combined analyses of over 2,000 subjects with T-ALL, found that those with CNS-1 and CNS-2 status at diagnosis had similar outcomes. Unlike with B-ALL, CNS-2 status in T-ALL does not impact outcome in the context of aBFM therapy, without additional intrathecal therapy, with or without CRT. Although nelarabine improved outcomes for those with CNS-3 status, novel approaches are needed for further improvements.

Theres no playbook for when your kid has cancer Desired elements of an electronic resource to support pediatric cancer communication.

Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, has a relatively favorable long-term prognosis. Yet the complexity of treatment and the emotionality of the diagnosis leave families feeling unprepared for many aspects of therapy. This qualitative study aimed to identify desired elements and format of a communication resource to support patients and families facing a diagnosis of ALL. Semi-structured interviews of 12 parents of children receiving ALL treatment, 10 parents of survivors of ALL, and eight adolescent and young adult (AYA) survivors of ALL were conducted between February and June 2021. The interviews focused on communication experiences throughout treatment and identified domains to be addressed in a resource in development. All participants supported the development of an interactive, electronic health (eHealth) resource to help navigate ALL treatment. They felt a website would be helpful in addressing information gaps and mitigating pervasive feelings of overwhelm. Participants specifically sought (a) information resources to address feelings of cognitive overload (b) practical tips to help navigate logistical challenges (c) clear depictions of treatment choices and trajectories to facilitate decision-making and (d) additional psychosocial resources and support. Two overarching themes that families felt should be interwoven throughout the eHealth resource were connections with other patientsfamilies and extra support at transitions between phases of treatment. A new diagnosis of ALL and its treatment are extremely overwhelming. Patients and families unanimously supported an eHealth resource to provide additional information and connect them with emotional support, starting at diagnosis and extending throughout treatment.

Unusual Presentation of Leukemic-Phase Mantle Cell Lymphoma A Case Report.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell lymphoma that can present in a variety of ways, including the leukemic phase, where it can occasionally be mistaken for acute leukemia due to the unusually high or rapidly growing number of leukocytes and the presence of circulating cancer cells that are morphologically similar to leukemic blasts in myeloid or acute lymphoblastic leukemia. We present the case of an 83-year-old Yemeni woman with multiple comorbidities who presented with abdominal pain and constitutional symptoms. She was found to have diffuse lymphadenopathy on clinical and radiological assessments. Her white blood cell count at presentation was 221 × 10

Copy Number Alterations in CDKN2A2B and MTAP Genes Are Associated With Low MEF2C Expression in T-cell Acute Lymphoblastic Leukemia.

The molecular heterogeneity of T-cell acute lymphoblastic leukemia (T-ALL) makes this disease complex. Early T-cell precursor ALL (ETP-ALL) is a recognized subtype of T-ALL associated with a high probability of induction failure with conventional therapy. Higher expression of myocyte enhancer factor 2C (

CLIC-01 Manufacture and distribution of non-cryopreserved CAR-T cells for patients with CD19 positive hematologic malignancies.

Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canadas publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsedrefractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkins lymphoma (n25) or acute lymphoblastic leukemia (n5) were infused with CLIC-1901 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 10 httpsclinicaltrials.govct2showNCT03765177, identifier NCT03765177.

Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia 80-months follow-up results.

The combination of ponatinib, a third-generation BCRABL1 tyrosine kinase inhibitor, with hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for stem cell transplantation (SCT) in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients with longer follow-up would establish this regimen as a new standard of care. Adults with newly diagnosed Ph-positive ALL were treated with the hyper-CVAD regimen. Ponatinib was added as 45 mg daily × 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR absence of a detectable BCRABL1 transcript by quantitative reverse transcription polymerase-chain reaction at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine-prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982. Eighty-six patients were treated. Their median age was 46 years (range, 21-80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty- patients (23%) underwent allogeneic SCT. With a median follow-up of 80 months (range, 16-129 months), the estimated 6-year event-free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3-5 adverse events included infection (n 80, 93%), increased liver transaminases (n 26, 31%) and total bilirubin (n 13, 15%), hypertension (n 15, 17%), pancreatitis (n 13, 15%), hemorrhage (n 12, 13%), and skin rash (n 9, 10%). Two ponatinib-related deaths from myocardial infarction (3% at months 2.6 and 4.3, respectively both in CR) in the first 37 patients treated led to the ponatinib dose-modifications mentioned earlier, with no further ponatinib-related deaths observed. The long-term results of ponatinib and hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.

Utility of propensity score-based Bayesian borrowing of external adult data in pediatric trials A pragmatic evaluation through a case study in acute lymphoblastic leukemia (ALL).

A fully powered randomized controlled cancer trial can be challenging to conduct in children because of difficulties in enrollment of pediatric patients due to low disease incidence. One way to improve the feasibility of trials in pediatric patients, when clinically appropriate, is through borrowing information from comparable external adult trials in the same disease. Bayesian analysis of a pediatric trial provides a way of seamlessly augmenting pediatric trial efficacy data with data from external adult trials. However, not all external adult trial subjects may be equally clinically relevant with respect to the baseline disease severity, prognostic factors, co-morbidities, and prior therapy observed in the pediatric trial of interest. The propensity score matching method provides a way of matching the external adult subjects to the pediatric trial subjects on a set of clinically determined baseline covariates, such as baseline disease severity, prognostic factors and prior therapy. The matching then allows Bayesian information borrowing from only the most clinically relevant external adult subjects. Through a case study in pediatric acute lymphoblastic leukemia (ALL), we examine the utility of propensity score matched mixture and power priors in bringing appropriate external adult efficacy information into pediatric trial efficacy assessment, and present considerations for scaling fixed borrowing from external adult data.

Real-world use of blinatumomab in adult patients with B-cell acute lymphoblastic leukemia in clinical practice results from the NEUF study.

This retrospective observational study (NEUF) included adult patients with B-cell acute lymphoblastic leukemia (B-cell ALL) who had received blinatumomab for the treatment of minimal residual disease-positive (MRD) or relapsedrefractory (RR) B-cell ALL via an expanded access program (EAP). Patients were eligible if blinatumomab was initiated via the EAP between January 2014 and June 2017. Patients were followed from blinatumomab initiation until death, entry into a clinical trial, the end of follow-up, or the end of the study period (December 31, 2017), whichever occurred first. Of the 249 adult patients included, 109 were MRD (83 Philadelphia chromosome-negative Ph- and 26 Philadelphia chromosome-positive Ph) and 140 had a diagnosis of RR B-cell ALL (106 Ph- and 34 Ph). In the MRD group, within the first cycle of blinatumomab treatment, 93% (n 4953) of Ph- and 64% (n 711) of Ph patients with evaluable MRD achieved an MRD response (MRD <0.01%). Median overall survival (OS) was not reached over a median follow-up time of 18.5 months (Ph-, 18.8 range 5.1-34.8 months Ph, 16.5 range 1.8-31.6 months). In the RR group, within two cycles of blinatumomab, 51% of Ph- and 41% of Ph patients achieved complete hematologic remission (CRCRhCRi), and 83% of Ph- and 67% of Ph MRD-evaluable patients in CRCRhCRi achieved an MRD response. Median (95% confidence interval) OS was 12.2 (7.3-24.2) months in the RR Ph- subgroup and 16.3 (5.3-not estimated) months in the RR Ph subgroup. This large, real-world data set of adults with B-cell ALL treated with blinatumomab confirms efficacy outcomes from published studies.

INPP5K controls the dynamic structure and signaling of wild type and mutated, leukemia-associated IL7 receptors.

Signaling downstream of the IL7 receptor plays important physiological and pathological roles, including differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain of function mutations in the IL7Rα chain, the specific component of the receptor for IL7, result in constitutive, IL7-independent signaling and trigger acute lymphoblastic leukemia. Here, we show that loss of the phosphoinositide 5-phosphatase INPP5K is associated with increased levels of the INPP5K substrate PtdIns(4,5)P2 and causes altered dynamic structure of the IL7 receptor. We discovered that the IL7Rα chain contains a very conserved positively-charged polybasic amino acid sequence in its cytoplasmic juxtamembrane region this region establishes stronger ionic interactions with negatively-charged PtdIns(4,5)P2 in the absence of INPP5K, freezing IL7Rα chain structure. This dynamic structural alteration causes defects in IL7 receptor signaling, culminating in decreased expression of EBF1 and PAX5 transcription factor, in microdomain formation, cytoskeletal reorganization and bone marrow B cell differentiation. Similar alterations following reduced INPP5K expression also impacted mutated, constitutively activated IL7Rα chains that trigger leukemia development, leading to reduced cell proliferation. Altogether, our results indicate that the lipid 5-phosphatase INPP5K hydrolyses plasma membrane PtdIns(4,5)P2, allowing the requisite conformational changes of the IL7Rα chain for optimal signaling.

