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Enniatin B induces expression changes in the electron transport chain pathway related genes in lymphoblastic T-cell line.

Enniatin B is a ionophoric and lipophilic mycotoxin which reaches the bloodstream and has the ability to penetrate into cellular membranes. The purpose of this study was to reveal changes in the gene expression profile caused by enniatin B in human Jurkat lymphoblastic T-cells after 24 h of exposure at 1.5, 3 and 5 μM by next generation sequencing. It was found that up to 27% of human genome expression levels were significantly altered (5750 genes for both down-regulation and up-regulation). In the three enniatin B concentrations studied 245 differentially expressed genes were found to be overlapped, 83 were down and 162 up-regulated. ConsensusPathDB analysis of over-representation of differentially expressed genes provided a list of gene ontology terms in which several biological processes related to nucleoside monophosphate metabolic process, respiratory chain complex, electron transport chain, oxidative phosphorylation and cellular respiration were the most altered. Also, an interesting correlation was found between enniatin B toxicity and the up-regulation of the UCP protein complex. In summary, the transcriptomic analysis revealed that mitochondria are the organelles showing more related differentially expressed genes. Consequently, differentially expressed genes involved in biological processes, molecular functions and pathways related to mitochondrial metabolism and respiration were significantly changed.

Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant.

Long-term disease-free survival in adults with T-cell acute lymphoblastic leukemia (T-ALL) remains poor, particularly after relapse, with few available salvage options. Preclinical data suggest that inhibition of the antiapoptotic protein BCL-2 (B-cell lymphoma 2) either alone or in combination with other agents, may be a unique therapeutic approach for the treatment of T-ALL. We present a case of a young male with T-ALL, relapsed after allogeneic hematopoietic stem cell transplant, who achieved a second complete remission following salvage therapy with combined venetoclax and decitabine. Assessment of measurable residual disease by next generation sequencing showed no evidence of residual disease of a sensitivity of 1 × 10

NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.

Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL. We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.

USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.

The role of genetic polymorphisms in the thymidylate synthase (TYMS) gene in methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia.

Methotrexate (MTX) is an important drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). MTX is cytotoxic as it impairs DNA and RNA synthesis by inhibiting the enzymes dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS). The association between genetic variants within the TYMS gene and MTX-induced toxicity has been studied, but results are inconsistent. We determined the role of three previously described variants within the TYMS gene and MTX-induced oral mucositis in a prospective cohort of Dutch children with ALL and performed a meta-analysis of the previous results. We analyzed the presence of a 28-base pair tandem repeat (rs34743033 2R3R), a single nucleotide polymorphism present within the 28-base pair repeat on the 3R allele (rs2853542 3RG>C) and a 6-base pair deletion (rs15126436 TTAAAG) within the TYMS gene in germline DNA of 117 pediatric patients with ALL. Oral mucositis was defined as grade≥3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.3.0. Data were analyzed for the individual rs34743033 (2R3R) and rs151264360 (6 bp deletion) polymorphisms, whereas rs2853542 (3RG>C) was combined with rs34743033 (2R3R) and analyzed according to predicted expression levels of TYMS low expression (2R2R, 2R3RC and 3RC3RC), median expression (2R3RG and 3RC3RG) and high expression (3RG3RG). We performed a meta-analysis of the current literature on these polymorphisms in relation to oral mucositis using a fixed effects model. The 2R2R genotype (rs34743033) was not significantly associated with developing MTX-induced oral mucositis compared with the 2R3R3R3R genotypes, which was confirmed in a meta-analysis odds ratio (OR) 1.17 (0.62-2.19). Patients carrying the low-expression TYMS genotype (2R2R, 2R3RC, 3RC3RC) had an increased odds of developing MTX-induced oral mucositis OR 2.42 (0.86-6.80), which did not reach statistical significance. The 6-bp deletion rs151264360, OR 0.79 (0.20-3.19) was not associated with the development of MTX-induced oral mucositis. The TYMS 6-bp deletion and 2R3R polymorphism were not associated with MTX-induced oral mucositis. Validation studies in prospective cohorts are necessary to assess the possible role of the low-expression TYMS genotypes in relation to MTX-induced oral mucositis.

Adult Acute Lymphoblastic Leukemia Limitations of Intensification of Therapy in a Developing Country.

Purpose Limited data exist on intensifying chemotherapy regimens in the treatment of adult acute lymphoblastic leukemia (ALL) outside the setting of a clinical trial. Materials and Methods Retrospectively, data from 507 consecutive adults (age ≥ 15 years) with a diagnosis of ALL treated at our center were analyzed. Standard-risk (SR) patients were offered treatment with a modified German Multicenter ALL (GMALL) regimen, whereas high-risk (HR) patients were offered intensification of therapy with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD). Because of resource constraints, a proportion of HR patients opted to receive the same treatment regimen as used for SR patients. Results There were 344 SR patients (67.8%) and 163 HR patients (32.2%) at diagnosis. Among the HR patients, 53 (32.5%) opted to receive intensification with the HCVAD regimen. The SR cohort showed a superior 5-year event-free survival rate compared with the HR cohort (47.3% v 23.6%, respectively P < .001). Within the HR subgroup, there was no statistically significant difference in overall survival or event-free survival between patients who received the modified GMALL regimen (n 59) and patients who received HCVAD (n 53). Conclusion Intensified therapy in the HR subset was associated with a significant increase in early treatment-related mortality and cost of treatment. A modified GMALL regimen was found to be cost-effective with clinical outcomes comparable to those achieved with more intensive regimens.

