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Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency.

IkarosIKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

Tisagenlecleucel for B-Cell Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma — Project Protocol, Clinical Section

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and children and young adults (25 years or younger) with relapsed or refractory B-cell acute lymphoblastic leukemia (rr-ALL). Tisagenlecleucel was approved by the FDA for the treatment of adult rr-DLBCL in May of 2018, and for the treatment of pediatric rr-ALL in August of 2017. Prior to implementation in Canada, various stakeholders will need to evaluate the projected number of patients eligible for tisagenlecleucel, models of care, and the feasibility of an integrated work plan for identifying pediatric and adult populations with appropriate indications for tisagenlecleucel therapy. Questions about clinical effectiveness, cost-effectiveness, and implementation considerations (such as locations for treatment, system capacity, and clinical delivery protocols) will also need to be addressed. Contingency plans must be established if a scheduled tisagenlecleucel infusion cannot proceed because of manufacturing error, if the patient becomes too ill to receive the infusion, or dies during the waiting period after leukapheresis. Differences in the practice and use of CAR T-cell therapy between jurisdictions may result from variations in the availability or capacity to establish logistical and workforce requirements to deliver CAR T-cell therapies in the various provinces and territories.

Up-regulation of HO-1 promotes resistance of B-cell acute lymphocytic leukemia cells to HDAC45 inhibitor LMK-235 via the Smad7 pathway.

HDAC45 and Smad7 are potential therapeutic targets for the onset and progression of B-cell acute lymphocytic leukemia (B-ALL) and indices for clinical prognosis. In contrast, HO-1 (heat shock protein 32) plays a key role in protecting tumor cells from apoptosis. HDAC45, HO-1 and Smad7 expressions in 34 newly diagnosed B-ALL cases were detected by real-time PCR and Western blot. Lentivirus and small interference RNA were used to transfect B-ALL cells. The expression of Smad7 was detected after treatment with LMK-235 or Hemin and ZnPP. Apoptosis and proliferation were evaluated by flow cytometry, CCK-8 assay and Western blot. HDAC45 was overexpressed in B-ALL patients with high HO-1 levels. Increasing the concentration of HDAC45 inhibitor LMK-235 induced the decrease of Smad7 and HO-1 expressions and the apoptosis of B-ALL cells by suppressing the phosphorylation of AKT (Protein kinase B). Up-regulating HO-1 alleviated the decrease of Smad7 expression and enhanced B-ALL resistance to LMK-235 by activating p-AKT which reduced the apoptosis of B-ALL cells and influenced the survival of leukemia patients. Silencing Smad7 also augmented the apoptosis rate of B-ALL cells by suppressing p-AKT. HO-1 played a key role in protecting tumor cells from apoptosis, and HDAC45 were related with the apoptosis of B-ALL cells. LMK-235 may be able to improve the poor survival of leukemia patients.

Ecthyma Gangrenosum Vulvar Ulcers, Pseudomonas, and Pancytopenia A Case Report of an 18-Month-Old Female Toddler.

An 18-month-old female toddler presented with severe vulvar ulcers and pancytopenia with investigations revealing Pseudomonas aeruginosa bacteremia. A previously healthy 18-month-old female toddler presented with 6 days of fevers, vulvar rash, and ulcers. Vulvar cultures showed Staphylococcus aureus and P aeruginosa. Bloodwork showed pancytopenia and P aeruginosa bacteremia. She started receiving broad-spectrum antibiotics. Bone marrow aspirate revealed a hypocellular marrow with erythroid dysplasia. Vulvar ulcers progressed rapidly, therefore magnetic resonance imaging was performed to rule out necrotizing fasciitis. She was diagnosed with ecthyma gangrenosum (EG). Three months after initial presentation, she was diagnosed with precursor B-cell acute lymphoblastic leukemia. This case highlights that health care providers should suspect EG when severe vulvar ulcers are present with P aeruginosa infection and neutropenia. Because EG poses significant morbidity and mortality, its presence should prompt aggressive antimicrobial therapy and mobilization of a multidisciplinary team to initiate workup for an underlying immunodeficiency syndrome or malignancy. This case also illustrates that surgical debridement might be avoided in certain patients with EG as long as meticulous wound care and close monitoring with a multidisciplinary team are in place.

Terminal deoxynucleotidyl transferase (TdT)-negative T-cell lymphoblastic lymphoma with loss of the T-cell lineage-specific marker CD3 at relapse a rare entity with an aggressive outcome.

Terminal deoxynucleotidyl transferase (TdT)-negative T-cell lymphoblastic lymphoma is a variant of T-cell lymphoblastic lymphomaT-cell lymphoblastic leukaemia. TdT is a marker of immaturity expressed in 90%-95% cases of lymphoblastic lymphoma and useful in differentiating it from other mature lymphomasleukaemias. It has been associated with poorer response to chemotherapy and a more aggressive outcome. Here we present a case of TdT-negative T-cell lymphoblastic lymphoma in a 28-year-old man who presented with superior vena cava syndrome. The patient was treated with hyper-cyclophosphamide,vincristine, Adriamycin, dexamethasone (CVAD), however unfortunately suffered a relapse 1 year later. A unique feature of our case was that on relapse, the patient lost expression of the T-cell lineage-specific marker CD3, which has previously not been reported in association with TdT-negative T-cell lymphoblastic lymphoma. The patient failed to respond to chemotherapy on his relapse and died.

Genetic polymorphisms of Th2 interleukins, history of asthma or eczema and childhood acute lymphoid leukaemia Findings from the ESCALE study (SFCE).

Previous studies on the putative role of allergy in the aetiology of childhood leukaemia have reported contradictory results. The present study aimed to analyse the relation between a medical history of asthma or eczema and childhood acute lymphoid leukaemia (ALL) in light of potential candidate gene-environment interactions. Analyses were based on a subset of 434 cases of ALL and 442 controls successfully genotyped and of European ancestry children enrolled in a French population-based case-control study conducted in 2003-2004. Information about medical history was obtained during a standardized interview with the mothers. Candidate polymorphisms in genes of the Th2 cytokines IL4, IL10, IL13 and IL4-receptor, were genotyped or imputed. None of the variant alleles were directly associated with childhood acute lymphoid leukaemia. A medical history of asthma or eczema was reported more often in the control group (OR 0.7 0.5-1.0). This association was mostly seen in the group of children not carrying the IL13-rs20541 variant allele (Interaction Odds Ratio IOR 1.9, p-interaction 0.07) and in those carrying the IL10 triple variant haplotype (IOR 0.5, p-interaction 0.04). No interaction was observed with the candidate polymorphisms in IL4 and IL4R. This study provides a new insight into the relationship between allergic symptoms and childhood acute lymphoid leukaemia, by suggesting this inverse association could be limited to children carrying certain genetic polymorphisms. If confirmed, these results could help better understand the biological mechanisms involved in the development of childhood acute lymphoid leukaemia.

Vincristine-Loaded and sgc8-Modified Liposome as a Potential Targeted Drug Delivery System for Treating Acute Lymphoblastic Leukemia.

Cytotoxic compounds vincristine sulphate (VCR) is widely used to against hemato-oncology, and especially the acute lymphoblastic leukemia (ALL). However, VCRs full therapeutic potential has been limited by its dose-limiting neurotoxicity, classically resulting in autonomic and peripheral sensory-motor neuropathy. Therefore, we developed a targeted liposomal drug delivery system (sgc8VCR-Lipo) for improving the therapeutic effects of VCR against leukemia and reducing its systematic adverse effects. sgc8VCR-Lipo could specifically bind to CCRF-CEM cells and significantly inhibit proliferation of cancer cells in vitro and tumor growth in vivo. The sgc8VCR-Lipo nanoparticles may improve the anti-tumor efficacy of VCR and reduce side effects induced by non-specific drug release. These results suggest that our findings provide scientific evidence for developing novel aptamer-based targeted drug delivery systems for leukemia treatment.

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Genetic compensation of RUNX family transcription factors in leukemia.

Runt (Runt domain)-related transcription factor 1 (RUNX1) is a transcription factor belonging to the core-binding factor (CBF) family. It is considered to be a master regulator of hematopoiesis and has been regarded as a tumor suppressor because it is essential for definitive hematopoiesis in vertebrates. It is one of the most frequent target genes of chromosomal translocation in leukemia, and germ line mutation of RUNX1 causes familial platelet disorder with associated myeloid malignancies. Somatic cell mutations and chromosomal abnormalities, including those of RUNX1, are observed in myelodysplastic syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia at a high frequency. In addition, recent studies reported by us and other groups suggested that WT RUNX1 is needed for survival and proliferation of certain types of leukemia. In this review, we describe the significance and paradoxical requirement of RUNX1 tumor suppressor in hematological malignancies based on recent findings such as Genetic compensation of RUNX family transcription factors in leukemia, RUNX1 inhibition-induced inhibitory effects on leukemia cells through p53 activation and our novel promising theory Cluster regulation of RUNX (CROX) through the RUNX gene switch method using pyrrole-imidazole polyamides as a new technique that could contribute to the next generation of leukemia treatment strategies.

Fatal massive hemolysis caused by immunoglobulin M anti-c antibody in a patient with newly diagnosed B-cell acute lymphoblastic leukemia a case report.

Delayed hemolytic transfusion reactions (DHTRs) occur secondary to slow, mild IgG-mediated processes against minor red blood cell antigens. Herein, we report the case of a rapidly fatal alloimmune anti-c IgM-mediated hemolysis, a rare, previously undescribed, pathophysiologic scenario. Early recognition of such phenomena can expedite supportive measures and optimize patient outcomes.

ETV6-NTRK3 induces aggressive acute lymphoblastic leukemia highly sensitive to selective TRK inhibition.

Lmo2 expression defines tumor cell identity during T-cell leukemogenesis.

The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stemprogenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stemprogenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of

Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia.

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood-cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system-specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.

Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients.

Breakthrough studies over the past decade have uncovered unique gene fusions implicated in acute lymphoblastic leukaemia (ALL). The critical gene, cytokine receptor-like factor 2 (CRLF2), is rearranged in 5-16% of B-ALL, comprising 50% of Philadelphia-like ALL and cooperates with genomic lesions in the Jak, Mapk and Ras signalling pathways. Children with Down Syndrome (DS) have a predisposition to developing CRLF2 rearranged-ALL which is observed in 60% of DS-ALL patients. These patients experience a poor survival outcome. Mutations of genes involved in epigenetic regulation are more prevalent in DS-ALL patients than non-DS ALL patients, highlighting the potential for alternative treatment strategies. DS-ALL patients also suffer greater treatment-related toxicity from current ALL treatment regimens compared to non-DS-ALL patients. An increased gene dosage of critical genes on chromosome 21 which have roles in purine synthesis and folate transport may contribute. As the genomic landscape of DS-ALL patients is different to non-DS-ALL patients, targeted therapies for individual lesions may improve outcomes. Therapeutically targeting each rearrangement with targeted or combination therapy that will perturb the transforming signalling pathways will likely improve the poor survival rates of this subset of patients.

PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature.

PRDM16 is a transcriptional coregulator involved in translocations in acute myeloblastic leukemia (AML), myelodysplastic syndromes, and T acute lymphoblastic leukemia that is highly expressed in and required for the maintenance of hematopoietic stem cells (HSCs), and can be aberrantly expressed in AML. Prdm16 is expressed as full-length (fPrdm16) and short (sPrdm16) isoforms, the latter lacking the N-terminal PR domain. The role of both isoforms in normal and malignant hematopoiesis is unclear. We show here that fPrdm16 was critical for HSC maintenance, induced multiple genes involved in GTPase signaling, and repressed inflammation, while sPrdm16 supported B cell development biased toward marginal zone B cells and induced an inflammatory signature. In a mouse model of human MLL-AF9 leukemia, fPrdm16 extended latency, while sPrdm16 shortened latency and induced a strong inflammatory signature, including several cytokines and chemokines that are associated with myelodysplasia and with a worse prognosis in human AML. Finally, in human NPM1-mutant and in MLL-translocated AML, high expression of PRDM16, which negatively impacts outcome, was associated with inflammatory gene expression, thus corroborating the mouse data. Our observations demonstrate distinct roles for Prdm16 isoforms in normal HSCs and AML, and identify sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.