The Vitamin D Status in Children With Newly Diagnosed Acute Lymphoblastic Leukemia and Its Potential Impact on the Primary Symptoms of Leukemia and Course of Induction Treatment.

Vitamin D deficiency is ubiquitous within the population of children. A similar problem is recognized among pediatric patients with acute lymphoblastic leukemia. The purpose of this study was to analyze the prevalence of vitamin D deficiency and to investigate the connection between vitamin D status and the course of induction treatment of ALL. A cross-sectional study including 59 patients with newly diagnosed ALL from May 2017 until November 2020. Vitamin D deficiency was found in 39% of the patients. There were no seasonal differences in vitamin D status. Patients with optimal 25(OH)D concentration presented more profound thrombocytopenia ( P 0.015) and required more frequent platelet transfusions ( P 0.018). Good prognosis factors such as B phenotype and hyperdiploidy were also more frequent among children with higher 25(OH)D concentration ( P 0.01 and 0.014, respectively). The study showed that patients with a higher serum concentration of 25(OH)D presented deeper thrombocytopenia and needed more frequent transfusions. Moreover, those patients showed higher rates of B-cell leukemia and hyperdiploid karyotype. We did not find any influence of the possible exposure to sunlight (defined as the season of the year on admission) on serum 25(OH)D concentration, which supports the argument for supplementing vitamin D all year round. Moreover, the supplementing of vitamin D seems to be safe and does not cause any renal complications connected to calcium and phosphorus imbalance as no correlation between their levels and 25(OH)D concentration was found.

Timing of Central Venous Line Insertion During Induction in Children With Acute Lymphoblastic Leukemia.

Central venous lines (CVL) in children with acute lymphoblastic leukemia (ALL) provide comfortable administration of intensive chemotherapy and blood sampling. The optimal time for the insertion of CVL in patients with ALL during induction therapy is controversial. This study aimed to investigate the frequency of CVL-related complications in children with ALL concerning the time of CVL insertion. We reviewed the records of 52 pediatric ALL patients with CVL. CVL placement before or on treatment day 15 was defined as early insertion, and after treatment day 15 was defined as late insertion. Demographics, preoperative blood counts, type of central line, time of CVL placement, CVL-related complications, and blood counts during complications were all noted. All the data were collected from those with the first catheter use. CVL was placed ≤15 days in 26 patients (50%) and after 15 days in 26 patients (50%). Regarding the infection rates, no statistical difference was found between early and late CVL-inserted groups ( P n.s.). Five patients developed thrombosis, and risk was found to be similar between early and late CVL-inserted groups ( P n.s.). Catheter-related mechanical complications were recorded in 7 patients (3 in early and 4 in late CVL-inserted group, ( P n.s.). The present study showed no relation between the timing of CVL placement during induction therapy and the occurrence of infection and thrombosis. Our results suggest that CVL can be placed safely at the time of diagnosis or early induction treatment to provide a comfortable administration of chemotherapy and decrease painful blood samplings.

A Comprehensive Review of Neuropsychologic Studies Supports the Concept That Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity.

To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue. A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects. Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue. Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.

β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia.

Understanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of β-cateninCTNNB1 in the evolution of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by β-catenin, TCFLEF factors and ZBTB33Kaiso in T-ALL cell lines, which is highly and significantly represented in five out of six refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of β-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of β-catenin in RNA and protein synthesis in T-ALL and provide in vitro and in vivo experimental evidence that β-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment. We propose that combination treatments involving chemotherapy plus β-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.

Coexpression of

Chimeric antigen receptor (CAR) T-cell therapy has achieved great success in treating patients with hematological tumors such as b-acute lymphoblastic leukemia and lymphoma. However, a growing number of clinical trials show that most of the second-generation CAR-T cells with different targeting single-chain fragment variables (scFv) did not exhibit comparable therapeutic effects with CD19-targeting CAR-T cells in solid tumors. To overcome this challenge, scientists have developed several methods to optimize the structure of CARs, including coexpression of a transcription factor called

Safety of AFM11 in the treatment of patients with B-cell malignancies findings from two phase 1 studies.

The prognosis for patients with relapsed andor refractory (RR) non-Hodgkins lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells. Two open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with RR CD19-positive B cell NHL (AFM11-101) and in patients with CD19 B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion. In AFM11-101, 16 patients with RR NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) including five serious AEs (SAEs), five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with RR ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination. AFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL therefore, further clinical development was terminated. NCT02106091 . Safety Study to Assess AFM11 in Patients With Relapsed andor Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911 . Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.

Systemic paracoccidioidomycosis in a patient with enzymatic myeloperoxidase deficiency and acute lymphoblastic leukemia case report.

Paracoccidioidomycosis is a systemic fungal infection that is potentially fatal, and the most prevalent of its kind in Latin America. The predisposition to infection appears to be related to abnormalities in cellular immunity, given its low prevalence in endemic regions. The role of myeloperoxidase deficiency has not been elucidated. We present a case of 48-year-old female patient with acute lymphoblastic leukemia, stem cell transplant candidate, who developed a fever with lymphadenopathy and lung nodules, consistent with paracoccidioidomycosis infection, in whom a myeloperoxidase deficiency was later discovered. The treatment of the hematologic malignancy had a good impact solving the enzymatic deficiency and antifungal therapy achieve controlling the infection. This case lays out the possible association between acute leukemia, an alteration in neutrophil function (needed to fight fungal infections) and an infection due to

Invasive rhinosinusitis due to

An adolescent boy with newly diagnosed T-cell acute lymphoblastic leukaemia developed right eye and facial pain, and a 1 cm × 2 cm area of black eschar over his hard palate. Initial differential diagnosis included rhinocerebral mucormycosis and aspergillosis, and he was started on liposomal amphotericin B. Later, he underwent nine surgical debridements of his sinus cavities, resection of a third of his palate and right orbital exenteration. While histological specimens exhibited features of both

Efficacy and Safety of Blinatumomab for the Treatment of RelapsedRefractory Acute Lymphoblastic Leukemia A Systemic Review and Meta-Analysis.

The aim was to evaluate the efficacy and safety of blinatumomab monotherapy for the treatment of relapsedrefractory acute lymphoblastic leukemia (RR B-ALL). PubMed, Embase, Web of Science, and Cochrane Library were searched to collect clinical studies related to blinatumomab. The primary outcome measures were complete remission (CR), and minimal residual disease (MRD) response. Prognostic indicators included overall survival (OS) and relapse-free survival time (RFS). Grade ≥3 adverse reactions were mainly analyzed for safety, including cytokine release syndrome (CRS), neurological events and hematological toxicity. The heterogeneity was quantified by I A total of 18 studies involving 1,373 patients were included. The analysis results showed a CR rate of 54% (95%CI44%-64%) and an MRD response rate of 43% (95%CI34%-51%). The CR rate was higher in patients with bone marrow (BM) blast <50% than in patients with BM blast ≥50% (71% vs. 34%). The median OS and RFS were 8.16 months (95%CI6.64-9.69) and 6.02 months (95%CI4.63-7.41), respectively. For safety analysis, the incidence of grade ≥3 adverse events (AEs) was 80% (95%CI72%-88%), the incidence of grade ≥3 neurological toxicity was 7% (95%CI4%-11%), and the incidence of grade ≥3 CRS was 3% (95%CI2%-5%). However, the mixture of retrospective and prospective studies led to heterogeneity to some extent in this meta-analysis. Blinatumomab is effective in the treatment of RR B-ALL with a controlled occurrence of AEs and a reliable safety profile.

CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses.

To date, T cells redirected with CD19-specific chimeric antigen receptors (CAR) have gained impressive success in B-cell malignancies. However, treatment failures are common and the occurrence of severe toxicities, such as cytokine release syndrome (CRS), still limits the full exploitation of this approach. Therefore, the development of cell products with improved therapeutic indexes is highly demanded. In this project, we investigated how CD4 and CD8 populations cooperate during CD19 CAR-T cell responses and what is their specific role in CRS development. To this aim, we took advantage of immunodeficient mice reconstituted with a human immune system (HuSGM3) and engrafted with the B-cell acute lymphoblastic leukemia cell line NALM-6, a model that allows to thoroughly study efficacy and toxicity profiles of CD19 CAR-T cell products. CD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of adverse events. Accordingly, toxicity assessment in HuSGM3 mice identified CD4 CAR-T cells as key contributors to CRS development, revealing a safer profile when they harbor CARs embedded with 4-1BB, rather than CD28. By comparing differentially co-stimulated CD4CD8 11 CAR-T cell formulations, we observed that CD4 cells shape the overall expansion kinetics of the infused product and are crucial for maintaining long-term responses. Interestingly, the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity, without impacting antitumor efficacy. Taken together, these data point out that the rational design of improved adoptive T-cell therapies should consider the biological features of CD4 CAR-T cells, which emerged as crucial for maintaining long-term responses but also endowed by a higher toxic potential.