Post‑transplant lymphoproliferative disorder in hematopoietic stem cell transplant patients A single center retrospective study between 2005 and 2012.

Post‑transplant lymphoproliferative disorder (PTLD), despite its rarity, is an important mortalitymorbidity event in transplant patients. The purpose of the present study was to retrospectively examine the clinical and pathologic characteristics, and outcomes of PTLD at the Portuguese Oncology Institute of Porto. A retrospective review of patient information was performed for patients that developed PTLD following allogeneic hematopoietic stem cell transplant (aHSCT) and were diagnosed between 2005 and 2012. The present study included a total of 15 patients, 8 females (53.3%) and 7 males (46.7%), with different clinicopathological characteristics. The most frequent clinical condition inducing aHSCT was acute lymphocytic leukemia (40.0%). Conditioning regimens consisted primarily in busulfan and cyclophosphamide, with anti‑thymocyte globulin, and myeloablation was the preferential treatment. Epstein‑Barr virus (EBV) was present in all patients with a median time of diagnosis following transplant of 75 days (range, 25‑485 days) and a median viral load of 4.75 log10 copiesml (range, 3.30‑6.26 log10 copiesml). PTLD diagnosis was mainly assessed by clinical findings, and histological confirmation was available for 5 patients 3 monomorphic, 1 polymorphic and 1 with early lesions of PTLD. To the best of our knowledge, this is the first study to describe PTLD cases in HSCT patients in Portugal. The data reinforces the importance of performing EBV monitoring in high‑risk patients, particularly those receiving a transplant from mismatchunrelated donors, and those with myeloablative conditioning regimen including antithymocyte globulin. The results also suggested that EBV viral load may be significant for the prediction of PTLD development.

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia.

CD19 immunotherapies based on T cells opened new avenues in the treatment of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, Fc engineered CD19 antibodies may also bear great potential. In light of recent preclinical and clinical data, perspectives of such antibodies designed for improved effectiveness in BCP-ALL are presented.

Culture filtrate ether extracted metabolites from Streptomyces levis ABRIINW111 increased apoptosis and reduced proliferation in acute lymphoblastic leukemia.

Despite the advances in the discovery of various types of anticancer drugs for curing acute lymphoblastic leukemia (ALL), their toxicity and unfavorable side effects remained as big limitations for therapeutical applications. In this regard, natural products such as Streptomyces -derived agents have shown potential applications as anticancer drugs. The present study deals with evaluating the anti-carcinogenic activity of the ether extracted metabolites derived from Streptomyces on nalm-6 and molt-4 ALL cell lines. MTT assay was performed to evaluate the cytotoxicity effect of Streptomyces sp on nalm-6 and molt-4 cell lines. Apoptosis and proliferation were evaluated by Flow cytometry. Quantitative real-time RT-PCR (qRT-PCR) and western blot were performed to investigate the effect of these metabolites on the mRNA and protein expression levels of P53, Bax, and Bcl2. In both cell lines, extracted metabolites significantly inhibited cell growth and increased apoptosis. Although P53, Bax mRNA and protein expressions were increased, Bcl-2 expression decreased in treated cells compared with control. In addition, the G0G1 arrest of Nalm-6 cells was induced. These findings of this work show that the ether-extracted metabolites from Streptomyces levis ABRIINW111 can be used as an anti-carcinogenic for acute lymphoblastic leukemia cells.

Neonatal Inflammatory Markers Are Associated with Childhood B-cell Precursor Acute Lymphoblastic Leukemia.

It has been proposed that children with acute lymphoblastic leukemia (ALL) are born with a dysregulated immune function that together with postnatal environmental exposures causes childhood ALL. Despite its importance for the understanding of ALL etiology, this hypothesis has been inadequately explored. In a population-based case-control study, we measured the concentrations of 10 cytokines and other inflammatory markers on neonatal dried blood spots from 178 children who at ages 1 to 9 years were diagnosed with B-cell precursor ALL and 178 matched controls. Through linkage with Danish nationwide registers, we also assessed whether neonatal inflammatory markers were associated with previously demonstrated risk factors for childhood ALL. Children who developed B-cell precursor ALL had significantly lower neonatal concentrations of IL8, soluble IL6 receptor (sIL6R) α, TGFβ1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP) and higher concentrations of IL6, IL17, and IL18 compared with matched controls. Concentrations of IL10 were below the detection level for both patients and controls. Birth order (IL18 and CRP), gestational age (sIL6Rα, TGFβ1, and CRP), and sex (sIL6Rα, IL8, and CRP), but not maternal age, infections during pregnancy, birth weight nor mode of delivery were significantly associated with the neonatal concentrations of inflammatory markers. Our findings support the hypothesis that children who later develop B-cell precursor ALL are born with a dysregulated immune function.

Insulin-dependent diabetes A chronic complication to acute pancreatitis in childhood acute lymphoblastic leukemia.

Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hyperglycaemia, need for mechanical ventilation, pseudocysts, and death. Here, we provide novel data on seven patients diagnosed with diabetes after pancreatitis and still requiring insulin treatment after a median follow-up of 4.2 years (range 1.7-9.2). We describe the clinical course of pancreatitis and illustrate the association between pancreatic pseudocysts, older age, and development of insulin-dependent diabetes. Together, this study documents the persisting burden of pancreatitis in childhood ALL and underlines the need for plasma glucose level monitoring.