Outcome of children and adolescents with Down syndrome treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols 00-001 and 05-001.

Children and adolescents with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are reported to have increased relapse rates and therapy-related mortality (TRM). Treatment regimens for DS-ALL patients often include therapy modifications. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for patients with and without DS. We compared clinical and outcome data of DS (n 38) and non-DS (n 1,248) patients enrolled on two consecutive DFCI ALL trials 00-001 (2000-2004) and 05-001 (2005-2011) with similar risk adapted therapy regardless of DS status. There was no difference in demographic or presenting clinical features between two groups except absence of T-cell phenotype and lower frequency of hyperdiploidy in DS-ALL group. All DS-ALL patients achieved complete remission four relapsed and one subsequently died. There was no TRM in DS-ALL patients. DS-ALL patients had significantly higher rates of mucositis (52% vs. 12%, p < 0.001), non-CNS thrombosis (18% vs. 8% p 0.036), and seizure (16% vs. 5%, p 0.010). Compared to non-DS-ALL patients, DS-ALL patients had a higher incidence of infections during all therapy phases. The 5-year event-free and overall survival rates of DS-ALL patients were similar to non-DS-ALL patients (91% 95% confidence interval (CI), 81-100 vs. 84% 95% CI, 82-86 97% 95% CI, 92-100 vs. 91% 95% CI, 90-93). The low rates of relapse and TRM indicate that uniform risk-stratified therapy for DS-ALL and non-DS-ALL patients on DFCI ALL Consortium protocols was safe and effective, although the increased rate of toxicity in the DS-ALL patients highlights the importance of supportive care during therapy.

Recovery of Pure Red Cell Aplasia Following Hematopoietic Stem Cell Transplantation Associated with Interleukin (IL)-6 Elevation Caused by Odontogenic Infection.

We herein report a case of long-lasting pure red cell aplasia (PRCA) after major ABO-incompatible allogeneic stem cell transplantation (SCT) for acute lymphoblastic leukemia. The patient needed red blood cell (RBC) transfusion every week after SCT. On day 236, he was diagnosed with odontogenic infection, and the serum levels of Interleukin (IL)-6 were elevated to 12.1 pgmL. After that, the numbers of reticulocyte rapidly began to increase, and RBC support was not needed from day 251. No standard care for PRCA following SCT has been established. The IL-6 elevation caused by the odontogenic infection therefore appears to have been affected by the improvement in PRCA.

Pediatric acute lymphoblastic leukemia update on pathophysiology and management.

The prognosis of pediatric acute lymphoblastic leukemia (ALL) has dramatically improved, both basic research and clinical studies are continuously conducted in pursuit of further improvement. Recent advances in genomic analysis technology have enabled us to comprehensively identify genomic alterations in leukemic cells and thus have contributed to the better understanding of the molecular pathogenesis underlying ALL development. These genomic alterations can be applied not only as prognostic factors but also as therapeutic targets. Although somatically acquired genomic alterations in leukemic cells have long been in the focus of molecular analysis for ALL, inherited genetic (germline) variations are now acknowledged as factors involved in the interpretation of ALL susceptibility, therapy response, and toxicities of ALL therapy. Integrated understanding of leukemia and host biology is thus required. In terms of treatment, stratified treatment based on minimal residual disease status and the adaptation of novel therapeutic agents, such as small molecule agents and immunotherapy, appears to be a promising strategy to improve relapsedrefractory ALL without excess complications. Clinical trials should focus on incorporating genome-based diagnosticsstratification and the use of these novel agents into standard therapy in the future.

Adult acute lymphoblastic leukemia update on pathophysiology and management.

For a long time, treatment for adult acute lymphoblastic leukemia (ALL) lacked significant improvements. Since 2000, new approaches, such as the treatments of adolescent and young adult ALL using pediatric-like protocols and Ph ALL treatments using tyrosine kinase inhibitor-combined chemotherapies. Further improvements are expected from the use of pediatric-like protocols to whole adults, and the use of newly approved anti-cancer drugs, such as inotuzumab ozogamicin and blinatumomab. Furthermore, comprehensive genetic analyses using next generation sequencing technology have recently discovered new recurrent fusion genes of ALL, such as DUX4 fusion genes, ZNF384 fusion genes, and MEF2D fusion genes. In this review, I will introduce these frontline studies and discuss about the treatment of patients with adult ALL.

Acute lymphoblastic leukemia among children in Ouagadougou (Burkina Faso) the results of treatment according to the protocol of the Franco-African Pediatric Oncology Group 2005.

acute lymphoblastic leukemia (ALL) is being diagnosed in an increasing number of children in our Department. In the developed countries, the treatment of this hematologic malignancy can cure almost 80% of children. In developing countries, few studies focus on acute leukemias in children. The results of cancer treatments in children are disappointing in most African countries, with a survival rate of 10-15%. This study aimed to investigate the clinical, biological, therapeutic and evolutionary features of ALL in children. we conducted a retrospective study of the medical records of children hospitalized for ALL between November 2009 and October 2011 in the pilot Paediatric Oncology Unit at the Charles de Gaulle University Pediatric Hospital Center, Ouagadougou (Burkina Faso). All children treated according to the protocol of the Franco-African Pediatric Oncology Group 2005 (FAPOG) were included in the study. in total, nine children with ALL were hospitalized during the two year study period. The average age of patients was 10.77± 2.82 years. They were predominantly male. The average time of hospitalization was 43.11 days ± 39.54 days. The main symptoms were alteration of general state and fever. Nearly all the patients had tumor syndrome and bone marrow failure. Myelogram showed ALL type 1 in six of the nine patients. Eight patients underwent chemotherapy according the protocol of FAPOG 2005. Childrens evolution was favorable in two patients who experienced remission, four patients had treatment failure. Six patients died. thanks to information campaigns, which will contribute to encourage early consultations, capacity-building measures for the medical staff allowing early diagnosis of ALL, the construction of a sufficiently equipped pediatric oncology center and a subsidy of anticancer drugs awarded by the state of Burkina Faso, the treatment of children with ALL would allow for better outcomes. La leucémie aiguë lymphoblastique (LAL) de lenfant est une pathologie de plus en plus diagnostiquée dans notre service. Dans les pays développés, le traitement de cette hémopathie maligne permet de guérir près de 80% des enfants. Dans les pays en développement, peu détudes sont consacrées aux leucémies aiguës chez lenfant. Les résultats du traitement des cancers de lenfant sont décevants dans la plupart des pays africains avec un taux de survie de lordre de 10 à 15%. Le but de cette étude était détudier les aspects cliniques, biologiques, thérapeutiques et évolutifs des cas de LAL de lenfant. Il sagissait dune étude rétrospective sur dossiers des enfants hospitalisés pour LAL entre Novembre 2009 et Octobre 2011 dans lunité pilote doncologie pédiatrique du Centre Hospitalier Universitaire Pédiatrique Charles De Gaulle de Ouagadougou (Burkina Faso). Etaient inclus, les enfants pris en charge selon le protocole du Groupe Franco-Africain dOncologie Pédiatrique (GFAOP) 2005. Au total, neuf cas de LAL étaient hospitalisés pendant les deux années étudiées. Lâge moyen des patients était 10,77 ans ± 2,82 ans. On notait une prédominance masculine. Le délai moyen dhospitalisation était 43,11 jours ± 39,54 jours. Les principaux signes dappel étaient laltération de létat général et la fièvre. Le syndrome tumoral et dinsuffisance médullaire étaient présents chez la quasi-totalité des patients. Six des neuf patients présentaient une LAL de type 1 au myélogramme. Huit patients ont bénéficié de la chimiothérapie selon le protocole du GFAOP 2005. Lévolution était favorable chez deux patients avec une rémission, quatre patients étaient en échec de traitement. Six patients sont décédés. Grâce à des campagnes dinformation qui contribueront à amener la population à consulter précocement, au renforcement des capacités du personnel qui permettra un diagnostic précoce des LAL, la construction dun centre doncologie pédiatrique suffisamment équipé et une subvention par lEtat burkinabè des médicaments anticancéreux, la prise en charge de la LAL chez lenfant permettraient dobtenir de meilleurs résultats.

Prognostic Value of Transferrin Receptor-1 (CD71) Expression in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer. Transferrin receptor 1 (CD71) is a trans-membrane glycoprotein which has important role in iron homeostasis by acting as a gatekeeper regulating iron uptake from transferrin and is an attractive target for anti-cancer agents, particularly those that aim to induce lethal iron deprivation in malignant hematopoietic cells. To assess the prognostic value of Transferrin receptor -1 (CD71) in children with newly diagnosed ALL. This study was carried out on 75 patients with newly diagnosed ALL. Transferrin receptor-1 expression was analyzed on the bone marrow blasts by flow cytometry at time of diagnosis with positive CD71 expression is considered when ≥20% of malignant cells express this marker while negative expression is considered when <20% of malignant cells express this marker. Transferrin receptor-1 positive expression was detected in 45 patients (60%) while negative expression was found in the remaining 30 patients (40%). CD71 expression was significantly higher on T- ALL patients compared with B-ALL patients. Positive CD71 expression at diagnosis was significantly associated with bad clinical and laboratory prognostic factors as lymphadenopathy, higher white blood cell count, higher hemoglobin level, lower platelets count, and higher blast cells in peripheral blood and bone marrow and higher lactate dehydrogenase levels. There were significant differences in disease free survival (DFS) and overall survival (OS) between positive and negative CD71 expression groups with significantly shorter DFS and OS in positive CD71 expression group compared to negative group. Positive Transferrin receptor -1 (CD71) expression in patients with ALL is adverse prognostic factor and should be taken in consideration in designing future therapeutic strategies based on patient- specific risk factors.

Neurocognitive Outcomes and Interventions in Long-Term Survivors of Childhood Cancer.

Recent research has demonstrated that survivors of childhood cancer are at risk for a myriad of late effects that affect physical and mental quality of life. We discuss the patterns and prevalence of neurocognitive problems commonly experienced by survivors of CNS tumors and acute lymphoblastic leukemia, the two most commonly researched cancer diagnoses. Research documenting the direct effects of tumor location and treatment type and intensity is presented, and patient characteristics that moderate outcomes (eg, age at diagnosis and sex) are discussed. Potential biologic mechanisms of neurotoxic treatment exposures, such as cranial irradiation and intrathecal and high-dose antimetabolite chemotherapy, are reviewed. Genetic, brain imaging, and neurochemical biomarkers of neurocognitive impairment are discussed. Long-term survivors of childhood cancer are also at risk for physical morbidity (eg, cardiac, pulmonary, endocrine) and problems with health behaviors (eg, sleep) research is reviewed that demonstrates these health problems contribute to neurocognitive impairment in survivors with or without exposure to neurotoxic therapies. We conclude this review with a discussion of literature supporting specific interventions that may be beneficial in the treatment of survivors who already experience neurocognitive impairment, as well as in the prevention of impairment manifestation.

l-Asparaginase a feasible therapeutic molecule for multiple diseases.

This note highlights our understanding and thinking about the feasibility of l-asparaginase as therapeutics for multiple diseases. l-asparaginase enzyme (l-asparagine amidohydrolase, EC 3.5.1.1) is prominently known for its chemotherapeutic application. It is primarily used in the treatment of acute lymphoblastic leukemia in children. It is also used in the treatment of other forms of cancer Hodgkin disease, lymphosarcoma, acute myelomonocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, reticulosarcoma and melanosarcoma (Lopes et al. Crit Rev Biotechnol 231-18, 2015). It deaminates l-asparagine present in the plasma pool causing the demise of tumor cell due to nutritional starvation. The anti-tumorigenic property of this enzyme has been exploited for over four decades and evidenced as a boon for the cancer patients. Presently, the medical application of l-asparaginase is limited only in curing various forms of cancer.