Phenotypic Characterization and Identification of Potential L-Asparaginase-Producing Thermohalophilic Bacteria from Wawolesea Hot Spring, North Konawe, Southeast Sulawesi, Indonesia.

ltbgtBackground and Objectiveltbgt L-asparaginase-producing thermohalophilic bacteria have the potential of producing an enzyme tolerant to high heat and salt levels. This enzyme, L-asparaginase, can be used as a biological agent for the cancer therapy of acute lymphoblastic leukemia and melanosarcoma as it has a specific ability to inhibit the formation of nutrients for cancer cells. This enzyme is also used effectively in food industries operating at high temperatures due to its ability to reduce acrylamide, a trigger of cancer cells. This study sought to figure out the phenotypic characters of and identify potential L-asparaginase-producing thermohalophilic bacteria from Wawolesea Hot Spring, North Konawe, Southeast Sulawesi. ltbgtMaterials and Methodsltbgt The characterization conducted on potential L-asparaginase-producing thermohalophilic bacterial isolates consisted of the following Colony morphological characterization, covering the shapes, edges, internal structures, elevations and colours of the colonies, cell morphological characterization, covering gram staining, endospore formation and motility, biochemical characterization, covering catalase, Methyl Red and Voges Proskauer (MR-VP), gelatin hydrolysis, citrate, indole and carbohydrate fermentation tests and physiological characterization, covering pH effect, salinity, oxygen demand and temperature effect tests. Bacterial isolate identification was carried out in two stages, namely phenetic identification based on the phenotypic characterization data determine through a preliminary identification and numeric-phenetic identification. ltbgtResultsltbgt The characterization results showed that the bacterial isolates AAT 1.4, AAT 3.2 and CAT 3.4 were ltigtbacillusltigt-shaped, Gram-positive, motile, catalase-positive and aerobic. Based on the numeric-phenetic analysis results, the isolates AAT 1.4 and CAT 3.4 had a 92.9% similarity to ltigtBacillus subtilisltigt, while isolate AAT 3.2 had a 92.9% similarity to ltigtBrevibacillus limnophilusltigt. ltbgtConclusionltbgt According to the numeric-phenetic analysis results, the isolates AAT 1.4 and CAT 3.4 belong to the species ltigtBacillus subtilisltigt, while isolate AAT 3.2 belongs to the species ltigtBrevibacillus limnophilusltigt.

Nanopore sequencing of clonal IGH rearrangements in cell-free DNA as a biomarker for acute lymphoblastic leukemia.

Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, and patients with relapsed ALL have a poor prognosis. Detection of ALL blasts remaining at the end of treatment, or minimal residual disease (MRD), and spread of ALL into the central nervous system (CNS) have prognostic importance in ALL. Current methods to detect MRD and CNS disease in ALL rely on the presence of ALL blasts in patient samples. Cell-free DNA, or small fragments of DNA released by cancer cells into patient biofluids, has emerged as a robust and sensitive biomarker to assess cancer burden, although cfDNA analysis has not previously been applied to ALL. We present a simple and rapid workflow based on NanoporeMinION sequencing of PCR amplified B cell-specific rearrangement of the (IGH) locus in cfDNA from B-ALL patient samples. A cohort of 5 pediatric B-ALL patient samples was chosen for the study based on the MRD and CNS disease status. Quantitation of IGH-variable sequences in cfDNA allowed us to detect clonal heterogeneity and track the response of individual B-ALL clones throughout treatment. cfDNA was detected in patient biofluids with clinical diagnoses of MRD and CNS disease, and leukemic clones could be detected even when diagnostic cell-count thresholds for MRD were not met. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient, even when blasts are not physically present in the biofluid sample. The Nanopore IGH detection workflow to monitor cell-free DNA is a simple, rapid, and inexpensive assay that may ultimately serve as a valuable complement to traditional clinical diagnostic approaches for ALL.

A Computational Model of Cytokine Release Syndrome during CAR T-cell Therapy.

Cytokine release syndrome (CRS) is a lethal adverse event in chimeric antigen receptor (CAR) T-cell therapy, hindering this promising therapy for cancers, such as B-cell acute lymphoblastic leukemia (B-ALL). Clinical management of CRS requires a better understanding of its underlying mechanisms. In this study, a computational model of CRS during CAR T-cell therapy is built to depict how the cellular interactions among CAR T-cells, B-ALL cells, and bystander monocytes, as well as the accompanying molecular interactions among various inflammatory cytokines, influence the severity of CRS. The model successfully defines the factors related to severe CRS and studied the effects of immunomodulatory therapy on CRS. The use of the model is also demonstrated as a precision medicine tool to optimize the treatment scheme, including personalized choice of CAR T-cell products and control of switchable CAR T-cell activity, for a more efficient and safer immunotherapy. This new computational oncology model can serve as a precision medicine tool to guide the clinical management of CRS during CAR T cell therapy.

Case Report Pediatric myeloidlymphoid neoplasm with eosinophilia and PDGFRA rearrangement The first case presenting as B-lymphoblastic lymphoma.

According to the latest WHO classification of hematopoietic malignancies, myeloid and lymphoid neoplasms with eosinophilia and gene rearrangements include three specific rare diseases and one provisional entity. Myeloidlymphoid neoplasms with platelet-derived growth factor receptor alpha (PDGFRA) rearrangements are the most frequent of these disorders and are usually present in adult males with a median age of the late 40s. Patients usually have chronic eosinophilic leukemia but can occasionally manifest as acute myeloid leukemia or extramedullary T- or B-lineage lymphoblastic lymphoma. We report a case of a previously healthy 2-year-old girl who presented with a right supraorbital swelling with no associated lymphadenopathy. Peripheral blood smear evaluation at initial presentation revealed microcytic hypochromic red blood cells and leukocytosis with marked eosinophilia, occasional myelocytes, and occasional blasts. Whole-body CT scans and PET scans revealed hypermetabolic potentially lymphomatous mass in the superior medial aspect of the right orbit in addition to splenomegaly but no evidence of hypermetabolic mediastinal, hilar, abdominal, or pelvic lymph nodes. Bone marrow aspirate and biopsy revealed hypercellular bone marrow with quantitatively decreased erythroid precursors and increased granulocytic precursors with 60% of the cells being eosinophilic cells in different stages of maturation. The diagnosis of myeloid neoplasm with eosinophilia and rearrangement of PDGFRA was made following confirmation by fluorescence

A Case of Severe

Bikram Das

Layered immunity and layered leukemogenicity Developmentally restricted mechanisms of pediatric leukemia initiation.

Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) arise in successive waves during ontogeny, and their properties change significantly throughout life. Ontological changes in HSCsMPPs underlie corresponding changes in mechanisms of pediatric leukemia initiation. As HSCs and MPPs progress from fetal to neonatal, juvenile and adult stages of life, they undergo transcriptional and epigenetic reprogramming that modifies immune output to meet age-specific pathogenic challenges. Some immune cells arise exclusively from fetal HSCsMPPs. We propose that this layered immunity instructs cell fates that underlie a parallel layered leukemogenicity. Indeed, some pediatric leukemias, such as juvenile myelomonocytic leukemia, myeloid leukemia of Down syndrome, and infant pre-B-cell acute lymphoblastic leukemia, are age-restricted. They only present during infancy or early childhood. These leukemias likely arise from fetal progenitors that lose competence for transformation as they age. Other childhood leukemias, such as non-infant pre-B-cell acute lymphoblastic leukemia and acute myeloid leukemia, have mutation profiles that are common in childhood but rare in morphologically similar adult leukemias. These differences could reflect temporal changes in mechanisms of mutagenesis or changes in how progenitors respond to a given mutation at different ages. Interactions between leukemogenic mutations and normal developmental switches offer potential targets for therapy.

Competitive Repopulation and Allo-Immunologic Pressure Determine Chimerism Kinetics after T Cell-Depleted Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion.

After allogeneic stem cell transplantation (alloSCT), patient-derived stem cells that survived the pretransplantation conditioning compete with engrafting donor stem cells for bone marrow (BM) repopulation. In addition, donor-derived alloreactive T cells present in the stem cell product may favor establishment of complete donor-derived hematopoiesis by eliminating patient-derived lymphohematopoietic cells. T cell-depleted alloSCT with sequential transfer of potentially alloreactive T cells by donor lymphocyte infusion (DLI) provides a unique opportunity to selectively study how competitive repopulation and allo-immunologic pressure influence lymphohematopoietic recovery. This study aimed to determine the relative contribution of competitive repopulation and donor-derived anti-recipient alloimmunologic pressure on the establishment of lymphohematopoietic chimerism after alloSCT. In this retrospective cohort study of 281 acute leukemia patients treated according to a protocol combining alemtuzumab-based T cell-depleted alloSCT with prophylactic DLI, we investigated engraftment and quantitative donor chimerism in the BM and immune cell subsets. DLI-induced increase of chimerism and development of graft-versus-host disease (GVHD) were analyzed as complementary indicators for donor-derived anti-recipient alloimmunologic pressure. Profound suppression of patient immune cells by conditioning sufficed for sustained engraftment without necessity for myeloablative conditioning or development of clinically significant GVHD. Although 61% of the patients without any DLI or GVHD showed full donor chimerism (FDC) in the BM at 6 months after alloSCT, only 24% showed FDC in the CD4

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years.