Activating PAX gene family paralogs to complement PAX5 leukemia driver mutations.

PAX5, one of nine members of the mammalian paired box (PAX) family of transcription factors, plays an important role in B cell development. Approximately one-third of individuals with pre-B acute lymphoblastic leukemia (ALL) acquire heterozygous inactivating mutations of PAX5 in malignant cells, and heterozygous germline loss-of-function PAX5 mutations cause autosomal dominant predisposition to ALL. At least in mice, Pax5 is required for pre-B cell maturation, and leukemic remission occurs when Pax5 expression is restored in a Pax5-deficient mouse model of ALL. Together, these observations indicate that PAX5 deficiency reversibly drives leukemogenesis. PAX5 and its two most closely related paralogs, PAX2 and PAX8, which are not mutated in ALL, exhibit overlapping expression and function redundantly during embryonic development. However, PAX5 alone is expressed in lymphocytes, while PAX2 and PAX8 are predominantly specific to kidney and thyroid, respectively. We show that forced expression of PAX2 or PAX8 complements PAX5 loss-of-function mutation in ALL cells as determined by modulation of PAX5 target genes, restoration of immunophenotypic and morphological differentiation, and, ultimately, reduction of replicative potential. Activation of PAX5 paralogs, PAX2 or PAX8, ordinarily silenced in lymphocytes, may therefore represent a novel approach for treating PAX5-deficient ALL. In pursuit of this strategy, we took advantage of the fact that, in kidney, PAX2 is upregulated by extracellular hyperosmolarity. We found that hyperosmolarity, at potentially clinically achievable levels, transcriptionally activates endogenous PAX2 in ALL cells via a mechanism dependent on NFAT5, a transcription factor coordinating response to hyperosmolarity. We also found that hyperosmolarity upregulates residual wild type PAX5 expression in ALL cells and modulates gene expression, including in PAX5-mutant primary ALL cells. These findings specifically demonstrate that osmosensing pathways may represent a new therapeutic target for ALL and more broadly point toward the possibility of using gene paralogs to rescue mutations driving cancer and other diseases.

Pax5 is the guardian of the B cell identity since it primes or enhances the expression of B cell specific genes and concomitantly represses the expression of B cell inappropriate genes. The tight regulation of

Thiopurine methyltransferase activity in children with acute myeloid leukemia.

Activity of the enzyme thiopurine methyltransferase (TPMT) determines the anti-leukemic effect of thiopurines used in the chemotherapy of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). TPMT status and its effects on treatment outcome have been studied extensively in ALL and autoimmune disorders, but few data is available on TPMT in AML. The present study assessed the genetic polymorphisms and activity of TPMT in children with AML at different treatment stages, and compared the results with those obtained for children with ALL. The study included 33 children with AML (0.7-19.7 years) treated with 6-thioguanine (6-TG) according to the AML-BFM 2004 Protocol. Blood samples were collected at diagnosis, during and following maintenance chemotherapy from 8, 10 and 17 patients with AML (the assay was performed at two time points in 2 patients), respectively. Blood samples from 105 children with ALL were obtained at diagnosis, during the maintenance chemotherapy and following the cessation of the chemotherapy from 16, 55 and 34 children, respectively. The activity of TPMT in red blood cells lysates was measured using an enzymatic reaction based on the conversion of 6-mercaptopurine into 6-methylmercaptopurine, involving S-adenozyl-L-methionine as the methyl group donor. TPMT mutations were determined using a polymerase chain reactionrestriction fragment length polymorphism method. Median TPMT activity at diagnosis, during maintenance chemotherapy and following chemotherapy was 43.1, 47,3 and 41.7 nmol 6-mMP g

Regulation of mPGES-1 composition and cell growth via the MAPK signaling pathway in jurkat cells.

Previous studies have suggested that microsomal prostaglandin E synthase-1 (mPGES-1) is highly expressed and closely associated with mitogen-activated protein kinase (MAPK) signaling pathways in various types of malignant cells. However, their expression patterns and function with respect to T-cell acute lymphoblastic leukemia (T-ALL) remain largely unknown. The present study investigated whether mPGES-1 served a crucial role in T-ALL and aimed to identify interactions between mPGES-1 and the MAPK signaling pathway in T-ALL. The results indicated that mPGES-1 overexpression in T-ALL jurkat cells was significantly decreased by RNA silencing. Decreasing mPGES-1 on a consistent basis may inhibit cell proliferation, induce apoptosis and arrest the cell cycle in T-ALL jurkat cells. Microarray and western blot analyses revealed that c-Jun N-terminal kinase served a role in the mPGES-1prostaglandin E2EP4MAPK positive feedback loops. In addition, P38 and extracellular signal-regulated kinase 12 exhibited negative feedback effects on mPGES-1. In conclusion, the results suggested that cross-talk between mPGES-1 and the MAPK signaling pathway was very complex. Therefore, the combined regulation of mPGES-1 and the MAPK signaling pathway may be developed into a new candidate therapy for T-ALL in the future.

The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only.

Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol. One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age interquartile range, 10.7-17.6 years median time since diagnosis, 7.5 years interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up. Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment.