Management of Recurrent Clostridium difficile Infection During Intensive Chemotherapy and Stem Cell Transplantation for Leukemia Case with Literature Review.

Immunocompromised patients undergoing chemotherapy for hematologic malignancy and hematopoietic stem cell transplant (HSCT) recipients are at increased risk of Clostridium difficile (C. difficile) infection (CDI). The recurrence of infection and its associated morbidity and mortality are due to multiple risk factors. Diarrhea is common in HSCT recipients, but the diagnosis of diarrhea caused by CDI is a therapeutic challenge due to frequent Clostridium difficile colonization with diarrhea secondary to non-infectious causes. The high recurrence rate is a significant challenge in the treatment of immunocompromised patients. Close monitoring of the patients, timely diagnosis, preventive measures, treatment with antibiotics, and the removal of offending agents can help in the management and cure of the disease. We review the literature on management and describe a patient with acute lymphoblastic leukemia (ALL) with multiple recurrences of CDI during leukemia therapy and allogeneic stem cell transplantation for leukemia.

Long-term outcomes of total body irradiation plus cyclophosphamide versus busulfan plus cyclophosphamide as conditioning regimen for acute lymphoblastic leukemia a comparative study.

The role of total body irradiation (TBI) in allogeneic hematopoietic stem cell transplantation (HCT) for adult acute lymphoblastic leukemia (ALL) remains controversial. Therefore, we investigated long-term treatment outcomes of transplanted ALL patients aiming to identify prognostic factors and the impact of conditioning. We enrolled consecutive ALL patients transplanted from 1990 to 2016, following TBI- or busulfan (Bu)-based conditioning regimen. We studied 151 ALL patients transplanted in first complete remission (CR) (60), other CR (33), or relapsedrefractory disease (58) from sibling (87), and HLA-matched (42) or mismatched (17) unrelated and alternative donors (5). High-dose fractionated TBI-based conditioning was administered in 84. No differences were observed in baseline characteristics, except for disease stage at transplant, donor type, and graft source. With a follow-up of 19.0 (0.5-170.5) in TBI and 14.5 (1.2-319.1) months in non-TBI patients, there was no difference in acute (grades II-IV) or chronic GVHD, thrombotic microangiopathy, and bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group. There was no significant difference in the cumulative incidence (CI) of treatment-related or relapse mortality and disease-free or overall survival (OS). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p 0.024), advanced disease stage (p 0.007), and female-to-male donor (p 0.006). Interestingly, TBI patients younger than 40 years had significantly higher OS (55.1%, p 0.023) and DFS (48.6%, p 0.020). In conclusion, high-dose TBI is feasible in younger patients providing better survival. The choice between TBI- or Bu-conditioning regimens remains challenging.

Transplantation of CCR5∆32 Homozygous Umbilical Cord Blood in a Child With Acute Lymphoblastic Leukemia and Perinatally Acquired HIV Infection.

Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day 73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC). HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days -8 and 22, and in the LN, colon, lung, and brain day 73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5CD3 cells in the LN postmortem. HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.

Differential Activity of Voltage- and Ca

Activation of resting T cells relies on sustained Ca

Acute Lymphoblastic Leukemia with Hypereosinophilia in a Child Case Report and Literature Review.

Donor-derived CAR-T Cells Serve as a Reduced-intensity Conditioning Regimen for Haploidentical Stem Cell Transplantation in Treatment of RelapsedRefractory Acute Lymphoblastic Leukemia Case Report and Review of the Literature.

Reduced-intensity conditioning (RIC) regimens with low tolerable toxicities have been used for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the relapse rate by this treatment is high. Treatment of CD19 B-cell relapsedrefractory acute lymphoblastic leukemia (rr ALL) with allogeneic chimeric antigen receptor-modified T (CAR-T) cells is safe and effective. Use of allogeneic CD19-CAR-T cells as a part of RIC regimens for treatment of rr ALL patients with haploidentical HSCT has not been investigated yet. A 12-year-old girl with CD19 rr ALL underwent haploidentical HSCT. The patient received fludarabine, busulfan, and cyclophosphamide combined with haploidentical donor-derived CD19-CAR-T cells as the conditioning regimen. Granulocyte colony-stimulating factor-mobilized peripheral blood stem cells and granulocyte colony-stimulating factor-mobilized bone marrow were infused on days 1 and 2, respectively. Mycophenolate mofetil and tacrolimus were administered on day 1, antithymocyte globulin was administered on days 14 and 15, and a short course of methotrexate was administered to prevent graft-versus-host disease. The time of peak CAR-T cell proliferation was detected after the first infusion of CAR-T cells on day 7. The patients engraftment and full-donor cell engraftment were established. The disease was in complete remission with minimal residual disease, which was undetectable by flow cytometry. No graft-versus-host disease or serious cytokine-release syndrome was found. Treatment of rr ALL with RIC including CD19-CAR-T cells followed by allo-HSCT was safe and effective, which suggest that CAR-T cells can be used as a part of RIC regimens in the treatment of rr ALL in haploidentical HSCT.

Intensified Therapy of Acute Lymphoblastic Leukemia in Adults Report of the Randomized GRAALL-2005 Clinical Trial.

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (BT lineage, 525 and 262, respectively median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16 P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

Cytotoxic Activity of Extracts from Plants of Central Argentina on Sensitive and Multidrug-Resistant Leukemia Cells Isolation of an Active Principle from

Plants are a significant reservoir of cytotoxic agents, including compounds with the ability to interfere with multidrug-resistant (MDR) cells. With the aim of finding promising candidates for chemotherapy, 91 native and naturalized plants collected from the central region of Argentina were screened for their cytotoxic effect toward sensitive and MDR P-glycoprotein (P-gp) overexpressing human leukemia cells by means of MTT assays. The ethanol extracts obtained from

Clinical significance of the TNF-α receptors, TNFRSF2 and TNFRSF9, on cell migration molecules Fascin-1 and Versican in acute leukemia.

In human hematologic malignancies, some of the TNF receptor family members are up-regulated and have the ability to evoke reactions favoring tumor progression. Moreover, cell migration molecules, Fascin-1 and Versican are involved in proliferation, migration and invasion of cancer cells. They are linked to many human cancers. Therefore, we conducted this study to evaluate both the plasma and leukocytes concentrations of tumor necrosis factor receptor super family 2 (TNFRSF2), TNFRSF9, Fascin-1 and Versican in patients with acute leukemia, as well as to correlate these values with clinical features and treatment outcome. Therefore, forty-eight patients with acute myeloid leukemia (AML), thirty-two patients with acute lymphoblastic leukemia (ALL) and fifteen control subjects were included. TNFRSF2, TNFRSF9, Fascin-1 and Versican were measured in plasma and leukocytes of all subjects by enzyme-linked immunosorbent assay. We found that plasma TNFRSF9 was highly elevated in ALL and AML as compared with the control group. In addition, AML patients who failed to achieve complete remission showed a significant increase in leukocytes TNFRSF9 level. TNFRSF2 is significantly increased in plasma and leukocytes of ALL patients when compared with the control group and AML patients. Fascin-1 significantly increased in AML, but not in ALL cases. Plasma and leukocytes levels of Versican significantly increased in AML compared to both control and ALL subjects. Plasma Versican correlated with poor response to induction of chemotherapy in AML cases. In conclusion, TNFRSF2 and TNFRSF9 could act as a possible prognostic biomarkers for the outcomes of ALL patients and TNFRSF9 could be a potential target in AML. Versican may be used as a diagnostic biomarker and as a predictor of the response to chemotherapy in AML. In addition, plasma Fascin-1 is a potential biomarker for AML.

PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts.

Clinical trials of CD19-specific chimeric antigen receptor (CAR19) T cells have demonstrated remarkable efficacy against relapsed and refractory B cell malignancies. The piggyBac transposon system offers a less complex and more economical means for generating CAR19 T cells compared to viral vectors. We have previously optimized a protocol for the generation of CAR19 T cells using the piggyBac system, but we found that CAR19 T cells had poor in vivo efficacy and persistence, probably due to deleterious FcγR interactions with the CARs IgG1 Fc-containing spacer domain. We therefore designed three CD19-specifc CARs that lacked the IgG1 Fc region, and we incorporated combinations of CD28 or 4-1BB transmembrane and co-stimulatory domains. PiggyBac-generated CAR19 T cells expressing these re-designed constructs all demonstrated reactivity in vitro specifically against CD19

Phase IIIII study in children and adolescents with newly diagnosed B-cell precursor acute lymphoblastic leukemia protocol for a nationwide multicenter trial in Japan.

B-cell precursor acute lymphoblastic leukemia is the most common pediatric malignancy, but its treatment needs to be modified to cause low acute toxicity and few late complications with a high cure rate. In this trial, we will stratify patients with B-cell precursor acute lymphoblastic leukemia into standard, intermediate and high risk groups according to prognostic factors. In addition, we will establish an evaluation system for minimal residual disease that will enable us to stratify patients based on minimal residual disease in subsequent clinical trials. We will clarify the impact of dexamethasonevincristine pulse therapy during maintenance therapy in the standard risk group, and intensive l-asparaginase therapy in the intermediate risk group. In the high risk group, usefulness of vincristine intensification will be assessed. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000009339 httpwww.umin.ac.jpctr.

Blast Percentage of Bone Marrow Aspirate on Day 14 of Induction Chemotherapy Predicts Adult Acute Lymphoblastic Leukemia Treatment Outcomes.

The prognosis of adult acute lymphoblastic leukemia is much worse than that of pediatric acute lymphoblastic leukemia, even when patients achieve complete remission. Early response to treatment can be an important alternative indicator of treatment outcomes. The purpose of our current study was to identify the prognostic value of the blast percentage of the induction interim bone marrow, which might predict relapse-free survival and overall survival in patients with adult acute lymphoblastic leukemia. A retrospective analysis was performed on 80 adult patients diagnosed with Philadelphia chromosome-negative acute lymphoblastic leukemia from 1994 to 2011. Complete remission was observed in 75 (93.8%) patients after induction chemotherapy. On multivariate analysis, a reduction of blasts to a level of 5% or less in the induction interim bone marrow and CD20 positivity were significant prognostic predictors of relapse-free survival (hazard ratio, HR 2.88, p 0.006, and HR 2.67, p 0.010) and overall survival (HR 2.10, p 0.033, and HR 2.39, p 0.013). The blast percentage of the induction interim bone marrow may be a useful prognostic factor to predict outcome.

Taxodione induces apoptosis in BCR-ABL-positive cells through ROS generation.

Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are hematopoietic malignancies caused by the constitutive activation of BCR-ABL tyrosine kinase. Although direct BCR-ABL inhibitors, such as imatinib, were initially successful in the treatment of leukemia, many patients developed drug resistance over time due to the gatekeeper mutation of BCR-ABL T315I. In the present study, we found that taxodione, a quinone methide diterpene isolated from Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which were transformed by BCR-ABL. Taxodione reduced the activities of mitochondrial respiratory chain (MRC) complexes III and V, which appeared to induce the production of reactive oxygen species (ROS). N-acetylcysteine (NAC), an antioxidant agent, canceled taxodione-induced ROS production, reductions in MRC activities, particularly complex V, and apoptotic cell death. Furthermore, in K562 cells treated with taxodione, BCR-ABL and its major signaling molecules, such as STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation, suggesting that these actions seem to be a mechanism how taxodione functions as an anti-tumor drug. Strikingly, NAC canceled these taxodione-caused anti-cancer effects. Taxodione induced apoptosis in transformed BaF3 cells induced not only by BCR-ABL, but also T315I-mutated BCR-ABL through the generation of ROS. Collectively, the present results suggest that in the treatment of leukemia, taxodione has potential as a compound with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells.