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval CI, 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio HR, 4.65 P .001), whereas transplantation in CR1 (HR, .30 P .004) and transplantation for Philadelphia chromosome-positive (Ph

Top advances of the year Leukemia.

In the year 2021, there were three new Food and Drug Administration approvals for all leukemia types asciminib (Scemblix) for chronic myeloid leukemia, brexucabtagene autoleucel (Tecartus) for relapsedrefractory B-cell acute lymphocytic leukemia, and asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) for acute lymphocytic leukemia. This is down from 2017-2018 when eight new therapies were approved for acute myeloid leukemia alone. However, this decrease from prior years does not imply that little progress was made in our understanding or treatment of leukemias in 2021. Asciminib and brexucabtagene autoleucel, in particular, are representative of major developing trends. Asciminib, a targeted therapy, is only one of many drugs in development that are products of a bedside-to-bench approach fueled by new sequencing and other genetic technologies that have greatly increased our understanding of the biology behind hematologic diseases. Brexucabtagene autoleucel, an adoptive cell therapy, is the newest of several similar treatments for B cell-associated neoplasms, and it is representative of a massive push to develop novel immunotherapies for a broad range of hematologic malignancies. This commentary reviews the development of asciminib and brexucabtagene autoleucel and describes other major advances in the associated fields of targeted therapy and immunotherapy for leukemias.

Pneumocystis jiroveci Pneumonia secondary to tyrosine kinase inhibitor with blinatumomab therapy A case report.

Pneumocystis jiroveci Pneumonia (PCP) is a common cause of opportunistic lung infection and is associated with high mortality in immunocompromised patients. Few reports describe pneumocystis jiroveci as a causative agent of tyrosine kinase inhibitor or blinatumomab related infections. Case presentation A 64-year-old man with philadelphia chromosome positive acute lymphoblastic leukemia (ALL) presented to the intensive care unit with intermittent high fever and shortness of breath. Three cycles of tyrosine kinase inhibitor (TKI) with blinatumomab therapy were given in recent 4 months. Next-generation sequencing of bronchoalveolar lavage fluid and peripheral blood showed pneumocystis jiroveci. After trimethoprim- sulfamethoxazole treatment and subsequent mechanical ventilation, the infection was controlled successfully. Due to susceptibility and early onset of PCP in ALL patients received TKI combined with blinatumomab therapy, so we should be alert to PCP when pulmonary infection occurred.

Chimeric antigen receptor T (CAR-T) cells Novel cell therapy for hematological malignancies.

Over the last decade, the emergence of several novel therapeutic approaches has changed the therapeutic perspective of human malignancies. Adoptive immunotherapy through chimeric antigen receptor T cell (CAR-T), which includes the engineering of T cells to recognize tumor-specific membrane antigens and, as a result, death of cancer cells, has created various clinical benefits for the treatment of several human malignancies. In particular, CAR-T-cell-based immunotherapy is known as a critical approach for the treatment of patients with hematological malignancies such as acute lymphoblastic leukemia (ALL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and non-Hodgkins lymphoma (NHL). However, CAR-T-cell therapy of hematological malignancies is associated with various side effects. There are still extensive challenges in association with further progress of this therapeutic approach, from manufacturing and engineering issues to limitations of applications and serious toxicities. Therefore, further studies are required to enhance efficacy and minimize adverse events. In the current review, we summarize the development of CAR-T-cell-based immunotherapy and current clinical antitumor applications to treat hematological malignancies. Furthermore, we will mention the current advantages, disadvantages, challenges, and therapeutic limitations of CAR-T-cell therapy.

Recurrence of methotrexate-induced leukoencephalopathy after methotrexate rechallenge A case report and literature review.

Methotrexate (MTX) is potent chemotherapeutic agent, often administered intrathecally to treat or prevent central nervous system involvement in lymphomas and leukemias, particularly T-cell lymphoblastic leukemia (T-LBL). MTX has been linked to adverse neurologic effects that mimic acute stroke, including facial drooping, hemiplegia, impaired consciousness, and seizures, as well as changes on imaging-known as MTX-induced leukoencephalopathy (LE). We report a case of a 17-year-old male diagnosed with T-LBL, who had been receiving MTX chemotherapy for 4 months. After receiving his fourth dose of MTX, he presented to the emergency department with fever, facial drooping, and acute left-sided weakness. Brain magnetic resonance imaging (MRI) revealed bilateral deep white matter T2 hyperintense foci, increased on the right, with associated diffusion restriction in the right centrum semiovale-consistent with MTX-induced LE. After his symptoms resolved, he was discharged on leucovorin. Six months afterward, he was rechallenged with MTX and developed recurrence of symptoms. Repeat MRI showed well-defined T2FLAIR hyperintensities in the right centrum semiovale without corresponding diffusion restriction. The left centrum semiovale hyperintensity became less conspicuous in comparison to the previous MRI study. We report a rare case of recurrence of LE after MTX rechallenge and discuss mechanisms, best imaging modalities, and possible treatment options for MTX-induced LE. Given the ominous presentation of MTX-induced LE, we urge clinicians to maintain a high index of suspicion for this condition. Further research is necessary to understand why only certain patients develop recurrence of LE after subsequent doses of MTX.

Lymphocytes from B-acute lymphoblastic leukemia patients present differential regulation of the adenosinergic axis depending on risk stratification.

Although risk-stratified chemotherapy regimens improve B-cell acute lymphoblastic leukemia (B-ALL) clinical outcome, relapse occurs in a significant number of cases. The identification of new therapeutic targets as well as prognostic and diagnostic biomarkers can improve B-ALL patients clinical outcomes. Purinergic signaling is an important pathway in cancer progression, however the expression of ectonucleotidases and their impact on immune cells in B-ALL lacks exploration. We aimed to analyze the expression of ectonucleotidases in B-ALL patients lymphocyte subpopulations. Peripheral blood samples from 15 patients diagnosed with B-ALL were analyzed. Flow cytometry was used to analyze cellularity, expression level of CD38, CD39, and CD73, and frequency of Formula see text, and Formula see text in lymphocyte subpopulations. Plasma was used for cytokines (by CBA kit) and adenine nucleosidesnucleotides detection (by HPLC). Comparing B-ALL patients to health donors, we observed an increase of CD4 and CD8 T-cells. In addition, a decrease in CD38 expression in B and Treg subpopulations and an increase in CD39 As immunomodulators, the expression of ectonucleotidases might be associated with activation states, as well as the abundance of different cellular subsets. We observed a pro-tumor immunity expression profile in B-ALL patients at diagnosis, being associated with cell exhaustion and immune evasion in B-ALL.

Novel

T-cell acute lymphoblastic leukemia (T-ALL) is a rare malignancy characterized by proliferation of early T-cell precursors that replace normal hematopoietic cells. T-ALL cells carry non-random chromosome aberrations, fusion genes, and gene mutations, often of prognostic significance. We herein report the genetic findings in cells from a T-ALL patient. Bone marrow cells from a patient with T-ALL were examined using G-banding, array comparative genomic hybridization (aCGH), RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and fluorescence in situ hybridization. G-banding revealed del(1)(p34), add(5)(q14), trisomy 8, and monosomy 21 in the leukemic cells. aCGH detected the gross unbalances inferred from the karyotyping results, except that heterozygous loss of chromosome 21 did not include its distal part 21q22.12-q22.3 was undeleted. In addition, aCGH detected a submicroscopic interstitial 7.56 Mbp deletion in the q arm of chromosome 19 from 19q13.2 to 19q13.33. RNA sequencing detected and RT-PCRSanger sequencing confirmed the presence of two novel chimeras, MYCBPEHD2 and RUNX1ZNF780A. They were generated from rearrangements involving subbands 1p34.3 (MYCBP), 19q13.2 (ZNF780A), 19q13.33 (EHD2), and 21q22.12 (RUNX1), i.e., at the breakpoints of chromosomal deletions. The leukemic cells showed the heterozygous loss of many genes as well as the generation of MYCBPEHD2 and RUNX1ZNF780A chimeras. Because the partner genes in the chimeras were found at the breakpoints of the chromosomal deletions, we believe that both the heterozygous losses and the generation of the two chimeras occurred simultaneously, and that they were pathogenetically important.