G9a Correlates with VLA-4 Integrin and Influences the Migration of Childhood Acute Lymphoblastic Leukemia Cells.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. As ALL progresses, leukemic cells cross the endothelial barrier and infiltrate other tissues. Epigenetic enzymes represent novel therapeutic targets in hematological malignancies, and might contribute to cells capacity to migrate across physical barriers. Although many molecules drive this process, the role of the nucleus and its components remain unclear. We report here, for the first time, that the expression of G9a (a histone methyltransferase related with gene silencing) correlates with the expression of the integrin subunit α4 in children with ALL. We have demonstrated that G9a depletion or its inhibition with BIX01294 abrogated the ability of ALL cells to migrate through an endothelial monolayer. Moreover, G9a-depleted and BIX01294-treated cells presented bigger nuclei and more adherent phenotype than control cells on endothelial monolayers. Blocking G9a did not affect the cell cytoskeleton or integrin expression of ALL cell lines, and only its depletion reduced slightly F-actin polymerization. Similarly to the transendothelial migration, G9a inhibition impaired the cell migration induced by the integrin VLA-4 (α4β1) of primary cells and ALL cell lines through narrow spaces in vitro. Our results suggest a cellular connection between G9a and VLA-4, which underlies novel functions of G9a during ALL cell migration.

IFNG 874 AT is associated with acute lymphoblastic leukemia in Mexican Mestizos.

Acute lymphoblastic leukemia (ALL), the most common type of cancer in children worldwide, has one of the highest incidence rates in Mexico. It is a multifactorial disease and different cytokine single nucleotide polymorphisms (SNP), have been associated with ALL expression. Few studies have been published analyzing IFNG 874 TA and IL2 -330 GT in this type of leukemia. These SNPs are involved in high or low expression, and are central to cellular immunity, influencing greatly tumor growth. The purpose of this work was to explore the association of IFNG 874 AT (rs2430561) and IL2 -330 GT (rs2069762) SNPs with ALL susceptibility andor protection in 488 Mexican Mestizos patients, as compared to 950 Mexican Mestizo healthy controls. The results demonstrated that IFNG 874 T allele (pc 0.00004, OR 0.673) and the TT genotype (pc 0.00015, OR 0.349), protect against ALL expression with no specific gender association however, the TT homozygote genotype (vs. TAAA) seems more protective in males (pc 0.00683). IL2 -330 GT does not contribute to the development of ALL. In healthy Mexicans, the most common genotypes for IL2 and IFNG, are the low cytokine producers, suggesting that the genetic background in this ethnic group, may be partly responsible for the high incidence of ALL. These results show for the first time in Mexicans, the relevant role that IFNG SNP has in the genetic etiology of ALL. Thus, a large group of patients belonging to different ethnicities will be very helpful to study in order to demonstrate if these SNPs contribute to the genetic etiology of ALL, as shown here in Mexican Mestizos.

Flow Cytometric Monitoring for Residual Disease in B Lymphoblastic Leukemia Post T Cell Engaging Targeted Therapies.

The use of targeted therapy is growing in the setting of hematopoietic neoplasms. Flow cytometry is a cornerstone of residual disease monitoring post therapy in this group of malignancies. Often, there is overlap between antigens targeted by immunotherapies and gating reagents utilized for population identification by flow cytometry. Such overlap can render a previously excellent gating reagent inadequate for disease detection. Recently, several anti-CD19 T cell-engaging immunotherapeutic agents and an anti-CD22 immunotoxin have been FDA approved for use in B lymphoblastic leukemia (B-LL), with an anti-CD22 T cell-engaging agent in development. In the setting of such targeted therapies, CD19 and CD22 expression may be altered, compromising the use of these reagents for identification of abnormal blasts. We describe herein a strategy for flow cytometric monitoring for residual disease in patients with B-LL post T cell-engaging anti-CD19 and anti-CD22 therapies. © 2018 by John Wiley Sons, Inc.

Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Pediatric B-Cell Acute Lymphoblastic Leukemia.

The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel was recently approved to treat relapsed or refractory pediatric acute lymphoblastic leukemia. With a one-time infusion cost of $475,000, tisagenlecleucel is currently the most expensive oncologic therapy. We aimed to determine whether tisagenlecleucel is cost effective compared with currently available treatments. Markov modeling was used to evaluate tisagenlecleucel in pediatric relapsed or refractory acute lymphoblastic leukemia from a US health payer perspective over a lifetime horizon. The model was informed by recent multicenter, single-arm clinical trials. Tisagenlecleucel (under a range of plausible long-term effectiveness) was compared with blinatumomab, clofarabine combination therapy (clofarabine, etoposide, and cyclophosphamide), and clofarabine monotherapy. Scenario and probabilistic sensitivity analyses were used to explore uncertainty. Main outcomes were life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). With an assumption of a 40% 5-year relapse-free survival rate, tisagenlecleucel increased life expectancies by 12.1 years and cost $61,000QALY gained. However, at a 20% 5-year relapse-free survival rate, life-expectancies were more modest (3.8 years) and expensive ($151,000QALY gained). At a 0% 5-year relapse-free survival rate and with use as a bridge to transplant, tisagenlecleucel increased life expectancies by 5.7 years and cost $184,000QALY gained. Reduction of the price of tisagenlecleucel to $200,000 or $350,000 would allow it to meet a $100,000QALY or $150,000QALY willingness-to-pay threshold in all scenarios. The long-term effectiveness of tisagenlecleucel is a critical but uncertain determinant of its cost effectiveness. At its current price, tisagenlecleucel represents reasonable value if it can keep a substantial fraction of patients in remission without transplantation however, if all patients ultimately require a transplantation to remain in remission, it will not be cost effective at generally accepted thresholds. Price reductions would favorably influence cost effectiveness even if long-term clinical outcomes are modest.

Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia.

Background Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster BFM protocol), as well as 100 or 0 blasts per microliter. Results Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the non-carriers (p 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p 0.036), below 100 (p 0.028) and to be blast negative (p 0.054), while GSTP1 GT haplotype and rs1138272 T allele carriers were more likely to be blasts positive (p 0.034 and p 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p 0.018). Conclusions Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.

The genetic basis and cell of origin of mixed phenotype acute leukaemia.

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, Tmyeloid (TM) and Bmyeloid (BM), are genetically distinct. Rearrangement of ZNF384 is common in BM MPAL, and biallelic WT1 alterations are common in TM MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.

Murine pre-B-cell ALL induces T-cell dysfunction not fully reversed by introduction of a chimeric antigen receptor.

Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CARTs) has demonstrated dramatic success in relapsedrefractory pre-B-cell acute lymphoblastic leukemia (ALL), but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T-cell function, but this has not been well studied in ALL and in the context of chimeric antigen receptor (CAR) expression. Using TCF3PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T-cell function in vivo. Vaccines protect against TCF3PBX1.3 but were ineffective when administered after leukemia injection, suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors, including PD1, Tim3, and LAG3, and were dysfunctional following adoptive transfer in a model of T-cell receptor (TCR)-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B-cell ALL induced inhibitory receptor expression, at least in part, in a TCR-independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation A Randomized Clinical Trial.

Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). There are limited data on the effect of antibiotic prophylaxis in children. To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT. In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups-acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients-at 76 centers in the United States and Canada, with follow-up completed September 2017. Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n 100) or no prophylaxis (n 100). Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n 210) or no prophylaxis (n 214). The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT). Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile-associated diarrhea, and musculoskeletal toxic effects. A total of 624 patients, 200 with acute leukemia (median interquartile range IQR age, 11 years 6-15 years 46% female) and 424 undergoing HSCT (median IQR age, 7 years 3-14 38% female), were enrolled. Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (21.9% vs 43.4% risk difference, 21.6% 95% CI, 8.8%-34.4%, P .001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (11.0% vs 17.3% risk difference, 6.3% 95% CI, 0.3%-13.0% P .06). Fever and neutropenia were less common in the levofloxacin group (71.2% vs 82.1% risk difference, 10.8% 95% CI, 4.2%-17.5% P .002). There were no significant differences in severe infection (3.6% vs 5.9% risk difference, 2.3% 95% CI, -1.1% to 5.6% P .20), invasive fungal disease (2.9% vs 2.0% risk difference, -1.0% 95% CI, -3.4% to 1.5%, P .41), C difficile-associated diarrhea (2.3% vs 5.2% risk difference, 2.9% 95% CI, -0.1% to 5.9% P .07), or musculoskeletal toxic effects at 2 months (11.4% vs 16.3% risk difference, 4.8% 95% CI, -1.6% to 11.2% P .15) or at 12 months (10.1% vs 14.4% risk difference, 4.3% 95% CI, -3.4% to 12.0% P .28) between the levofloxacin and control groups. Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia. However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT.

STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca

Significance of CNS 2 cerebrospinal fluid status post-induction in pediatric and adolescent patients with acute lymphoblastic leukemia.

At diagnosis, there are prognostic implications of low-level leukemic blasts (CNS 2) in the cerebrospinal fluid (CSF) of patients with acute lymphoblastic leukemia (ALL). However, the significance of post-induction CNS 2 results and the impact of equipment on CNS 2 prevalence have not been well studied. A single-institution retrospective cohort study was conducted to analyze the outcome of patients with ≥1 post-induction CNS 2. A subanalysis compared the proportion of CNS 2 CSF results using 2 different cytocentrifuges the Shandon Cytospin used from 2005 to 2008 and the Wescor Cytopro used from 2010 to 2014. Over 4500 post-induction CSF samples were analyzed, of which 59 were CNS 2. In covariate-adjusted analyses, post-induction CNS 2 did not significantly increase relapse risk. The proportion of CNS 2 results increased 4.3-fold in noninfants and 6.3-fold in infants using the Wescor Cytopro. Cytocentrifuge machine did not affect CNS 3 prevalence. These findings support our current practice of not changing management based on a post-induction CNS 2 CSF and highlight how equipment changes can significantly influence testing results. More data are needed to analyze relapse by subpopulations, such as those with repeated CNS 2 findings.

Effect of transplant status in CD19-targeted CAR T-cell therapy a systematic review and meta-analysis.

Chimeric antigen receptor (CAR) T-cell therapy has shown promise for relapsedrefractory malignancies. Many patients have undergone prior hematopoietic stem cell transplant (HSCT), yet effects of transplant status on CAR T-cell therapy efficacy and safety have not been reported. The purpose of the study is to systematically evaluate the likelihood of achieving optimum response, severe cytokine release syndrome (sCRS), and neurotoxicity in the context of CAR T-cell therapy for HSCT-naïve patients versus those with prior HSCT. Trials were identified in ClinicalTrials.gov, Cochrane Library, and PubMed, and through reference pearl growing. Included studies used CD19-directed CAR T-cells for relapsedrefractory B-lineage Acute Lymphoblastic Leukemia and B cell Chronic Lymphocytic Leukemia, enrolled both HSCT-naïve and prior-HSCT patients, and denoted transplant status with outcomes. Six studies were included for optimum response, five for sCRS incidence, and four for neurotoxicity incidence. The pooled odds ratio for optimum response was 1.57 favoring HSCT-naïve patients (95% CI 0.54-4.61), whereas the pooled odds ratios for sCRS and neurotoxicity were 1.41 (95% CI 0.51-3.94) and 1.37 (95% CI 0.28-6.77), respectively, toward HSCT-naïve patients. Odds ratios were non-statistically significant. Overall risk of bias was moderate. While pooled estimates showed an advantage among HSCT-naïve patients for achieving optimum response and increased likelihood for sCRS and neurotoxicity, findings were not statistically significant. Any differences in efficacy and safety of CAR T-cell therapy cannot be verifiably attributed to transplant status, and additional controlled trials with increased sample sizes are needed to determine whether suggestive patterns favoring HSCT-naïve patients are validated.