A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 33 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stressUPR pathways, and treatment response were assessed. Fourteen patients were enrolled all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mgm The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mgm

Current status and future clinical directions in the prevention and treatment of relapse following hematopoietic transplantation for acute myeloid and lymphoblastic leukemia.

In recent years we have seen a dramatic evolution of therapeutic approaches in the management of acute leukemia with hematopoietic stem cell transplantation (HCT). For both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), alloHCT provides the best chance of long-term disease-free survival for significant subsets of patients. During this interval, we have witnessed an evolution of HCT from a therapy based on high-dose conditioning to our current understanding that its success depends both on cytoreduction and graft-versus-leukemia (GVL) effects mediated by adoptively transferred donor immune cells. Improvements in conditioning, infectious disease monitoring and management, histocompatibility testing and graft selection have successively improved outcomes, primarily due to a reduction in non-relapse mortality. Unfortunately, disease relapse remains a significant cause of treatment failure in both AML and ALL. Here, two distinguished experts, Prof. Charles Craddock and Prof. Dieter Hoelzer, reflect on the significant challenge of disease relapse following allogeneic HCT for AML and ALL, respectively. This is a review of the biology, current approaches, and future directions in the field and reflects concepts that were presented at the Third International Workshop on Biology, Prevention, and Treatment of Relapse after Stem Cell Transplantation held in Hamburg, Germany in November 2016 under the auspices of the EBMT and the ASBMT.

Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current chemotherapy is quite toxic in growing children and more directed therapeutics are being sought. The IL-7R pathway is a major driver of ALL and here we evaluate two drugs directed to that pathway using a model of T cell ALL. Mutant gain-of-function IL-7Rα was transduced into an IL-7-dependent murine thymocyte line conferring ligand-independent survival and growth. JAK1 is associated with IL-7Rα and mediates signaling from the mutant receptor.

In vivo RNAi screening identifies

Despite the addition of tyrosine kinase inhibitors (TKIs) to the treatment of patients with

SOHO State of the Art Update and Next Questions Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

The widespread adoption of Bcr-Abl-directed tyrosine kinase inhibitors (TKIs) into first-line regimens for patients with Philadelphia chromosome (Ph)-positive (Ph

The Use of Ommaya Reservoirs to Deliver Central Nervous System-Directed Chemotherapy in Childhood Acute Lymphoblastic Leukaemia.

Prophylactic eradication of central nervous system (CNS) leukaemia is the current standard of care in treating childhood acute lymphoblastic leukaemia (ALL). This is conventionally achieved through regular lumbar punctures with intrathecal injections of methotrexate into the cerebrospinal fluid (CSF). Ommaya reservoirs are subcutaneous implantable devices that provide a secure route of drug delivery into the CSF via an intraventricular catheter. They are an important alternative in cases where intrathecal injection via lumbar puncture is difficult. Among UK Paediatric Principal Treatment Centres for ALL we found considerable variation in methotrexate dosing when using an Ommaya reservoir. We review the current safety and theoretical considerations when using Ommaya reservoirs and evidence for methotrexate dose adjustments via this route. We conclude by summarising the pragmatic consensus decision to use 50% of the conventional intrathecal dose of methotrexate when it is administered via Ommaya reservoir in front-line ALL therapy.

Empirical treatment with parenteral acyclovir in a child with herpes simplex virus hepatitis and acute lymphoblastic leukemia.

Hepatitis secondary to Herpes Simplex Virus (HSV) infection is a complication that often leads to fatal hepatic failure. Early treatment with the anti-viral drug, acyclovir, is life-saving. In view of the non-specific nature of the signs and symptoms associated with HSV hepatitis, diagnosis is often made late during the course of the disease a factor that largely contributes to the high mortality rate of this treatable disease complication. There is thus a growing consensus in the field to initiate empirical treatment with acyclovir once suspicion of HSV hepatitis is raised even before reaching a conclusive diagnosis. We present clinical evidence on the benefit of starting empirical acyclovir treatment on the outcome of patients suffering from HSV hepatitis. We report two cases of HSV hepatitis in children with cancer. One case presented with fulminant hepatitis which was fatal and the diagnosis was only reached post mortem. In the second case, there was enough suspicion of HSV hepatitis to start early empirical acyclovir therapy. The diagnosis was confirmed 48 hours following the initiation of treatment and the early intervention with anti-virals proved to be life-saving. In both cases above, the following symptoms were shared fever, elevated transaminase levels and mucositis without clear cutaneous lesions. HSV hepatitis should thus be considered in the differential diagnosis of immuonocomprimised patients exhibiting the above symptoms. Due to the frequent delay in HSV diagnosis and the safety of acyclovir, we recommend empirically administering acyclovir in patients suspected of HSV hepatitis.

Effects of Hypoxia on Biology of Human Leukemia T-cell Line (MOLT-4 cells) Co-cultured with Bone Marrow Mesenchymal Stem Cells.

One of the most significant problems in the treatment of leukemia is the expansion of resistance to chemotherapeutic agents. Therefore, assessing the drug resistance and especially the drug resistance genes of leukemic cells is important in any treatment. The impact of Mesenchymal Stem Cells (MSCs) and hypoxic condition have been observed in the biological performance of majority of leukemic cells. MOLT-4 cells were co-cultured with MSCs in the hypoxic condition induced by Cobalt Chloride (CoCl The hypoxic condition for MOLT-4 cells co-cultured with MSCs could significantly increase the expression of MDR1 and BCRP genes (p<0.05) which are involved in drug resistance. Also, the results indicated that this condition significantly increases the expression of BCL2 (p<0.05) and reduces the apoptosis in MOLT-4 cells co-cultured with MSCs in the hypoxic condition. These effects can demonstrate the important role of hypoxia and MSCs on the biological behavior of Acute Lymphoblastic Leukemia (ALL) cells that may lead to particular treatment outcomes.

Maintenance and pharmacologic targeting of ROR1 protein levels via UHRF1 in t(119) pre-B-ALL.

Expression of the transmembrane pseudokinase ROR1 is required for survival of t(119)-pre-B-cell acute lymphoblastic leukemia (t(119) pre-B-ALL), chronic lymphocytic leukemia, and many solid tumors. However, targeting ROR1 with small-molecules has been challenging due to the absence of ROR1 kinase activity. To identify genes that regulate ROR1 expression and may, therefore, serve as surrogate drug targets, we employed an siRNA screening approach and determined that the epigenetic regulator and E3 ubiquitin ligase, UHRF1, is required for t(119) pre-B-ALL cell viability in a ROR1-dependent manner. Upon UHRF1 silencing, ROR1 protein is reduced without altering ROR1 mRNA, and ectopically expressed UHRF1 is sufficient to increase ROR1 levels. Additionally, proteasome inhibition rescues loss of ROR1 protein after UHRF1 silencing, suggesting a role for the proteasome in the UHRF1-ROR1 axis. Finally, we show that ROR1-positive cells are twice as sensitive to the UHRF1-targeting drug, naphthazarin, and undergo increased apoptosis compared to ROR1-negative cells. Naphthazarin elicits reduced expression of UHRF1 and ROR1, and combination of naphthazarin with inhibitors of pre-B cell receptor signaling results in further reduction of cell survival compared with either inhibitor alone. Therefore, our work reveals a mechanism by which UHRF1 stabilizes ROR1, suggesting a potential targeting strategy to inhibit ROR1 in t(119) pre-B-ALL and other malignancies.

Author Correction A causal mechanism for childhood acute lymphoblastic leukaemia.

The article as originally published cited the incorrect paper as reference 123. The correct reference is Kroll, M. E., Draper, G. J., Stiller, C. A. Murphy, M. F. G. Childhood leukemia incidence in Britain, 1974-2000 time trends and possible relation to influenza epidemics. J. Natl Cancer Inst. 98, 417-420 (2006). This has been corrected in the online and print versions of the article.

Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design.

Recent clinical advances with chimeric antigen receptor (CAR) T cells have led to the accelerated clinical approval of CD19-CARs to treat acute lymphoblastic leukemia. The CAR T cell therapy is nevertheless associated with toxicities, especially if the CARs are not entirely tumor-specific. Therefore, strategies for controlling the CAR T cell activity are required to improve their safety profile. Here, by using the multiple myeloma (MM)-associated CD38 molecule as target molecule, we tested the feasibility and utility of a doxycycline (DOX) inducible Tet-on CD38-CAR design to control the off-target toxicities of CAR T cells. Using CARs with high affinity to CD38, we demonstrate that this strategy allows the proper induction of CD38-CARs and CAR-mediated T cell cytotoxicity in a DOX-dose dependent manner. Especially when the DOX dose was limited to 10ngml, its removal resulted in a relatively rapid decay of CAR- related off-tumor effects within 24 hours, indicating the active controllability of undesired CAR activity. This Tet-on CAR design also allowed us to induce the maximal anti-MM cytotoxic activity of affinity-optimized CD38-CAR T cells, which already display a low toxicity profile, hereby adding a second level of safety to these cells. Collectively, these results indicate the possibility to utilize this DOX inducible CAR-design to actively regulate the CAR-mediated activities of therapeutic T cells. We therefore conclude that the Tet-on system may be more advantageous above suicide-genes to control the potential toxicities of CAR T cells without the need to destroy them permanently.

Label-Free, Flow-Imaging Methods for Determination of Cell Concentration and Viability.

To investigate the potential of two flow imaging microscopy (FIM) techniques (Micro-Flow Imaging (MFI) and FlowCAM) to determine total cell concentration and cell viability. B-lineage acute lymphoblastic leukemia (B-ALL) cells of 2 different donors were exposed to ambient conditions. Samples were taken at different days and measured with MFI, FlowCAM, hemocytometry and automated cell counting. Dead and live cells from a fresh B-ALL cell suspension were fractionated by flow cytometry in order to derive software filters based on morphological parameters of separate cell populations with MFI and FlowCAM. The filter sets were used to assess cell viability in the measured samples. All techniques gave fairly similar cell concentration values over the whole incubation period. MFI showed to be superior with respect to precision, whereas FlowCAM provided particle images with a higher resolution. Moreover, both FIM methods were able to provide similar results for cell viability as the conventional methods (hemocytometry and automated cell counting). FIM-based methods may be advantageous over conventional cell methods for determining total cell concentration and cell viability, as FIM measures much larger sample volumes, does not require labeling, is less laborious and provides images of individual cells.

Cost-utility of Protocols of BFM-ALL and UK-ALL for Treatment of Children with Acute Lymphoblastic Leukemia in Iran.

There is a requirement to assess the effectiveness and resources used in two protocols United Kingdom (UK-ALL) and Berlin-Frankfurt-Munster (BFM-ALL) that are most commonly used to treatment of ALL patients by oncologists in Iran. Accordingly, we analyzed the cost of treatment and utility of children treated with two protocols in Iran. The entire medical direct costs of patients in BFM ALL protocol and UK ALL protocol in multi-centers calculated from Apr 2010 to Jun 2015. For calculating utility and Quality Adjusted Life Year (QALY) of the patients, we used standard questionnaire Health Utilities Index 3 (HUI3). The patients and their parents were interviewed. Data were analyzed using software SPSS18 and EXCEL. The average direct medical cost for each patient for BFM-ALL was 15026 USD and UK-ALL was 8282 USD which showed a significant difference in the total cost of the treatment in the two protocols ( UK-ALL is dominant and BFM protocol is dominated by both sides total costs and utility and QALY. Mainly, more hospital stay in BFM ALL protocol is the cause of raised costs in this protocol. Consequently, by considering different QALYs in the methods and low costs in UK ALL protocol, UK ALL protocol is more preferred.

Peripheral Neuropathy, Sensory Processing, and Balance in Survivors of Acute Lymphoblastic Leukemia.