A scoping review to compare and contrast quality assurance aspects of l-asparaginase biosimilars.

l-asparaginase is a first-line medicine used for the treatment of acute lymphoblastic leukemia. Differing quality of marketed l-asparaginase biosimilars has been reported to adversely influence treatment outcomes. Herein, the quality of l-asparaginase biosimilars intended for clinical use was reviewed in sight of quality assurance parameters using English and Chinese language database searching, which provided information for possible improvements to the manufacture of this medicine. Ten articles met inclusion criteria, and quality attributes that measured potency, specific activity, purity and host cell proteins (HCPs) were identified. Biosimilars manufactured in high-income countries represented good quality in all aspects. Biosimilars manufactured in high-middlemiddle-income countries, however, suggested poorer quality control particularly over removal of HCPs. Future work should now focus on establishing pharmacopeia monographs to establish equivalent quality assurance for l-asparaginase biosimilars manufactured between countries. Standardization of the quality profile, analytical methods and the limits of critical quality parameters, are essential to ensure appropriated efficacy and safety of clinical grade l-asparaginase.

Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Hepatotoxic effects, including hyperbilirubinemia and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, are common during all phases of therapy and are linked to several chemotherapeutic agents, including asparaginase, mercaptopurine, and methotrexate. To determine which genetic variants were associated with hyperbilirubinemia and elevated ALT and AST levels in children, adolescents, and young adults treated for ALL. This retrospective analysis of a multiethnic genome-wide association study was conducted between January 1, 2019, and April 15, 2022, including patients treated as part of Childrens Oncology Group (COG) trials with centers in the United States, Canada, and Australia, which accrued data from December 29, 2003, to January 21, 2011 (AALL0232), and from January 22, 2007, to July 24, 2014 (AALL0434). Germline genotypes were interrogated using genome-wide arrays and imputed using a National Institutes of Health TOPMed Imputation server. Mixed-effects logistic regressions were used to account for multiple episodes for an individual patient. Genotype × treatment phase interaction was tested to uncover phase-specific genetic risk factors. Total duration of multiagent protocol chemotherapy ranging from 2.5 to 3.5 years. The primary outcomes were National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) hyperbilirubinemia of grade 3 or higher and elevated liver ALT and AST levels. A total of 3557 participants were included in the analysis (2179 61.3% male median age, 11.1 range, 1-30 years). Among 576 known variants associated with these liver function test results in the general population, UGT1A1 variant rs887829 and PNPLA3 variant rs738409 were associated with increased risk of hyperbilirubinemia (odds ratio OR, 2.18 95% CI, 1.89-2.53 P 6.7 × 10-27) and ALT and AST levels (OR, 1.27 95% CI, 1.15-1.40 P 3.7 × 10-7), respectively, during treatment for ALL. Corresponding polygenic risk scores were associated with hepatotoxic effects across all therapy phases and were largely driven by UGT1A1 and PNPLA3 variants. Genome-wide association analysis revealed an age-specific variant near the CPT1A gene that was only associated with elevated ALT and AST levels among patients younger than 10 years (OR, 1.28 95% CI, 1.18-1.39 P 8.7 × 10-10). These results suggest a strong genetic basis for interpatient variability in hyperbilirubinemia and aminotransferase level elevations during leukemia chemotherapy.

Corrigendum Blinatumomab for treating pediatric B-lineage acute lymphoblastic leukemia A retrospective real-world study.

This corrects the article DOI 10.3389fped.2022.1034373..

Intensity of induction regimen and outcomes among adults with PhALL undergoing allogeneic hematopoietic stem cell transplantation.

Tyrosine kinase inhibitors (TKIs) are essential for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) and have allowed for effective, low intensity induction regimens including no or minimal chemotherapy. Whether the use of low intensity induction regimens impacts outcomes after allogeneic hematopoietic stem cell transplant (alloHCT) is less understood. We identified consecutive adult patients with Ph ALL undergoing alloHCT in first complete remission (CR1) at our center from 2010 to 2021 and examined the impact of pre-transplant induction intensity on outcomes. Among the 87 identified patients, 44 (51%) received low intensity induction and 43 (49%) received induction with high intensity chemotherapy. Patients receiving low intensity induction were older (median age 60 vs. 47 years, p < 0.01). Following induction, measurable residual disease (MRD) negativity by BCRABL1 RT-PCR was similar in the low and high intensity induction cohorts (54% and 52% respectively). Receipt of reduced intensity transplant conditioning was not associated with intensity of induction regimen (39% vs. 19% in low vs. high, respectively, p 0.06). At a median follow-up of 21 months from transplant, there was no difference between low and high intensity induction with respect to 2-year disease-free survival (58% vs. 56%), 2-year overall survival (62% vs. 63%), 2-year cumulative incidence of relapse (9% vs. 17%), and 2-year non-relapse mortality (33% vs. 29%). We also found no difference in outcomes when patients were segmented by both induction and conditioning regimen intensities. Our retrospective analysis suggests that induction intensity does not impact post-transplant outcomes among patients with Ph ALL transplanted in CR1.

Synergistic effect of combined PI3 kinase inhibitor and PARP inhibitor treatment on BCRABL1-positive acute lymphoblastic leukemia cells.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) function by inhibiting base excision repair and inducing synthetic lethality in homologous recombination repair-deficient cells, such as BRCA12-mutated cancer cells. The BCRABL1 fusion protein causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph

An Overview of Conventional Drugs and Nano Therapeutic Options for the Treatment and Management of Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a common form of pediatric cancer affecting the lymphoblast, a type of white blood cell found in the bone marrow. In this disease, the normal lymphoblast cells transform into leukemic cells and subsequently enter the bloodstream. Leukemic cells found in patients with ALL have shown differences in cholesterol uptake and utilization. Current treatment consists of chemotherapy, chimeric antigen receptor (CAR) therapy, and hematopoietic stem cell transplantation (HSCT). In addition, minimal residual disease (MRD) has become an effective tool in measuring treatment efficacy and the potential for relapse. Chemotherapy resistance remains a significant barrier in the treatment of ALL. Biomarkers such as an upregulated Akt signaling pathway and an overexpressed VLA-4 integrin-protein have been associated with drug resistance. Nanoparticles have been used to favorably alter the pharmacokinetic profile of conventional drug agents. These drug-delivery systems are designed to selectively deliver their drug payloads to desired targets. Therefore, nanoparticles offer advantages such as improved efficacy and reduced toxicity. This review highlights conventional treatment options, distinctive characteristics of pediatric ALL, therapeutic challenges encountered during therapy, and the key role that nanotherapeutics play in the treatment of ALL.

The effect of pre-conditioning immunoglobulin and absolute lymphocyte count on the outcomes of allogeneic hematopoietic cell transplantation.

The prevention of mortality and morbidity related to the increasingly used allogeneic hematopoietic cell transplantation (allo-HCT), along with the effects of pre- and post-transplant immune status on transplant outcomes, have become the focus of the studies conducted on this subject in recent years. In parallel, this study was designed to investigate the effects of pre-conditioning immunoglobulin (pre-conditioning-Ig) and pre-conditioning absolute lymphocyte count (pre-conditioning-ALC) levels on transplant outcomes. This study was designed as a retrospective, observational and cross-sectional study. The objective of the study is to investigate the effects of pre-conditioning-Ig and ALC levels primarily on the rate of patients with febrile neutropenia (FEN) and the duration of FEN and length of hospital stay (LoS), and secondarily on acute graft-versus-host disease (aGVHD), cytomegalovirus (CMV) viremia, and mortality in the acute leukemia patients who underwent allo-HCT. A total of 104 acute leukemia patients, of whom 55 had acute lymphoblastic leukemia (ALL) and 49 had acute myeloid leukemia (AML), were included in the study. Compared to the AML group, the median pre-conditioning-IgG, IgA, and IgM levels were found to be significantly lower in the ALL group (11.3 vs. 6.6, p < 0.001 1.8 vs. 0.9, p < 0.001 and 0.7 vs. 0.4, p < 0.001 respectively). But, there was no significant difference between the groups in pre-conditioning-Ig and ALC levels and transplant outcomes. However, subgroup analysis revealed that high pre-conditioning-ALC levels were significantly correlated with aGVHD levels (Odds Ratio 1.02 p 0.034) and low pre-conditioning-IgM levels were significantly correlated with increased mortality rate (Hazard Ratio 0.08 p 0.042) in AML patients. The significant difference determined between the ALL and AML groups in pre-conditioning-Ig levels was not reflected on the effects of pre-conditioning-Ig and ALC levels on transplant outcomes. However, we observed that pre-conditioning-IgM and ALC levels have an impact on transplant outcomes in AML patients.

Aberrant expression of CD5 in a case of B acute lymphoblastic leukemia positive Philadelphia chromosome.