Ceramide synthase-6 confers resistance to chemotherapy by binding to CD95Fas in T-cell acute lymphoblastic leukemia.

Ceramide synthases (CERS) produce ceramides which are key intermediators in the biosynthesis of complex sphingolipids and play an important role in cell proliferation, differentiation, apoptosis and senescence. CERS6 is an isoform of ceramide synthases known to generate ceramides with C16 acyl chain (C

Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients.

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation.

To determine the relationship between dose rate and other factors in the development of idiopathic pneumonia syndrome (IPS) in patients with acute lymphoblastic leukemia or acute myeloid leukemia who are undergoing total body irradiation (TBI)-based myeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT). From 2006 to 2016, 202 patients with acute leukemia (111 acute lymphoblastic leukemia, 91 acute myeloid leukemia) ranging in age from 1 to 57 years (median, 25 years) underwent allogeneic HCT at University of Minnesota. Pretransplantation conditioning included cyclophosphamide (120 mgkg) with (68%) or without fludarabine (75 mgm IPS developed in 42 patients (21%) between 4 and 73 days (median, 16 days) after transplantation. HDR TBI was associated with a higher rate of IPS compared with LDR TBI (29% vs 10% P < .01). On multiple regression analysis, HDR remained a significant predictor of IPS (hazard ratio, 2.6 95% confidence interval, 1.2-5.3 P .01), and this led to inferior 1-year overall survival (60% vs 76% P .01) and increased 1-year nonrelapse mortality (28% vs 15% P .02). TBI dose rates ≤15 cGymin reduce the risk of posttransplantation IPS and improve overall survival. LDR TBI should be strongly considered as an easily implemented parameter to improve the safety of pretransplantation TBI-based conditioning.

Plethysmographic and biochemical markers in the diagnosis of endothelial dysfunction in pediatric acute lymphoblastic leukemia survivors - new applications.

Acute lymphoblastic leukemia (ALL) and its treatment are associated with endothelial dysfunction (ED) and increased cardiovascular risk in adulthood. There are no data on ED in children after successful treatment of ALL. We aimed to assess new ED in these children using the plethysmographic reactive hyperemia index (RHI) and biomarkers that are known to be related to ED. In all, 22 children (mean 15.6 years), after successful treatment of ALL, and 18 healthy subjects were included in this prospective study. RHI, plasma concentrations of asymmetric dimethyl arginine (ADMA), high-sensitive CRP (hsCRP) and E-selectin were measured in all children. RHI values were significantly lower in ALL patients when compared with healthy controls (p<0.05). hsCRP was significantly increased in ALL patients compared with the control group (p<0.001). E-selectin plasma levels were higher in ALL patients as compared to healthy controls (p0.05). This is the first study that combines both plethysmographic and biochemical methods to assess ED in ALL survivors. Significantly decreased RHI with elevated plasma concentrations of biochemical markers imply a possible association with premature ED in ALL patients. The combined diagnostic approach seems to be a valuable tool for more accurate detection of ED and preventive cardiovascular management in these patients.

Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis A single center experience of 296 cases.

Single nucleotide polymorphism array (SNP-A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP-A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances >5 Mb and microdeletions targeting the BTG1, CDKN2AB, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T-cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP-A analyses that either revealed additional imbalances >5 Mb or better characterized the changes found by G-banding. Of 260 B-cell precursor (BCP) ALL cases, SNP-A analyses identified additional copy number alterations, including the above-mentioned microdeletions, or better characterized the imbalances found by G-banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41260 (16%) BCP ALL cases was revised based on the SNP-A findings. Of the subtype revisions, 1241 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype-specific minimal residual disease stratification. We conclude that SNP-A analyses dramatically improve the cytogenetic characterization of both T-cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.

KMT2A (MLL) rearrangements observed in pediatricyoung adult T-lymphoblastic leukemialymphoma A 10-year review from a single cytogenetic laboratory.

T-lymphoblastic leukemialymphoma (T-ALLLBL) accounts for approximately 15% of pediatric and 25% of adult ALL. While the underlying frequency of KMT2A (MLL) gene rearrangements has been identified in approximately 4-8% of T-ALLLBL cases, a paucity of literature is available to characterize further the KMT2A rearrangements in pediatricyoung adult T-ALLLBL. A 10-year retrospective review was performed to identify KMT2A rearrangements in specimens sent for T-ALLLBL fluorescence in situ hybridization studies in patients under the age of 30 years. Of 806 T-ALLLBL FISH studies performed on unique individuals, 27 (3.3%) harbored KMT2A rearrangements. Nineteen patients were male and eight were female (MF ratio, 2.41) with ages ranging from 1 to 20 years (mean 12, median 12). Of the 27 cases, nine (33%) had KMT2AMLLT1 fusions, eight (30%) had KMT2AAFDN fusions, two (7%) had KMT2AELL fusions, and one (4%) had a KMT2AMLLT10 fusion. In addition, five (19%) had KMT2A rearrangements with unidentified gene fusion partners and two (7%) had 3KMT2A deletions. Our results indicate that MLLT1 and AFDN account for the majority (63%) of KMT2A gene partners in pediatricyoung adult T-ALLLBL, while no KMT2AAFF1 or KMT2AMLLT3 fusions were observed despite their common identification in B-ALL and acute myeloid leukemia, respectively. In addition to diagnostic and prognostic value, detecting specific KMT2A fusions may also be of clinical importance in the era of targeted therapies.