Purpose To compare peripheral nervous system function and balance between adult survivors of childhood acute lymphoblastic leukemia (ALL) and matched controls and to determine associations between peripheral neuropathy (PN) and limitations in static balance, mobility, walking endurance, and quality of life (QoL) among survivors. Patients and Methods Three hundred sixty-five adult survivors of childhood ALL and 365 controls with no cancer history completed assessments of PN (modified Total Neuropathy Score mTNS), static balance (Sensory Organization Test SOT), mobility (Timed Up and Go), walking endurance (6-minute walk test), QoL (Medical Outcomes Study 36-Item Short Form Survey), and visual-motor processing speed (Wechsler Adult Intelligence Scale). Results PN, but not impairments, in performance on SOT was more common in survivors than controls (41.4% v 9.5%, respectively P < .001). In multivariable models, higher mTNS scores were associated with longer time to complete the Timed Up and Go (β 0.15 95% CI, 0.06 to 0.23 P < .001), shorter distance walked in 6 minutes (β -4.39 95% CI, -8.63 to -0.14 P .04), and reduced QoL (β -1.33 95% CI, -1.79 to -0.87 P < .001 for physical functioning β -1.16 95% CI, -1.64 to -0.67 P < .001 for role physical and β -0.88 95% CI, -1.34 to -0.42 P < .001 for general health). Processing speed (β 1.69 95% CI, 0.98 to 2.40 P < .001), but not mTNS score, was associated with anterior-posterior sway on the SOT. Conclusion PN in long-term ALL survivors is associated with movement, including mobility and walking endurance, but not with static standing balance. The association between processing speed and sway suggests that static balance impairment in ALL survivors may be influenced by problems with CNS function, including the processing of sensory information.

Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Results of Childrens Oncology Group Trial AALL0622.

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Childrens Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations SD) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n 48 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n 9 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib 5-year OS of 81% ± 6% versus 86% ± 5% ( P .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

Down-regulation of CD19 expression inhibits proliferation, adhesion, migration and invasion and promotes apoptosis and the efficacy of chemotherapeutic agents and imatinib in SUP-B15 cells.

The survival rate of childhood acute lymphoblastic leukemia (ALL) has increased while that of Philadelphia-positive (Ph) ALL remains low. CD19 is a B-cell specific molecule related to the survival and proliferation of normal B cells. However, there is little information available on the effects of CD19 on the biological behavior of Ph ALL cells. In this study, we explored a lentiviral vector-mediated short hairpin RNA (shRNA) expression vector to stably reduce CD19 expression in Ph ALL cell line SUP-B15 cells and investigated the effects of CD19 downregulation on cell proliferation, apoptosis, drug sensitivity, cell adhesion, cell migration and cell invasion in vitro. CD19 mRNA and protein expression levels were inhibited significantly by CD19 shRNA. Down-regulation of CD19 could inhibit cell proliferation, adhesion, migration and invasion, and increase cell apoptosis and the efficacy of chemotherapeutic agents and imatinib in SUP-B15 cells. Moreover, we found that down-regulation of CD19 expression inhibits cell proliferation and induces apoptosis in SUP-B15 cells in a p53-dependent manner. Taken together, our results suggest that lentiviral vector-mediated RNA interference of CD19 gene may be a promising strategy in the treatment of Ph ALL.

Effective Response Metric a novel tool to predict relapse in childhood acute lymphoblastic leukaemia using time-series gene expression profiling.

Accurate risk assignment in childhood acute lymphoblastic leukaemia is essential to avoid under- or over-treatment. We hypothesized that time-series gene expression profiles (GEPs) of bone marrow samples during remission-induction therapy can measure the response and be used for relapse prediction. We computed the time-series changes from diagnosis to Day 8 of remission-induction, termed Effective Response Metric (ERM-D8) and tested its ability to predict relapse against contemporary risk assignment methods, including National Cancer Institutes (NCI) criteria, genetics and minimal residual disease (MRD). ERM-D8 was trained on a set of 131 patients and validated on an independent set of 79 patients. In the independent blinded test set, unfavourable ERM-D8 patients had >3-fold increased risk of relapse compared to favourable ERM-D8 (5-year cumulative incidence of relapse 38·1% vs. 10·6% P 2·5 × 10

Long-term survival after childhood acute lymphoblastic leukaemia population-based trends in cure and relapse by clinical characteristics.

Cure models offer additional information to traditional epidemiological approaches to assess survival for cancer patients by simultaneously estimating the proportion cured and the survival of those uncured. The proportion cured is a summary of long-term survival while the median survival time of the uncured provides important information on those who are not long-term survivors. Population-based trends in the cure proportion and survival of the uncured for childhood acute lymphoblastic leukaemia (ALL) by clinical prognostic risk factors were estimated using flexible parametric cure models, based on overall survival and event-free survival. Children aged 1-17 years diagnosed between 1990 and 2011 in Yorkshire, UK, were included (n 492). The percentage cured increased from 77% (95% confidence interval 70-84%) in 1990-1997 to 89% (84-93%) in 2003-2011, while the median survival time of the uncured decreased from 3·2 years (2·2-4·1 years) to 0·7 years (0-1·5 years). Models based on event-free survival showed a similar trend. The 5-year cumulative incidence of relapse substantially decreased from 35% in 1990-97 to 9% in 2003-2011. These results show selective improvement in survival between 1990 and 2011 with a significant reduction in the risk of relapse alongside a reduced absolute duration of survival for those destined to be uncured.

CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.

Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL)

Voriconazole associated mucormycosis in a patient with relapsed acute lymphoblastic leukemia and hematopoietic stem cell transplant failure A case report.

The patients with hematologic malignancies and hematopoietic stem cell transplantation (HSCT) recipients are at high risk for invasive fungal diseases (IFDs) mainly due to the severe and prolonged neutropenia related to high-dose chemotherapy. Voriconazole prophylaxis is recommended for possible IFDs. Mucormycosis is a fulminant infection, which may occur after voriconazole prophylaxis for invasive aspergillosis in immunocompromised hosts. Here, we report mucormycosis after 4 months of voriconazole prophylaxis in a young patient with relapsed acute lymphoblastic leukemia and hematopoietic stem cell transplant failure and discuss the clinical manifestation, imaging, laboratory findings and therapeutic regimens. Clinicians awareness of this entity and timely diagnosis using conventional and molecular methods are the promising approach for the management of this devastating infection.

Neonatal leukaemia.

Neonatal leukaemia is defined as occurring within the first 28 days of life and most, if not all, cases are congenital. With the exception of Down syndrome-associated transient abnormal myelopoiesis, which is not considered here, neonatal leukaemias are rare. In two-thirds of patients the disease manifests as an acute myeloid leukaemia, frequently with monocyticmonoblastic characteristics. Most other cases are acute lymphoblastic leukaemia, particularly B lineage, but some are mixed phenotype or blastic plasmacytoid dendritic cell neoplasms. The most frequently observed cytogeneticmolecular abnormality is t(411)(q21.3q23.3)KMT2A-AFF1 followed by t(122)(p13.3q13.1)RBM15-MKL1 and t(816)(p11.2p13.3)KAT6A-CREBBP. Common clinical features include prominent hepatosplenomegaly and a high incidence of skin involvement, sometimes in the absence of bone marrow disease. A distinctive feature is the occurrence of spontaneous remission in some cases, particularly in association with t(816). In this review, we summarise current knowledge of the clinical, cytogenetic and molecular features of neonatal leukaemia and discuss clinical management of these cases.

To report on the first recorded case of necrotizing soft tissue infection (NSTI) in an immunocompromised individual caused by We report a case of NSTI caused by Providers should consider atypical organisms as causative in NSTI in immunocompromised patients and recognize that these patients may present without classic clinical and laboratory findings.

Acute pro-B-Cell lymphoblastic leukemia transformed from myelodysplastic syndrome with an ASXL1 missense mutation A case report with literature review.

The development of acute lymphoblastic leukemia (ALL) from myelodysplastic syndrome (MDS) is a very rare event. The current report presents a rare case of a 33-year-old man who was diagnosed with MDS with multiple-lineage dysplasia (MDS-MLD) that transformed into pro-B-ALL. A missense mutation (S1231F) of the additional sex combs like 1, transcriptional regulator gene was identified, which may have a substantial role in the progression, however does not act as an unfavorable prognostic marker. The patient died during induction chemotherapy. The present study further conducted an analysis on 30 patients to determine progression to ALL. Patients were predominantly male (76.7%, 2330) with a median age of 56 years (3-90 years). The median time to transformation was 5.5 months (2-50 months). The most common type of MDS with ALL transformation comprised of MDS-excess blasts (MDS-EB 40%, 1230), MDS with single-lineage dysplasia (MDS-SLD 30%, 930) and MDS with ring sideroblasts (MDS-RS 16.7%, 530). The majority of the patients transformed to B-cell (66.7%, 1624) followed by T-cell (33.3%, 824) ALL. From the 25 cases where data was available, the complete remission rate was 75% (1520) with ALL-directed chemotherapy and the median remission duration was 15 months (range 4.5 to 51 months). However, the results indicated that ALL following MDS is characterized by a high rate of early death (20%, 525).

Acute lymphoblastic leukemia following temozolomide treatment in a patient with glioblastoma A case report and review of the literature.

Temozolomide (TMZ) is a second-generation oral alkylating agent that functions against a number of central nervous system neoplasms, and is generally used to treat high-grade gliomas, including anaplastic astrocytoma and glioblastoma multiforme. Therapy-related secondary myelodysplastic syndrome and acute myeloid leukemia have been reported in patients following prolonged exposure to TMZ. However, TMZ-related acute lymphoblastic leukemia (ALL) is extremely rare. The present study describes the case of an 11-year-old boy with a 3-day history of generalized tonic-clonic seizures and a contrast-enhanced lesion in the left temporooccipital region with focal cystic degeneration, as detected by magnetic resonance imaging. The patient underwent craniotomy and gross-total resection andpathological analysis confirmed the diagnosis of giant cell glioblastoma. Postoperatively, the patient received TMZ-based concurrent chemoradiation during radiotherapy, and developed B-cell ALL 6 months following TMZ treatment. A thorough literature search identified only six published cases of TMZ-related ALL. The chemotherapeutic efficacy of TMZ has been identified, however, its leukemogenic potential should be emphasized among practitioners and patients. Further studies are required to determine the specific pathogenic mechanism of TMZ-related ALL. Close hematological monitoring of patients following TMZ treatment is vital and a high index of suspicion is necessary.

Overexpression of dihydrofolate reductase is a factor of poor survival in acute lymphoblastic leukemia.

Dihydrofolate reductase (DHFR) has an important function in DNA synthesis and is a target of methotrexate, which is a crucial treatment option for acute lymphoblastic leukemia (ALL). However, the number of studies conducted to date on DHFR expression in childhood ALL is limited. The aim of the present study was to determine whether the expression of DHFR is associated with survival in childhood ALL. The expression of DHFR in 96 children with ALL and 100 control individuals was determined using reverse transcription-quantitative polymerase chain reaction. The results of the present study demonstrated that the expression of DHFR mRNA in children with ALL was significantly increased (P<0.001), compared with that in the control group. In addition, increased levels of DHFR mRNA were observed in patients with B-cell lineage, compared with patients with T-cell lineage ALL (P<0.05). The Kaplan-Meier estimator analysis revealed that children with ALL who exhibited increased levels of DHFR mRNA had a decreased overall survival time (P<0.05). It was observed that certain patient prognostic features (including age, sex, white blood cell count and high DHFR expression), are associated with poor survival (log-rank test, P<0.05). Therefore, the results of the present study indicated that DHFR upregulation is a factor for poor survival in ALL.

Expression of aberrant antigens in hematological malignancies A single center experience.