B acute lymphoblastic leukaemia (B-ALL) is a proliferation of hematopoietic precursor cells characterized by the expression of various B-cell antigens. Expression of T cell antigens has rarely been reported in B-ALL. We report the second case CD5 (Cluster of differentiation 5) B-ALL associated with Philadelphia chromosome (Phi). A 38-year old male presented with anorexia and generalized weakness for the last ten days. Hemogram revealed bicytopenia and hyperleukocytosis made of 93% difficult to classify cells. A diagnosis of diffuse large B-cell lymphoma was suspected. An immunophenotyping on peripheral blood was performed. The panel for B- cell lineage chronic lymphoproliferative disorders (B-CLPD) was used. The dim expression of CD45 and the lack of surface immunoglobuline helped to exclude a CD5 expressing mature B cell neoplasm. Then, the diagnosis of ALL was confirmed by ALL panels. Karyotype showed a Phi. Thus, a diagnosis of B-ALL with aberrant expression of CD5 and Phi was established. The patient received chemotherapy according to the modified group for research on adult acute lymphoblastic leukemia philadelphia positive 2005 protocol (GRAAPH 2005). A complete remission at the end of induction was obtained. The patient received consolidation and then, hematopoietic stem cell transplantation. The patient is in complete hematological remission till the date of submission of this report. Aberrant expression of CD5 associated with Phi has rarely been reported in B cell lineage ALL and having a poor prognosis. Pathologists and clinicians should be aware of this entity to avoid confusion with other tumors.

Blastic plasmacytoid dendritic cell neoplasm a diagnosis not to be missed, about three case reports.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a proliferation of plasmacytoid cell precursors. It is a rare and difficult-to-diagnose hematological malignancy with a poor outcome. We report three cases of BPDCN diagnosed in patients of different nationalities (Tunisian, Algerian and Libyan) and varying ages (eight, 65 and 74 years old). Cutaneous involvement was present in all three cases. Cytology was inconclusive in the first case, in favor of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) in the second and third case respectively. The diagnosis was retained by flow cytometry, highlighting the Cluster of Differentiation (CD) 4 CD56 phenotype of the blast population. These observations illustrate diagnosis challenges, the importance of biologicalclinical confrontation in order not to misdiagnose this entity. Flow cytometry is an essential diagnostic tool.

PAX5 and TDT-Negative B-Acute Lymphoblastic Leukemia with Unusual Genetic Mutations A Case Report.

B-acute lymphoblastic leukemia (B-ALL) is commonly encountered in clinical practice. Patients present with increased percentage of lymphoblasts in bone marrow andor peripheral blood. Immunophenotypic study by flow cytometry or immunohistochemistry is essential to establish the diagnosis. Paired box-5 (PAX5) is a B cell lineage protein and terminal deoxynucleotidyl transferase (TDT) is an immature marker, both of which are routinely tested in the pathologic workup of acute leukemia. In this report, we describe a case of B-ALL in a 37-year-old woman in which both PAX5 and TDT were negative. Next-generation sequencing test detected mutations in DNA methyltransferase 3 α and Fms related receptor tyrosine kinase 3 genes, which are frequently mutated in acute myeloid leukemia rather than B-ALL. The constellation of these rare findings in a single case signifies the importance of examining a wide panel of markers when the diagnosis of ALL is suspected.

Cost-effectiveness analysis of dasatinib versus imatinib in pediatric philadelphia chromosome-positive acute lymphoblastic leukemia patients in China.

Dasatinib and imatinib are the recommended tyrosine kinase inhibitors (TKIs) for treating pediatric Philadelphia-positive acute lymphoblastic leukemia (Ph ALL), and the one which has been approved indication in China is imatinib. Recently, clinical demand for Ph ALL treatment is becoming unmet gradually with the increasing resistance of imatinib. There are some studies reporting the better efficacy and comparative safety of dasatinib compared with imatinib, but no economic comparison has been published. This study aims to supplement economic evidence by comparing the cost-effectiveness between imatinib and dasatinib in treating pediatric patients with Ph ALL in China, and to help clinical rational drug use via multi-dimensional value assessment. A decision tree model combined with a 10-year Markov model were established based on the disease progression. The parameters were collected from published literatures and our hospitals electronic medical records. From the health system perspective, the incremental cost-effectiveness ratio (ICER) between the two treatment groups was calculated through cost-effectiveness analysis and then compared with the willingness-to-pay (WTP) threshold. The set WTP threshold in this study was 1 times per capita gross domestic product (GDP) of China, as recommended by the World Health Organization. Direct medical costs and quality-adjusted life years (QALYs) were calculated and discounted at 5%. The sensitivity analyses were conducted to assess the uncertainty and robustness of the results. The total costs were CNY 1,020,995.35 and CNY 1,035,788.50 in imatinib group and dasatinib group during the 10-year simulation, and the total QALYs were 2.59 and 4.84. Compared with the imatinib treatment group, the ICER was around CNY 6,575.78 QALY, which was less than the set threshold CNY 70,892 QALY. The sensitive analyses indicated the robustness of the results. The cost-effectiveness analysis shows the potential cost-effective advantages of adding dasatinib comparing with adding imatinib for pediatric Ph ALL patients in China under the set WTP threshold, which indicates that those patients could achieve more QALYs by paying acceptable fee.

A Case Of Precursor B-Acute Lymphoblastic Leukaemia Masquerading As Hypereosinophilia And Space Occupying Lesion In A 14-Year-Old Boy.

Peripheral blood eosinophilia is associated with a variety of benign and neoplastic conditions. Rarely, marked eosinophilia can mask an underlying Acute Leukaemia, delaying the correct diagnosis and treatment. Here, we report a case of 14-year-old boy, who presented with marked eosinophilia and space occupying lesion in the brain. Bone marrow biopsy and biopsy of brain lesion were performed to assess the underlying disorder, revealing the unexpected diagnosis of Precursor B- Acute Lymphoblastic Leukaemia in this patient. Cytogenetic studies revealed a normal male karyotype. This case highlights the significance of considering the rare possibility of Acute Lymphoblastic Leukaemia among the differential diagnosis of persistent eosinophilia in order to facilitate prompt and appropriate treatment.

Fishing for ETV6RUNX1 fusion and MLL gene rearrangements and their additional abnormalities in childhood acute lymphoblastic leukemia patients of Kashmir.

Evidence suggests that ETV6RUNX1 translocation in pediatric acute lymphocytic leukemia shows geographical variation. Therefore, the present study aimed at unveiling the incidence of ETV6RUNX1 fusion in pediatric acute lymphocytic leukemia cases of this region using fluorescent in-situ hybridization. Besides, we aimed to determine the incidence of MLL gene rearrangement and the pattern of chromosomal abnormalities in this study group. Samples from 57 acute lymphocytic leukemia cases of pediatric age group were subjected to fluorescent in-situ hybridization and conventional cytogenetic analysis using standard methods. Conventional cytogenetic analysis revealed chromosomal abnormalities in 19.3% cases. The other major chromosomal abnormalities reported were monosomies in 10.5%, hypodiploidy in 7%, marker chromosomes in 3.5% and deletions in 3.5% cases. We found a 44,XX,-7,-18, r(5), i(17q) complex karyotype in one of the cases. Fluorescent in-situ hybridization analysis revealed ETV6RUNX1 translocation to be present in 28.07% cases and MLL gene rearrangement in 3.5% cases. 12.5% of ETV6RUNX1 fusion positive cases were found to have a loss of ETV6 allele. Besides, 8.8% cases were found to exhibit a signal pattern suggestive of RUNX1 amplification. ETV6 gene deletion and MLL gene amplification was detected in 3.5% cases each, of our study. Frequency of ETV6RUNX1 fusion oncogene was found to be higher in pediatric ALL cases of Kashmir region as compared to that reported from other parts of India. Besides, a case was found to have a karyotype viz 44,XX,-7,-18, r(5), i(17q) that has not been reported elsewhere in the childhood ALL.

Interventional treatment of keratoacanthoderma a case report.

This current case report describes a 56-year-old male patient with a skin mass on his lip that had been growing for 1 year. The pathological findings demonstrated that the epidermis was characterized by hyperkeratosis, hyperplasia and hypertrophy and was formed in the shape of a crater. The skin on both ends had developed into a ball-like growth that resembled a volcanic cone. There was invasive growth of heterotype squamous epithelium and a small number of inflammatory cells infiltrating the dermis. Immunohistochemistry demonstrated an increase in P16 (the focus, ) and the hot spot Ki-67 index. The diagnosis was of tumour-like hyperplasia, malignancy and moderate-to-severe dysplasia confirming that it was keratoacanthoma. The patient underwent surgical resection and was discharged from hospital, but the tumour returned. Paclitaxel and cisplatin were administered intraoperatively and bilateral lingual artery perfusion chemoembolization was undertaken six times. This procedure led to an excellent postoperative recovery and discharge from hospital. Tumour therapy was regarded as successful. The patients medical history included acute lymphoblastic leukaemia L1 and long-term immunosuppressant use. After a 6-month period of follow-up, he died from systemic organ failure as a consequence of having too many ailments.

Characterization, Anti-proliferative Activity, and Bench-Scale Production of Novel pH-Stable and Thermotolerant L-Asparaginase from Bacillus licheniformis PPD37.