Association between miR-34bc rs4938723 polymorphism and risk of cancer An updated meta-analysis of 27 case-control studies.

Several studies investigated the association between miR-34bc rs4938723 polymorphism and the risk of several human cancers, but the findings remain inconclusive. To evaluate the impact of miR-34bc rs4938723 on cancer risk, we performed a meta-analysis on all available studies including 12 361 cancer cases and 14 270 controls. Eligible studies were identified by searching PubMed, Web of Science, Scopus, and Google scholar databases. Pooled odds ratios with 95% confidence intervals were calculated in codominant, dominant, recessive, overdominant, and allele models to quantitatively estimate the association. The overall findings showed no significant association between miR-34bc rs4938723 polymorphism and cancer risk in codominant, dominant, recessive, overdominant, and allele inheritance model. However, in stratified analysis by cancer types, the rs4938723 polymorphism significantly increased the risk of gastrointestinal cancer, hepatocellular carcinoma. In addition, the rs4938723 polymorphism was associated with decreased risk of esophageal squamous cell carcinoma, colorectal cancer, and acute lymphoblastic leukemia. The findings did not support an association between rs4938723 variant and digestive tract as well as gastric cancer. In summary, the findings of this meta-analysis indicated that the miR-34bc rs4938723 polymorphism might be associated with some cancer development. Larger and well-designed studies are necessary to estimate this association in detail.

Non-malignant CSF lymphocytosis in a patient with acute lymphoblastic leukemia.

Patients with haematological malignancy are often profoundly immune suppressed, and more so if they require more than one line of therapy. Infection should always be considered when they become unwell. We discuss the differential diagnoses of a young man with multiply-relapsed Philadelphia chromosome-positive B-cell acute lymphoblastic leukaemia who presented with neurological symptoms and cerebrospinal fluid lymphocytosis. The diagnostic approach needs to be rapid and structured, and may require microbiology and neurology support.

Antibacterial prophylaxis in pediatric patients with leukemia.

Bacterial infections in pediatric patients with leukemia are associated with increased risks for morbidity and mortality. Few Recommendations have been made on the use of antibacterial prophylaxis in pediatrics with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). To determine the role of antibacterial prophylaxis in pediatric patients with leukemia and the most appropriate regimen that can be safely and effectively used. Literature search was conducted independently by 3 reviewers to find studies on the safety and effectiveness of antibacterial prophylactic regimens. The search strategy resulted in 13 studies most of them were observational studies. The available evidence recommends use of antibiotics with Gram-positive bacterial coverage in AML patients. In ALL patients, prophylaxis was used during the intensive phases of chemotherapy with ciprofloxacin being recommended most commonly. Antibacterial prophylaxis mainly with coverage against Gram-positive bacteria is recommended in pediatric patients with AML. For ALL patients, prophylaxis may be considered for patients who are undergoing intensive chemotherapy phases and are at high risk for infections with ciprofloxacin being the most commonly used agent. In general more studies are needed to determine the role of antibacterial prophylaxis in pediatric patients with leukemia.

NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia.

The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means (

Acute Lymphoblastic Leukemia - Diagnostics, Subgroups and Therapies.

The acute lymphoblastic leukemia (ALL) is a heterogenous rare malignant disease of lymphoblastic precursor cells. The peak of incidence lies in childhood (5.3100 000), but the incidence rises again from the age of 50 onwards, showing a second peak at patients > 80 years old (2.3100 000). The ALL is an acute life-threatening disease which untreated leads to death within a short time. The therapeutic objective is cure. By the characterization of subgroups, their targeted therapy and therapy optimization cure rates could be improved (from less than 10 % in the eighties) to more than 50 - 70 % (depending on the subgroup). To this achievement the approach has contributed with risk adapted therapy protocols, with improved supportive therapy and in particular with taking the minimal residual disease (the most important prognostic factor) as a basis for the therapy decision. Recently, with the new immunotherapies there exist further promising options of targeted therapies.

Importance of Acute Lymphoblastic Leukemia-type Therapy for Bilineal Acute Leukemia.

We examined 3 pediatric patients with bilineal acute leukemia. Patient 1 with B-cell acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) with B-ALL dominance responded well to prednisolone and ALL-type induction therapy. Patients 2 and 3 with T-ALL and AML with AML dominance responded poorly to prednisolone. Patient 2 was resistant to AML-type therapy patient 3 was resistant to ALL-type induction therapy until day 15. However, all 3 patients eventually achieved complete remission after ALL-type induction therapy. Thus, ALL-type induction therapy should be initiated for bilineal acute leukemia even with AML-dominant, poor prednisolone response, or poor early response features.