Aberrant phenotype is a phenomenon of abnormal expression or loss of expression of cell specific lineage marker not associated with specific cell type. Aberrant phenotype expression due to genetic defects may be associated with unfavorable outcome. It can be used to determine minimal residual disease status. The purpose of the study was to find out the occurrence of aberrant phenotypes in leukemialymphoma patients. One milliliter peripheral blood or bone marrow samples were analyzed on FACS Calibur flowcytometer. The cells were lysed and stained following standard protocol. Data was acquired and analyzed by CellQuest-Pro software. The Antigenic expression was rated as positive when the percentage of positive blast cells was ≥ 20%. In that manner, aberrant phenotype was considered positive when 20% of blast cells show expression of markers. Of a total 145 cases analyzed, 26 were acute myeloid leukemia, 71 of acute lymphoblastic leukaemia, 48 were of Chronic Lymphoid leukemia on the basis of morphological features and confirmed by flow cytometry. Overall, 19% (28) cases showed aberrant expression of antigens. In 32% (928) AML patients, CD5, CD7, CD64dim, CD10, CD117, CD25 and TdT were expressed while in 25% (728) ALL patients CD33, CD13, HLA-DR and CD3 were detected. Among chronic leukemia, all aberrant expressions were seen in cases of B-CLL (1028) only with CD11c, CD3 and CD10 as the aberrantly expressed markers. Variability in aberrant phenotype expression was observed in different types of acute and chronic leukemia patients with no prognostic implications on treatment response.

The second generation tyrosine kinase inhibitor dasatinib induced eryptosis in human erythrocytes-An in vitro study.

Dasatinib, a new tyrosine kinase inhibitor, is used clinically to kill chronic myelogenous leukemia and acute lymphoblastic leukemia through apoptosis. Obviously, anemia is developed in many patients receiving dasatinib for treatment. Until now, the mechanism for the cytotoxic effects of dasatinib in human erythrocytes is not fully understood. As many tyrosine kinases are found in human erythrocytes, it is therefore logical to hypothesize that dasatinib is able to induce apoptosis (or eryptosis) in human erythrocytes. True to our expectation, dasatinib inhibited tyrosine kinase and induced eryptosis in human erythrocytes with early denature of esterase, cell shrinkage, loss of membrane integrity with inside-out phosphatidylserine, increase in the cytosolic Ca

Association Between NR3C1 Gene Polymorphisms and Toxicity Induced by Glucocorticoids Therapy in Saudi Children with Acute Lymphoblastic Leukemia.

Background Glucocorticoids (GCs) are key hormones used for the treatment of acute lymphoblastic leukemia (ALL) in children, but their cytotoxic effects are not well defined. The aim of this study was to evaluate the association between polymorphisms in NR3C1 encoding for protein involved in the GCs metabolism and its role in the development of ALL and the toxicity outcome, in terms of liver toxicity, glucose abnormality and infections, in ALL Saudi children. Methods The following polymorphisms BCII rs41423247, ER2223 EK rs6189 and rs6190 and N363S rs6195 in NR3C1 were analyzed in 70 children with ALL treated according to the ALL 2000 study protocol in comparison to 60 control subjects. Treatment toxicities and their association with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC). Results This study demonstrated that the NR3C1 did not contribute to the development of childhood ALL. Homozygous ER2223EK polymorphism was not found in both ALL patients and in control group whereas the heterozygous polymorphism was only observed in the control group (6.66%). The toxicology data in this study showed a significant difference between ALL patients carrying N363S polymorphism and wild type (40% and 6.51% respectively, P 0.009) and a high-risk factor in the toxicity of glucose abnormality (OR10.167 1.302-79.339). BCII shows increased risk factors towards the liver toxicity (OR2.667 0.526-7.330) as well as the glucose abnormality (OR7.5 1.039-54.116). Conclusion This study suggested that the polymorphisms in NR3C1 were not associated with the development of ALL in children. N363S polymorphism was sensitive to glucocorticoids and it may contribute to the glucose abnormality for these patients.

Identification of early B cell precursors (stage 1 and 2 hematogones) in the peripheral blood.

Differentiating malignant B-lymphoblasts from early benign B cell precursors (hematogones) is a vital component of the diagnosis of B-lymphoblastic leukaemia. It has been previously reported that only late-stage B cell precursors circulate in the peripheral blood. Consequently, flow cytometric detection of cells with immunophenotypic findings similar to earlier stage precursors in the peripheral blood justifiably raises concern for involvement by B-lymphoblastic leukaemia. We report here, however, that benign early B cell precursors can indeed be detected in the peripheral blood, thus complicating the interpretation of flow cytometric findings derived from these sample types. A retrospective search of our collective databases identified 13 cases containing circulating early stage B cell precursors. The patients ranged in age from 15 days to 85 years old. All positive cases demonstrated that the earlier B cell precursors were associated with later stage precursors, a finding that could help differentiate these cells from B-lymphoblastic leukaemia.

Implementation of Medication Safety Practice in Childhood Acute Lymphoblastic Leukemia Treatment.

Objective Medical Safety Practice (MSP) is a safe procedure in medication process. It is important to investigate the use of MSP among childhood cancer patients because pediatric oncology is a high-risk area for potentially harmful adverse events. The purpose of this study is to determine the effects of the implementation of MSP in chemotherapy on the incidence of medication errors in childhood ALL patient at Dr. Sardjito Hospital, including in 1) transcribing, 2) administering, 3) monitoring, 4) the incidence of adverse drugs events. (ADEs). Methods The study design is a quasi-experimental study with pre- and post-intervention without control. The sample consists of ALL patients who are taken care of at an academic hospital in Indonesia from 2012 to 2013. The sample was consecutively collected during the period of study. The data were collected through medical records, research form, observation, and discussion with the nurse. The intervention given is training and implementation of medical safety practice in chemotherapy. Result Based on the analysis of the effect of the implementation of MSP (75 and 106 medical records of pre- and post-intervention), it is obtained 1) the adherence of chemotherapy transcribing post-intervention increases significantly compared to pre-intervention (p<0.05), 2) the adherence of chemotherapy administering increases significantly in almost every aspect (p<0.05), except in preparing drugs by two different health worker, patient’s confirmation of ADEs management, and verification of drug’s expired date, 3) The adherence of chemotherapy monitoring improved significantly post-intervention (p<0.05), 4) Adverse Drug Events (ADE) decreased significantly post-intervention (p<0.05), from 52.1% to 30.5%. Conclusion The implementation of MSP decreased the incidence of medication errors in ALL patients at Dr. Sardjito Hospital in ordering, dispensing, transcribing, administering, and monitoring chemotherapy. It also reduced the incidence of ADEs related to chemotherapy. Specific training for nurses are needed in order to improve the knowledge and skills, especially for medication error and skill in patients’ care.

Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in 65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner.

The horizon of medical attention in pediatrics what to do in the case of children who are in abandonment, conflict, harm or danger situations in combination with a severe disease.

Laws refer that minors do not have the capability to give informed consent for their own medical attention. However, there are special conditions in which they are allowed to decide about their health. The greater the judgement and experience limitations in minors, the less weight is given to the values and objectives they express. Also, the more adverse consequences might be, the higher the level of authority that is demanded to decide on behalf of the minor, thus granting the State the capability to guarantee the well-being of the minor. 12-year-old female patient with a diagnosis of acute lymphoblastic leukemia, with precarious social and family background evolution of the disease obstructed by the disregard of the treatment due to her unsanitary and extreme poverty conditions. Both of her parents died soon after the start of the treatment and she was kept under the care of her half-sister of legal age. The work and the ethical dilemma of the pediatrician and the staff of Hospital Infantil de México Federico Gómez are exposed within the building of support -networks with the objective of prioritizing the minors well-being, without allowing family break-up or disintegration, thus succeeding in her recovery. The case was submitted to the Hospital Bioethics Committee. Inter-institutional support networks were built in order to improve dynamics of the family, thus solving the needs of the minor. Despite the misfortune of the situation, the disease was successfully overcome. Las leyes refieren que los menores no tienen la capacidad para dar su consentimiento informado para su propia atención médica sin embargo, hay condiciones especiales en las que se les permite determinar lo referente a su salud. Cuanto mayores sean las limitaciones de juicio y experiencia en los menores, menos peso se otorga a los valores y objetivos que expresan cuanto más adversas sean las consecuencias, se deberá exigir un nivel más alto de autoridad para decidir en nombre del menor, dejando al Estado la capacidad de garantizar el bienestar del menor. Niña de 12 años con diagnóstico de leucemia linfoblástica aguda LI, con antecedentes familiares y sociales precarios evolución entorpecida por el desapego al tratamiento y sus condiciones insalubres y pobreza extrema. Ambos padres fallecieron al poco tiempo de iniciar su tratamiento, quedando ella al cuidado de su medio hermana mayor de edad. Se exponen la labor y el dilema ético del oncólogo tratante y del personal del Hospital Infantil de México Federico Gómez en la creación de redes de apoyo con el objetivo de priorizar el bienestar de la menor, sin dar lugar al quebrantamiento y la desintegración familiar, consiguiendo exitosamente su recuperación. El caso fue sometido al Comité de Bioética Hospitalaria. Se formaron redes de apoyo interinstitucionales para intervenir en la dinámica familiar, resolviendo los requerimientos de la menor, y se consiguió con éxito superar la enfermedad.

Author Correction Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10q21.2.

This corrects the article DOI 10.1038ncomms14616.

Severe hematuria in a hematopoietic cell transplant recipient caused by Ureaplasma urealyticum not by BK virus or adenovirus infection.

A 17-year-old male with acute lymphoblastic leukemia developed severe hematuria and scrotal swelling after haploidentical hematopoietic cell transplantation (HCT). Urine culture was negative. BK virus and adenovirus were negative. However, Ureaplasma urealyticum was detected. He showed dramatic improvement after doxycycline treatment. This is the first report in the literature of hemorrhagic cystitis caused by U. urealyticum in a HCT recipient. In HCT recipients with hemorrhagic cystitis, U. urealyticum should be considered as a potential cause.

Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia.

A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias. Lineage switch following CAR-T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.

Late mortality and morbidity among long-term leukemia survivors with Down syndrome A nationwide population-based cohort study.

Late health consequences of treatment for childhood leukemia are well documented. Although individuals with Down syndrome (DS) have a substantially increased risk of leukemia, information on late effects in this group is almost nonexistent. The aim of this study was to evaluate the mortality and morbidity among 5-year leukemia survivors with DS. We compared 5-year leukemia survivors with leukemia-free individuals with DS. All individuals born with DS in Denmark between 1960 and 2007 and in Sweden between 1973 and 2009 were included. Long-term morbidity was estimated by comparing hospitalization rates between survivors and leukemia-free individuals. In total, we found 6,705 individuals with DS, 84 of whom were 5-year survivors of leukemia. Survivors had a higher risk of death (hazard ratio HR 5.9 95% confidence interval CI 2.7-13) compared with leukemia-free individuals. All deaths (n 7) among 5-year leukemia survivors were due to relapse. Survivors had a higher hospitalization rate (HR 4.4 95% CI 3.1-6.2). However, most of these hospitalizations were due to relapse. Censoring individuals who either had a relapse or were being treated for a relapse more than 5 years from the initial diagnosis (n 9) attenuated the association (HR 1.4 95% CI 1.0-2.1). In this study, we found that relapse was the main reason for death and hospitalization among leukemia survivors with DS, and not late effects. These results are reassuring for individuals treated for DS associated with leukemia and their parents.

Sudden spinal hemorrhage in a pediatric case with total body irradiation-induced cavernous hemangioma.

Compared to cerebral radiation-induced cavernous hemangiomas (RICHs), little is known about intraspinal RICHs. A 13-year-old male suddenly developed symptomatic spinal hemorrhage eight years after hematopoietic stem cell transplantation using a total body irradiation (TBI) based myeloablative regimen. A solitary small hemangioma was detected on follow-up T2 star weighted magnetic resonance imaging of the spine. His neurological symptoms gradually improved with supportive treatment and rehabilitation, although he experienced rebleeding 2 years later. Intraspinal RICH is very rare but should be recognized as a possible late adverse effect in pediatric patients who received TBI.