Bacterial L-asparaginase (LA) is a chemotherapeutic drug that has remained mainstay of cancer treatment for several decades. LA has been extensively used worldwide for the treatment of acute lymphoblastic leukemia (ALL). A halotolerant bacterial strain Bacillus licheniformis sp. isolated from marine environment was used for LA production. The enzyme produced was subjected to purification and physico-chemical characterisation. Purified LA was thermotolerant and demonstrated more than 90% enzyme activity after 1 h of incubation at 80 °C. LA has also proved to be resistant against pH gradient and retained activity at pH ranging from 3.0 to 10. The enzyme also had high salinity tolerance with 90% LA activity at 10% NaCl concentration. Detergents like Triton X-100 and Tween-80 were observed to inhibit LA activity while more than 70% catalytic activity was maintained in the presence of metals. Electrophoretic analysis revealed that LA is a heterodimer ( 63 and 65 kDa) and has molecular mass of around 130 kDa in native form. The kinetic parameters of LA were tested with LA having low K

Efficient preclinical treatment of cortical T cell acute lymphoblastic leukemia with T lymphocytes secreting anti-CD1a T cell engagers.

The dismal clinical outcome of relapsedrefractory (RR) T cell acute lymphoblastic leukemia (T-ALL) highlights the need for innovative targeted therapies. Although chimeric antigen receptor (CAR)-engineered T cells have revolutionized the treatment of B cell malignancies, their clinical implementation in T-ALL is in its infancy. CD1a represents a safe target for cortical T-ALL (coT-ALL) patients, and fratricide-resistant CD1a-directed CAR T cells have been preclinically validated as an immunotherapeutic strategy for RR coT-ALL. Nonetheless, T-ALL relapses are commonly very aggressive and hyperleukocytic, posing a challenge to recover sufficient non-leukemic effector T cells from leukapheresis in RR T-ALL patients. We carried out a comprehensive study using robust We show that CD1a-T cell engagers bind to cell surface expressed CD1a and CD3 and induce specific T cell activation. Recruitment of bystander T cells endows CD1a-STAbs with an enhanced Our data suggest that CD1a-STAb T cells could be an alternative to CD1a-CAR T cells in coT-ALL patients with aggressive and hyperleukocytic relapses with limited numbers of non-leukemic effector T cells.

Cirrhosis With Splenomegaly and Pancytopenia Complicating a Concurrent Diagnosis of Acute Lymphoblastic Leukemia.

Pancytopenia, a hematologic condition, is a decrease in all three blood cell lines. The two main etiologies include decreased production or increased destruction of cells, as seen in nutritional deficiencies or liver cirrhosis, respectively. Pancytopenia commonly presents with fever, splenomegaly, and lymphadenopathy. Initial workup includes complete blood count, metabolic panel, peripheral smear, anemia panel, erythrocyte sedimentation rate, C-reactive protein, and lactate dehydrogenase. Workup also involves excluding toxins, human immunodeficiency virus (HIV), drug effects, and infectious etiologies. Malignancies can cause impaired production of cell lines. For hematologic malignancies, a bone marrow biopsy is performed. In patients above the age of 55 who are diagnosed with acute leukemia, acute lymphoblastic leukemia (ALL) is known to make up approximately 20% of all cases. Furthermore, ALL requires the presence of more than 20% lymphoblasts seen on bone marrow biopsy. Treatment includes induction, consolidation, and maintenance chemotherapy. We report the case of a 63-year-old male with a history of liver cirrhosis from non-alcoholic fatty liver disease who presented for consultation due to pancytopenia without signs of fever or lymphadenopathy. Imaging revealed cirrhosis, ascites, and moderate splenomegaly while the workup for toxins, infections, and HIV was negative. He presented to the hospital with worsening anasarca and acutely worsening pancytopenia. Peripheral smear showed pancytopenia with no definitive blasts, whereas bone marrow biopsy revealed B-lymphoblastic leukemia. He was transferred to a tertiary center for induction chemotherapy but ultimately transitioned to supportive care due to intolerance. This case demonstrates the importance of having a high suspicion for leukemia with an acute decline in all three cell lines, thereby prompting a bone marrow biopsy. Although lacking in the literature, adult patients with ALL can present with splenomegaly without fever or lymphadenopathy. These examination findings are clinical clues to evaluate for underlying malignancies in patients with pancytopenia, although coexisting etiologies may exist. Lastly, peripheral smear alone is insufficient to screen for diagnosis of ALL as it can be normal despite bone marrow involvement.

Alterations in cellular metabolisms after TKI therapy for Philadelphia chromosome-positive leukemia in children A review.

Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCRABL kinase activity, the prognosis of children with CML and Ph ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.

Parent Acceptance toward Inactivated COVID-19 Vaccination in Children with Acute Lymphoblastic Leukemia The Power of Oncologist and Alliance.

Objectives The current study aims to survey the willingness of parents to vaccinate their children, who are childhood acute lymphoblastic leukemia survivors (CALLS), and identify factors associated with vaccine acceptance. Methods Parents of CALLS onoff treatment, with the general condition of being amendable to vaccination, were recruited for interviews with attending oncologists about COVID-19 vaccination acceptance from July to November 2021 in China. After controlling for socioeconomic factors, the Association of Oncologists’ recommendations and parent−oncologist alliance with acceptance status were investigated. For validation, propensity score-matched (PSM) analysis was used. Results A total of 424 families were included in the study, with CALLS mean remission age of 5.99 ± 3.40 years. Among them, 91 (21.4%) agreed, 168 (39.6%) hesitated, and 165 (38.9%) parents disagreed with the vaccination. The most common reason that kept parents from vaccinating their children was lack of recommendations from professional personnel (84165, 50.9%), and massive amounts of internet information (78175, 44.6%) was the main nonhealthcare resource against vaccination. Logistic regression analysis showed that only the recommendation from the oncologist was associated with parents’ vaccine acceptance (OR 3.17, 95% CI 1.93−5.20), as demonstrated by PSM comparison (42 in recommendation group vs. 18 in nonrecommendation group among 114 pairs, p < 0.001). An exploratory analysis revealed that parents with a better patient−oncologist alliance had a significantly higher level of acceptance (65.6% in alliance group vs. 15.6% in nonalliance group among 32 pairs, p < 0.001). Conclusions Due to a lack of professional recommendation resources and the potential for serious consequences, parents were generally reluctant to vaccinate their CALLS. The recommendation of oncologists, which was influenced by the parent−oncologist alliance, significantly increased acceptance. This study emphasizes the critical role of oncologists in vaccinating cancer survivors and can be used to promote COVID-19 vaccines among vulnerable populations.

Identification of Potential Treatments for Acute Lymphoblastic Leukemia through Integrated Genomic Network Analysis.

The advancement of high-throughput sequencing and genomic analysis revealed that acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease. The abundance of such genetic data in ALL can also be utilized to identify potential targets for drug discovery and even drug repurposing. We aimed to determine potential genes for drug development and further guide the identification of candidate drugs repurposed for treating ALL through integrated genomic network analysis. Genetic variants associated with ALL were retrieved from the GWAS Catalog. We further applied a genomic-driven drug repurposing approach based on the six functional annotations to prioritize crucial biological ALL-related genes based on the scoring system. Lastly, we identified the potential drugs in which the mechanisms overlapped with the therapeutic targets and prioritized the candidate drugs using Connectivity Map (CMap) analysis. Forty-two genes were considered biological ALL-risk genes with

A Validated HPLC-Diode Array Detection Method for Therapeutic Drug Monitoring of Thiopurines in Pediatric Patients From Bench to Bedside.

Thiopurine drugs are part of the therapeutic armamentarium for pediatric patients suffering from inflammatory bowel disease (IBD) and acute lymphoblastic leukemia (ALL). The therapeutic drug monitoring of these drugs, consisting of measurements of the thiopurine metabolites thioguanine nucleotides (TGN) and methylmercaptopurine nucleotides (MMPN) are used to optimize the effectiveness of treatment and prevent adverse effects. In this context, we developed and validated a high-performance liquid chromatography-diode array detection (HPLC-DAD) method for the simultaneous quantification of thiopurine metabolites according to the most recent International Council for Harmonisation (ICH) guidelines. The calibration curves were built in the clinically relevant range of concentrations for TGN of 300-12,000 nM and for MMPN of 3000-60,000 nM. The limit of detection and the lower limit of quantification were 100 and 300 nM for TGN and 900 and 3000 nM for MMPN, respectively. The percentage of inter-day accuracy and precision (CV%) varied between 85 and 104% and 1.6 and 13.8%. Stability was demonstrated for both of the metabolites for at least 50 days at -20 °C. The proposed HPLC-DAD method showed an appropriate selectivity, specificity, linearity, accuracy, precision and good applicability to samples from patients with IBD and ALL undergoing thiopurine treatment.

Mucin (MUC) Family Influence on Acute Lymphoblastic Leukemia in Cancer and Non-Cancer Native American Populations from the Brazilian Amazon.

The mucin (MUC) family includes several genes aberrantly expressed in multiple carcinomas and mediates diverse pathways essentials for oncogenesis, in both solid and hematological malignancies. Acute Lymphoblastic Leukemia (ALL) can have its course influenced by genetic variants, and it seems more frequent in the Amerindian population, which has been understudied. Therefore, the present work aimed to investigate the MUC family exome in Amerindian individuals from the Brazilian Amazon, in a sample containing healthy Native Americans (NAMs) and indigenous subjects with ALL, comparing the frequency of polymorphisms between these two groups. The population was composed of 64 Amerindians from the Brazilian Amazon, from 12 different isolated tribes, five of whom were diagnosed with ALL. We analyzed 16 genes from the MUC family and found a total of 1858 variants. We compared the frequency of each variant in the ALL vs. NAM group, which led to 77 variants with a significant difference and, among these, we excluded those with a low impact, resulting in 63 variants, which were distributed in nine genes, concentrated especially in MUC 19 (

Peripheral Bone Relapse of Paediatric TCF3-HLF Positive Acute Lymphoblastic Leukaemia during Haematopoietic Stem Cell Transplantation A Case Report.

The present case report features a highly uncommon form of a paediatric TCF3-HLF positive acute lymphoblastic leukaemia (ALL) relapse, an extramedullary, peripheral bone manifestation. Following complete remission, during the conditioning for haematopoietic stem cell transplantation (HSCT), our sixteen-year-old male patient complained of fever, pain and swelling of the right forearm. Radiography suggested acute osteomyelitis in the right ulna with subsequent surgical confirmation. Intraoperatively obtained debris culture grew

Relapses Childrens Acute Lymphoblastic Leukemia, Single Center Experience.

The prognosis in children and adolescents with relapsed ALL, despite intensive therapy, including hematopoietic stem cell transplantation, is still challenging. This study aims to analyze the incidence of relapsed ALL and survival rates in correlation to the risk factors. Materials and methods 125 pediatric patients with ALL diagnosed in our department between 2000-2018 age 1−18 years old (median 6.4) female 53.6% vs. male 46.4%. Results 19 pts (15.2%) were diagnosed with a relapse. Three pts (15.8%) had been diagnosed with very early relapses (23 T-ALL), 12 pts (63.1%) as an early relapse, and 4 pts (21.1%) as a late relapse. Bone marrow was the most frequent relapses localization. The five-year survival has been achieved by six patients (31.6%). A significant difference was found in regard to the five-year overall survival and relapse type (p < 0.05). The group with very early relapses (33 100%) has not reached the five-year survival. Conclusions 1. The main prognostic factor in children’s ALL relapses is still the time of the onset of the relapse. 2. The T lineage acute lymphoblastic leukemia is a worse prognostic factor. 3. The analysis of the above relapse risk factors alongside cytogenethic markers and flow cytometry or polymerase chain reaction minimal residual disease is very important for first-line chemotherapy improvement and a more personalized choice of therapy for ALL patients.

Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTKFLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (2139) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 120 MRX-2843venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL.

Frequency Of CD34 Expression In Acute Lymphoblastic Leukaemia And Its Correlation With Clinicopathological Characteristics A Single Centre Experience From Pakistan.

This study was carried out to determine the frequency of CD34 positivity in acute lymphoblastic leukaemia (B-ALL) in our population and to report its association with the clinicopathological profile at the time of diagnosis. The cross-sectional study was conducted at National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan, from March 2020 till December 2020.Newly diagnosed patients were selected, from both genders and all age groups. Relevant history and findings of physical examination were recorded. Immunohistochemistry was done on trephine biopsy and molecular studies were carried on bone marrow aspirates or peripheral blood samples. Out of 105 patients enrolled, 67 (63.8%) were males, with a male to female ratio (M F) 1.81. Of the total patients, 62 (59.04%) were above 15 years of age. CD34 was expressed in 73 (69.5%) cases. Lymphadenopathy, splenomegaly, and hepatomegaly were separately noted in context to CD 34 expression in 22 (66.6%), 24 (64.8%), and 14 (58.3%) patients, respectively. CNS disease was seen in a total of 3(2.75%) subjects, in which 2 (66.6%) of the patients had CD34 expression. Total 81 patients in our study fall into the high-risk group out of which CD 34 expression was seen in 58(71.6%) subjects. Cytogenetic analysis, BCR-ABL p190, and MLL gene rearrangement were investigated in all participants. Cytogenetic analysis revealed an abnormality in 20 (19%) cases out of which 13 (17.8%) cases were from CD34 positive group. Our study reported CD34 expression in more than two-thirds of cases. High-risk disease was significantly associated with CD34 expression.

Cytogenetic Profile Of Acute Lymphoblastic Leukaemia Patients And Its Association With Induction Remission Status.

Acute lymphoblastic leukaemia is characterized by the presence of more than or equal to 20% lymphoblast (early lymphoid precursors) in peripheral blood andor in bone marrow. Lymphoblast can infiltrate different organs and clinically patients can present with fatigue, pallor, fever, bone pain, bleeding or bruises and lymphadenopathy. ALL is the most common type of malignancy in children. To determine the cytogenetic abnormalities in patients of Acute Lymphoblastic Leukaemia as a predictor of response to induction chemotherapy. It was a descriptive cross-sectional study. This study was conducted at the Armed Forces Institute of Pathology, Rawalpindi over a period of six months from June to November 2019. Bone marrow and peripheral blood samples of newly diagnosed 80 patients of all the age groups and either gender, who received one month treatment for ALL,were analyzed for cytogenetic study. Patients who were previously diagnosed with ALL, who presented with relapse and those who required induction treatment outside the trial hospital were excluded. UK ALL 2011 treatment protocol was adopted for patients up to 25 years old and for patients above 25years old UK ALL 2014 treatment protocol as induction chemotherapy was adopted. Evaluation for remission was carried out at the termination of initial induction chemotherapy on day 29 of treatment. A total of 80 patients were enrolled in the study, comprising 36 (45%) females 44 (55%) males. The median age of paediatric patients was 5years (<19 years) who were 5680 (70%) in number whereas the median age of adults was 27 years (>19 years) who constituted 2480 (30%) of the participants. Cytogenetic of 51 (63.75%) patients revealed hyperdiploidy (chromosome number 51-66) whereas 29(36.25%) of the participants had miscellaneous mutations (Hypodiploidy, t (9 22), t (1 19) and t (12 21). On immunophenotyping 5180 (63.7%) of the leukemias were of B cell origin and 29 (36.25%) of T-cell origin. Patients with hyperdiploidy, t (1221) ETV6RUNX1 and t(119)TCF3PBX1 had better prognosis and higher remission rate compared to those with the other mutations like t(922)Ph and hypodiploid which were associated with poor prognosis. Association of gender with remission was not statistically significant.

Extracellular vesicle microRNAs contribute to Notch signaling pathway in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive T-cell malignancy characterized by genotypically-defined and phenotypically divergent cell populations, governed by adaptive landscapes. Clonal expansions are associated to genetic and epigenetic events, and modulation of external stimuli that affect the hierarchical structure of subclones and support the dynamics of leukemic subsets. Recently, small extracellular vesicles (sEV) such as exosomes were also shown to play a role in leukemia. Here, by coupling miRNome, bulk and single cell transcriptome profiling, we found that T-ALL-secreted sEV contain NOTCH1-dependent microRNAs (EV-miRs), which control oncogenic pathways acting as autocrine stimuli and ultimately promoting the expansionsurvival of highly proliferative cell subsets of human T-cell leukemias. Of interest, we found that NOTCH1-dependent EV-miRs mostly comprised members of miR-17-92a cluster and paralogues, which rescued in vitro the proliferation of T-ALL cells blocked by γ-secretase inhibitors (GSI) an regulated a network of genes characterizing patients with relapsedrefractory early T-cell progenitor (ETP) ALLs. All these findings suggest that NOTCH1 dependent EV-miRs may sustain the growthsurvival of immunophenotypically defined cell populations, altering the cell heterogeneity and the dynamics of T-cell leukemias in response to conventional therapies.

Mild blurry vision as the initial presentation of central nervous system relapses of acute lymphoblastic leukemia a case report.

Leukemia relapses after hematopoietic stem cell transplantation can sometimes occur from the central nervous system prior to relapse from the bone marrow, and manifestations varied. We present a case of mild blurry vision as the initial symptom of central nervous system relapse of adult acute lymphoblastic leukemia. A 30-year-old man presented with a 1 week history of painless visual loss in both eyes. At that time there were no headaches or other systemic features. The neurological examination was without positive findings except bilateral optic nerve edema. He had a history of acute lymphoblastic leukemia and hematopoietic stem cell transplantation, which had been in clinical remission post-transplant for 1 year. Lumbar puncture revealed relapsed disease within the central nervous system, confirmed with cerebrospinal fluid leukemic blasts. It highlights the need for ophthalmologists to be aware of the possibility of central nervous system involvement in patients with the setting of leukemia when visual symptoms as the initial manifestation.