DIVERGT screening procedure predicts general cognitive functioning in adult long-term survivors of pediatric acute lymphoblastic leukemia A PETALE study.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Because of major improvements in treatment protocols, the survival rate now exceeds 80%. However, ALL treatments can cause long-term neurocognitive sequelae, which negatively impact academic achievement and quality of life. Therefore, cognitive sequelae need to be carefully evaluated. The DIVERGT is a battery of tests proposed as a screening tool, sensitive to executive function impairments in children and adolescent cancer survivors. Our study aimed at verifying the predictive value of the DIVERGT on general cognitive functioning in adult long-term survivors of ALL. ALL survivors completed the DIVERGT 13.4 years, on average, after remission (N 247). In addition, 49 of these survivors (equally selected amongst those with low, average, and high DIVERGT scores) as well as 29 controls completed a more comprehensive neuropsychological evaluation within a 3-year period from DIVERGT administration. Multivariate regression analysis was used to assess the predictive value of the DIVERGT on general intelligence, mathematics, verbal memory, and working memory. As a follow-up analysis, three performance groups were created based on the DIVERGT results. Multivariate analysis of variance (MANOVA) assessed neuropsychological differences between groups. The DIVERGT accurately predicted General Ability Index (GAI) (P < 0.0001), mathematics (P < 0.0001) and verbal memory (P 0.045). Moreover, the low-performance group consistently had poorer performance than the high-performance and control groups on the neuropsychological tests. The DIVERGT is a useful, time-effective screening battery for broader neurocognitive impairments identification in long-term adult ALL survivors. It could be implemented as routine examination in cancer follow-up clinics.

Involvement of SNPs in miR-3117 and miR-3689d2 in childhood acute lymphoblastic leukemia risk.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Numerous studies have shown that microRNAs (miRNAs) could play a role in this disease. Nowadays, more than 2500 miRNAs have been described, that regulate more than 50% of genes, including those involved in B-cell maturation, differentiation and proliferation. Genetic variants in miRNAs can alter their own levels or function, affecting their target gene expression, and then, may affect ALL risk. Therefore, the aim of this study was to determine the role of miRNA genetic variants in B-ALL susceptibility. We analyzed all variants in pre-miRNAs (MAF > 1%) in two independent cohorts from Spain and Slovenia and inferred their functional effect by

SRCABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia.

Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the

Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukemia.

Graft-versus-host disease (GVHD) occasionally leads to morbidity and mortality but is thought to reduce the risk of relapses in patients with a hematological malignancy. However, information on the effect of GVHD in pediatric leukemia is limited. Using a nationwide registry, we retrospectively analyzed 1526 children who underwent allogeneic stem cell transplantation for leukemia. Grades 0-I acute GVHD were associated with a higher relapse rate at three years after transplantation, at 25.4 and 24.3%, respectively, than grades II, III, or IV acute GVHD at 18.9%, 21.2%, and 2.6%, respectively. In contrast, the overall survival curve of the grades 0 and I GVHD groups (79.0% and 79.5%, respectively) approximated that of the grade II GVHD group (76.3%), and the probability of survival was worst in the severe GVHD groups (66.9% for grade III and 42.5% for grade IV). Chronic GVHD also reduced the relapse risk but conferred no survival advantage. Acute lymphoblastic leukemia was more sensitive to acute GVHD than acute myeloid leukemia (AML) while AML was more sensitive to chronic GVHD. Our study reproduced the preventive effects of GVHD against pediatric leukemia relapses but failed to demonstrate a significant survival advantage.

Simultaneous involvement of 11q23 translocation resulting in chimeric MLL-AFF1 and a second translocation t (921) (p13 p11.2) in an infant acute lymphoblastic leukemia patient at relapse A case report.

Three-way translocations occasionally occur in MLL-AFF1 fusion and other fusion gene. However, the complex chromosomal rearrangements in the study were the first report. We present novel cryptic and complex chromosomal rearrangements der (21) t (9 21) (p13 p11.2) in an infant patient with relapsed acute lymphoblastic leukemia (ALL). The diagnosis was based on morphologic, cytochemical, and immunophenotypic criteria proposed by the French-American-British Committee, and karyotype, fluorescence in situ hybridization, array comparative genomic hybridization. The patient was given chemotherapy with standard protocol for ALL. The patient had unfavorable prognostic outcome based on the cytogenetic and molecular cytogenetic markers. After short remission, the patient relapsed. MLL-AFF1, resulting from t(411)(q21q23), is regarded as the hallmark of infant t(411) pre-Bmixed B-ALL. It is associated with a dismal prognosis and the multiple-way translocation involving chromosomes 4, 11 and 11 may function as an enhancer.

Related donor transplants has posttransplantation cyclophosphamide nullified the detrimental effect of HLA mismatch

We sought to identify whether posttransplantation cyclophosphamide (PT-Cy) reduces or eliminates the detrimental impact of HLA mismatching on outcomes of HLA-haploidentical related donor transplantation for acute leukemia. Data from 2143 donor-recipient pairs (n 218 haploidentical sibling n 218 offspring n 1707 HLA-matched sibling) with acute myeloid or lymphoblastic leukemia were studied. All received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis while high-dose PT-Cy was also given to recipients of haploidentical transplant. Patient age correlated with donor-recipient relationship haploidentical siblings donated to patients aged 18 to 54 years whereas offspring donated to patients aged 55 to 76 years. Therefore, transplant outcomes were examined separately in the 2 patient age groups. In patients aged 18 to 54 years, there were no significant differences in outcomes except chronic GVHD, which was lower after haploidentical sibling compared to HLA-matched sibling transplant (hazard ratio HR, 0.63

Aberrant DNA methylation of key genes and Acute Lymphoblastic Leukemia.

DNA methylation is a dynamic process influencing gene expression by altering either coding or non-coding loci. Despite advances in treatment of Acute Lymphoblastic Leukemia (ALL) relapse occurs in approximately 20% of patients. Nowadays, epigenetic factors are considered as one of the most effective mechanisms in pathogenesis of malignancies. These factors are reversible elements which can be potentially regarded as therapy targets and disease prognosis. DNA methylation, which primarily serves as transcriptional suppressor, mostly occurs in CpG islands of the gene promoter regions. This was shown as a key epigenetic factor in inactivating various tumor suppressor genes during cancer initiation and progression. We aimed to review methylation status of key genes involved in hematopoietic malignancies such as IKZF1, CDKN2B, TET2, CYP1B1, SALL4, DLC1, DLX family, TP73, PTPN6, and CDKN1C and their significance in pathogenesis of ALL. The DNA methylation alterations in promoter regions of the genes have been shown to play crucial roles in tumorigenesis. Methylation -based inactivation of these genes has also been reported as associated with prognosis in acute leukemia. In this review, we also addressed the association of gene expression and methylation pattern in ALL patients.

Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia.

The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated. Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided. Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate. Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

Fludarabine and neurotoxicity in engineered T-cell therapy.

Adoptive T-cell therapy, incorporating engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs), target tumor antigens with high affinity and specificity. To increase the potency of adoptively transferred T cells, patients are conditioned with lymphodepleting chemotherapy regimens prior to adoptive T-cell transfer (ACT), and data suggest that fludarabine is an important component of an effective regimen. In a recent clinical trial using CAR-T cells engineered to target the CD19 B-cell antigen to treat acute lymphoblastic leukemia, JCAR-015 (NCT02535364), two patient deaths due to cerebral edema led to trial suspension. The lymphodepleting agent fludarabine was suggested as the causative agent, in part due to its known association with neurotoxicity and its ability to induce greater potency. In a similar CAR-T study also incorporating fludarabine in the preconditioning regimen, ZUMA-1 (NCT02348216), one patient died of cerebral edema. However, subsequent deaths in the JCAR-015 study after removal of fludarabine and improved understanding behind the mechanisms of CAR-T-related encephalopathy syndrome (CRES) indicate that fludarabine is not the primary causative agent of cerebral edema and that it can be safely incorporated into the preconditioning regimen for ACT. Since entering clinical use in the late 1980s as a chemotherapy agent, fludarabine and similar analogs have been associated with lethal neurological toxicity, yet the manifestation and timing of symptoms are distinct to those observed recently in ACT. Herein, we review the history of fludarabine development as a chemotherapeutic agent, and discuss the safety of its continued use in preconditioning regimens for ACT.

Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition.

Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.

Bone Morbidity and Recovery in Children With Acute Lymphoblastic Leukemia Results of a Six-Year Prospective Cohort Study.

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline interquartile range IQR, 5.5 to 9.4 versus 4.8 years IQR, 3.6 to 6.2, p 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 IQR, 1.0 to 8.0 versus 0.5 IQR, 0.0 to 1.0, p 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research.

Copy number abnormality of acute lymphoblastic leukemia cell lines based on their genetic subtypes.

In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph

Acute Lymphoblastic Leukemia following Lenalidomide Maintenance for Multiple Myeloma Two Cases with Unexpected Presentation and Good Prognostic Features.

Lenalidomide maintenance following autologous stem cell transplant (ASCT) is considered the standard of care for eligible patients with multiple myeloma (MM). A recent meta-analysis has provided additional evidence that lenalidomide maintenance is associated with a higher incidence of second primary malignancies, including both hematologic and solid malignancies. Acute lymphoblastic leukemia (ALL) as a second primary malignancy is rarely described in the literature. Herein, we describe two patients with MM treated with induction therapy, ASCT, and lenalidomide maintenance that experienced cytopenias while on maintenance. ALL was unexpectedly diagnosed on bone marrow biopsy. One patient was diagnosed on routine biopsy performed as part of requirements of the clinical trial. Both patients had B-cell ALL, without known poor risk cytogenetics, and were managed with standard induction therapies resulting in complete remission. We also reviewed the literature for similar cases of secondary ALL (sALL) in MM patients exposed to immunomodulatory drugs (IMiDs). In conclusion, persistent cytopenias in responding MM patients receiving IMiDs maintenance should be an indication for bone marrow biopsy. Patients develop sALL after median of 32.5 months (range, 20-84) from being on lenalidomide or thalidomide maintenance, often presenting with cytopenias, display low tolerance to chemotherapy, but remission can often be achieved.

A causal mechanism for childhood acute lymphoblastic leukaemia.

In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1)

Emerging Treatment Options for Acute Lymphoblastic Leukemia Focus on CAR T-Cell Therapy.

Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of diseases with different morphologic, cytogenetic, and molecular subgroups, some of which have significant therapeutic implications. It typically presents with an aggressive clinical course, and among adults, responds poorly to standard chemotherapy, and carries a high risk for relapse. Despite the significant progress made in inducing remission, frequent relapses remain a challenge. Novel drugs, such as potent later-generation tyrosine kinase inhibitors, antibody-drug conjugates, bispecific monoclonal antibodies, and chimeric antigen receptor (CAR) T-cell therapies, are being investigated in patients with ALL. This summary describes therapies currently approved for the treatment of patients with ALL, identifies emerging targeted immunotherapies for patients with ALL, and discusses adverse events and mechanisms of resistance.

Factors influencing the documentation of fertility-related discussions for adolescents and young adults with cancer.

A cancer diagnosis and treatment may have significant implications for a young patients future fertility. Documentation of fertility-related discussions and actions is crucial to providing the best follow-up care, which may occur for many years post-treatment. This study examined the rate of medical record documentation of fertility-related discussions and fertility preservation (FP) procedures for adolescents and young adults (AYAs) with cancer in Australia. A retrospective review of medical records for 941 patients in all six Australian states. Patients were identified through population-based cancer registries (four states) and hospital admission lists (two states). Trained data collectors extracted information from medical records using a comprehensive data collection survey. Records were reviewed for AYA patients (aged 15-24 years at diagnosis), diagnosed with acute myeloid leukaemia, acute lymphoblastic leukaemia, central nervous system (CNS) tumours, soft tissue sarcomas (STS), primary bone cancer or Ewings family tumours between 2007 and 2012. 47.2% of patients had a documented fertility discussion and 35.9% had a documented FP procedure. Fertility-related documentation was less likely for female patients, those with a CNS or STS diagnosis and those receiving high-risk treatments. In multivariable models, adult hospitals with an AYA focus were more likely to document fertility discussions (odds ratioOR 1.60 95%CI 1.08-2.37) and FP procedures (OR 1.74 95%CI 1.17-2.57) than adult hospitals with no AYA services. These data provide the first national, population-based estimates of fertility documentation for AYA cancer patients in Australia. Documentation of fertility-related discussions was poor, with higher rates observed in hospitals with greater experience of treating AYA patients.

Revisiting CD28 Superagonist TGN1412 as Potential Therapeutic for Pediatric B Cell Leukemia A Review.

Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising therapeutic agent that yielded outstanding results in both in vitro studies and animal trials. It is a CD28 superagonist monoclonal antibody that activates T regulatory (T

The NOTCH1CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model.

NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse.

White Matter Microstructure and Information Processing at the Completion of Chemotherapy-Only Treatment for Pediatric Acute Lymphoblastic Leukemia.

Little is known about white matter microstructure and its role in information processing abilities of children treated for acute lymphoblastic leukemia (ALL) early posttreatment. Twenty-one survivors of ALL and 18 controls (7-16 years) underwent neurocognitive assessment. A subsample underwent diffusion-weighted magnetic resonance imaging. The ALL group performed poorer on measures of processing capacity, and had widespread areas of decreased fractional anisotropy and increased radial diffusivity. Significant group by white matter microstructure interactions was found when predicting processing speed. Findings provide evidence for an atypical brain-behavior relationship early posttreatment for childhood ALL. Replication in a larger sample is required.

Quantitative Glycomic Analysis by Mass-Defect-Based Dimethyl Pyrimidinyl Ornithine (DiPyrO) Tags and High-Resolution Mass Spectrometry.

We recently developed a novel amine-reactive mass-defect-based chemical tag, dimethyl pyrimidinyl ornithine (DiPyrO), for quantitative proteomic analysis at the MS

Epigenetic dysregulation of ZEB1 is involved in LMO2-promoted T-cell acute lymphoblastic leukaemia leukaemogenesis.

T-cell acute lymphoblastic leukaemia (T-ALL) is a hematological malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. ZEB1, a member of zinc finger-homeodomain family transcription factor, exhibits crucial function in promoting T-cell differentiation and potentially acts as a tumor suppressor in T-ALL. However, the molecular mechanism by which ZEB1 regulates T-ALL leukaemogenesis remains obscure. Here, we showed that oncogenic LIM only 2 (LMO2) could recruit Sap18 and HDAC1 to assemble an epigenetic regulatory complex, thus inducing histone deacetylation in ZEB1 promoter and chromatin remodeling to achieve transcriptional repression. Furthermore, downregulation of ZEB1 by LMO2 complex results in an increased leukaemia stem cell (LSC) phenotype as well as unsensitivity in response to methotrexate (MTX) chemotherapy in T-ALL cells. Importantly, we demonstrated that Trichostatin A (TSA, a HDAC inhibitor) addition significantly attenuates MTX unsensitivity caused by dysfunction of LMO2ZEB1 signaling. In conclusion, these findings have identified a molecular mechanism underlying LMO2ZEB1-mediated leukaemogenesis, paving a way for treating T-ALL with a new strategy of epigenetic inhibitors.

ETV6RUNX1-positive childhood acute lymphoblastic leukemia (ALL) The spectrum of clonal heterogeneity and its impact on prognosis.

The prognostic significance of the ETV6RUNX1-fusion and of the accompanying aberrations is disputable whether co-existing sub-clones are responsible for delayed MRD-clearance and thus, moderate outcome, remains to be clarified. We studied, in a paediatric cohort of 119 B-ALLs, the relation between the ETV6RUNX1 aberration and the co-existing subclones with (a) presenting clinicalbiological features, (b) early response to treatment(MRD) and (c) long-term outcome over a 12-year period. Patients were homogeneously treated according to BFM-based-protocols. 27119 patients (22.7%) were ETV6RUNX1-positive 1927 (70.4%) harbored additional genetic abnormalities while 919 (33.3%) presented with clonal heterogeneity. The most common abnormalities were del12p13 (37%), 3-6×21q22 (22.2%), del9p21 (18.5%) and 2-3xETV6RUNX1 (18.5%). MRD

Investigating chemoresistance to improve sensitivity of childhood T-cell acute lymphoblastic leukemia to parthenolide.

Current therapies for childhood T-cell acute lymphoblastic leukemia have increased survival rates to above 85% in developed countries. Unfortunately, some patients fail to respond to therapy and many suffer from serious side effects, highlighting the need to investigate other agents to treat this disease. Parthenolide, a nuclear factor kappa (κ)B inhibitor and reactive oxygen species inducer, has been shown to have excellent anti-cancer activity in pediatric leukemia xenografts, with minimal effects on normal hemopoietic cells. However, some leukemia initiating cell populations remain resistant to parthenolide. This study examined mechanisms for this resistance, including protective effects conferred by bone marrow stromal components. T-cell acute leukemia cells co-cultured with mesenchymal stem cells demonstrated significantly enhanced survival against parthenolide (73±11%) compared to cells treated without mesenchymal stem cell support (11±9%). Direct cell contact between mesenchymal cells and leukemia cells was not required to afford protection from parthenolide. Mesenchymal stem cells released thiols and protected leukemia cells from reactive oxygen species stress, which is associated with parthenolide cytotoxicity. Blocking cystine uptake by mesenchymal stem cells, using a small molecule inhibitor, prevented thiol release and significantly reduced leukemia cell resistance to parthenolide. These data indicate it may be possible to achieve greater toxicity to childhood T-cell acute lymphoblastic leukemia by combining parthenolide with inhibitors of cystine uptake.

Real-life Experience With Ponatinib in Chronic Myeloid Leukemia A Multicenter Observational Study.

The strict recruitment criteria of patients for clinical trials often lead to reduced generalizability of the findings. We studied how ponatinib is used outside clinical trials in patients with chronic myeloid leukemia (CML). The present retrospective study included all patients with a diagnosis of CML who had received ponatinib in 7 medical centers in Israel. From 2011 to 2016, we identified 37 patients with CML who had received ponatinib, 21 in the chronic phase and 16 in the advanced phase. Only 9 patients (26%) harbored the T315I (threonine to isoleucine mutation at position 315) mutation. All patients had received ≥ 1 previous tyrosine kinase inhibitor. The median age in our cohort was 43 years (range, 9-82 years), significantly younger than expected for patients with relapsed or refractory CML and 20 years younger than the median age of patients who participated in the PACE (ponatinib Philadelphia-positive acute lymphoblastic leukemia and CML evaluation) trial. During a median follow-up of 14 months (range, 1-51 months), the overall response rate was 85%. Of 34 patients, 16 (47%) experienced at least a major molecular response. Of the 37 total patients, another 16 patients (43%) discontinued treatment because of disease progression (n 6), vascular complications (n 1), severe cytopenia (n 2), or for other reasons (n 7). In real life, ponatinib is a niche-drug reserved for a unique population of exceptionally young patients with CML with or without the T315I mutation. In this highly selected group, very different from the PACE cohort, ponatinib achieved high overall response rates.

Phenotyping and Target Expression Profiling of CD34

Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34

Cardiac Profile of Chimeric Antigen Receptor T Cell Therapy in Children A Single-Institution Experience.

Immunotherapy with chimeric antigen receptor (CAR)-modified T cells targeting CD19 for pediatric acute lymphoblastic leukemia (ALL) has demonstrated significant efficacy. The principle toxicity is cytokine release syndrome with resultant hypotension. However, the spectrum of cardiovascular effects associated with CAR T cell therapy has not been systematically evaluated. We reviewed all patients who received CD19-directed CAR T cells at the Childrens Hospital of Philadelphia between April 2012 and September 2016. The primary endpoint was hypotension-requiring inotropic support. Secondary endpoints included echocardiographic dysfunction at discharge and 6-month follow-up. Descriptive and univariate analyses were performed, and 98 encounters were included (55% male patients mean age, 11.8 years range, 1.7 to 27.1) 98% had B-ALL. Before infusion 10 had cardiomyopathy and 1 had single-ventricle physiology. Primary endpoint occurred in 24 patients with mean onset 4.6 days (range, 1 to 9) after CAR T cell infusion, including 6 patients receiving milrinone. Worsened systolic function occurred in 10 patients there were no cardiac-related deaths. Pretreatment factors associated with primary endpoint included higher pretreatment blast percentage on bone marrow biopsy (blast > 25% odds ratio, 15.5 95% confidence interval, 5.1 to 47.1 P < .001) and baseline lower ejection fraction (P .019) or diastolic dysfunction (P .021) neither pre-existing cardiomyopathy (P .062), total body irradiation (P .629), nor anthracycline dose (P .444) were associated. At discharge, 7 patients had worsened echocardiographic function, but persistent dysfunction by the 6-month follow-up was rare. Pretreatment factors were not associated with persistent dysfunction at discharge. This is the first study to describe the cardiovascular effects of pediatric CAR T cell therapy. Although 10% had new systolic dysfunction after treatment, persistence was rare. Pretreatment blast count > 25% or pre-existing cardiac dysfunction increased the risk for hypotension-requiring inotropic support these patients may warrant close observation.

Allogeneic Stem Cell Transplantation from HLA-Mismatched Donors for Pediatric Patients with Acute Lymphoblastic Leukemia Treated According to the 2003 BFM and 2007 International BFM Studies Impact of Disease Risk on Outcomes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is beneficial for pediatric patients with relapsed or (very) high-risk acute lymphoblastic leukemia (ALL) in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007 I-BFM study and were stratified according to relapse risk (standard versus high versus very high risk of relapse) and donor type (matched sibling versus matched donor versus mismatched donor). A total of 148 patients (60% boys median age, 8.7 years B cell precursor ALL, 75%) were transplanted from mismatched donors, which was defined as either less than 910 HLA-compatible donors or less than 56 unrelated cord blood after myeloablative conditioning regimen (total body irradiation based, 67%) for high relapse risk (HRR n 42) or very HRR (VHRR) disease (n 106). The stem cell source was either bone marrow (n 31), unmanipulated peripheral stem cells (n 28), T cell ex vivo depleted peripheral stem cells (n 59), or cord blood (n 25). The median follow-up was 5.1 years. The 4-year rates of overall survival (OS) and event-free survival were 56% ± 4% and 52% ± 4%, respectively, for the entire cohort. Patients transplanted from mismatched donors for HRR disease obtained remarkable 4-year OS and event-free survival values of 82% ± 6% and 80% ± 6%, respectively, whereas VHRR patients obtained values of 45% ± 5% and 42% ± 5% (P < .001), respectively. The cumulative incidence of relapse was 29% ± 4% and that of nonrelapse mortality 19% ± 3%. The cumulative incidence of limited and extensive chronic graft-versus-host disease was 13% ± 3% and 15% ± 4%, respectively, among the 120 patients living beyond day 100. Multivariate analysis showed that OS was lower for transplanted VHRR patients (P .002 hazard ratio HR, 3.62 95% confidence interval CI, 1.60 to 8.20) and for patients beyond second complete remission (CR2) versus first complete remission (P < .001 HR, 3.68 95% CI, 1.79 to 7.56) relapse occurred more frequently in patients with VHRR disease (P .026 HR, 3.30 95% CI, 1.16 to 9.60) and for those beyond CR2 (P .005 HR, 4.16 95% CI, 1.52 to 10.59). Nonrelapse mortality was not significantly higher for cytomegalovirus-positive recipients receiving cytomegalovirus-negative grafts (P .12 HR, 1.96 95% CI, .84 to 4.58). HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared with HSCT with better matched donors, at least for patients transplanted for VHRR disease. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before andor after transplantation.