Hemofiltration Successfully Eliminates Severe Cytokine Release Syndrome Following CD19 CAR-T-Cell Therapy.

Cytokine release syndrome (CRS) remains to be a major adverse effect of chimeric antigen receptor T (CAR-T) cell therapy in B-cell acute lymphoblastic leukemia (B-ALL) and lymphoma. It was urgent to explore novel strategy for managing severe CRS. We conducted a clinical trial to assess the safety and efficacy of CD19-targeting CAR-T-cells in the treatment of relapsed and chemotherapy-refractory B-ALL and lymphoma. A 10-year-old boy with B-ALL who never achieved minimal residual disease (MRD) negative status after 5 courses of chemotherapy was enrolled into our study and received a total of 3.19×10kg autologous CD19 CAR-T-cells. Before CAR-T-cell infusion, naive lymphocytes made up 41.8% of bone marrow cells, which were reduced to 1% at the 14th day after transfusion, with MRD<10. However, this patient developed grade 4 CRS, multiple organ failure, hemophagocytic syndrome, neurotoxicity, and severe pulmonary infection after CAR-T-cell therapy. Tocilizumab and glucocorticoids treatment were ineffective for controlling the adverse effects and in contrast, hemofiltration immediately ameliorated the severe CRS and prevented the exacerbation of multiple organ dysfunction, pneumonia, and hydrosarca caused by CAR-T-cell therapy. All side effects disappeared within days following hemofiltration. Hemofiltration helped quickly clear cytokines, speeded up patient recover, and successfully resolved the severe CRS crisis. This was the first report, reporting the successful use of hemofiltration to eliminate adverse reactions of CAR-T-cell therapy.

The Effect of Soy Nut Compared to Cowpea Nut on Body Weight, Blood Cells, Inflammatory Markers and Chemotherapy Complications in Children with Acute Lymphoblastic Leukemia A Randomized Controlled Clinical Trial.

No previous studies were found to examine the effect of soy as a whole food on patients with leukemia. The present randomized controlled clinical trial studied the effect of soy nut on children with B-cell acute lymphoblastic leukemia (ALL) who were in the maintenance phase of chemotherapy. The eligible patients were randomized to receive 30 gday soy or cowpea nut powder for 12 weeks. Dietary intake, physical activity, anthropometric measurements, complete blood count, serum albumin, serum highly sensitive C-reactive protein (hs-CRP), and Tumor necrosis factor alpha (TNF-α) as well as chemotherapy side effects were assessed at the start and the end of the study. In total 29 and 27 children completed the study (aged 6.34 ± 2.44 and 5.85 ± 2.35 years) in soy and cowpea nut groups, respectively. The total energy and protein intake, and physical activity as well as body weight, body mass index, number of red blood cells, hemoglobin and hematocrit levels, and fatigue were significantly improved in the soy nut group compared to patients who consumed cowpea nut (P < 0.05). Soy nut intake might improve the nutritional status, anemia, and fatigue in children with ALL. Studies targeting blood cell fractions and disease recurrence are highly recommended.

Therapeutic targeting of Aurora A kinase in Philadelphia chromosome-positive ABL tyrosine kinase inhibitor-resistant cells.

Abelson murine leukemia viral oncogene homolog (ABL) tyrosine kinase inhibitors (TKIs) have been shown to be effective for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia patients. However, resistance to ABL TKIs can develop as a result of breakpoint cluster region-ABL point mutations. Aurora kinases regulate many processes associated with mitosis. In this study, we investigated whether inhibiting Aurora kinase can reduce the viability of Ph leukemia cells. Treatment with the Aurora kinase A inhibitor alisertib blocked Ph leukemia cell proliferation and Aurora kinase A phosphorylation it also induced G2M-phase arrest and increased the intracellular levels of reactive oxygen species. Combined treatment of Ph cells with ABL TKIs and alisertib was cytotoxic, with the fraction of senescent cells increasing in a time- and dose-dependent manner. Aurora A gene silencing suppressed cell proliferation and enhanced ABL TKI efficacy. In a mouse xenograft model, co-administration of ponatinib and alisertib enhanced survival and reduced tumor size moreover, the treatments were well tolerated by the animals. These results indicate that inhibiting Aurora kinase can enhance the cytotoxic effects of ABL TKIs and is, therefore, an effective therapeutic strategy against ABL TKI-resistant cells, including those with the T315I mutation.

Economic Burden of Veno-occlusive Disease in Patients With B-cell Acute Lymphoblastic Leukemia in the United States.

The goal of this study was to evaluate the incidence, inpatient mortality, and economic burden of hepatic veno-occlusive disease (VOD) in adults with B-cell acute lymphoblastic leukemia (ALL) in the United States. Using MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database, data for patients with B-cell ALL from April 1, 2009, to October 31, 2016, were extracted by using diagnosis codes. VOD was identified based on clinical criteria and expert opinions. Patients with VOD were followed up from diagnosis of VOD until the earliest occurrence of inpatient death, end of continuous enrollment, end of study period, or for a maximum of 100days. The incidence of VOD and VOD-associated inpatient mortality were calculated. VOD-related health care costs based on paid adjudicated claims were calculated. Of the 2571 adults with B-cell ALL, the overall incidence of VOD was low at 3.4% (88 of 2571). Of these patients with VOD, 52% (46 of 88) experienced multiorgan failure and were identified as having severe VOD. VOD was only identified in patients having undergone hematopoietic stem cell transplantation (5.4% 88 of 1624). The inpatient mortality rate of those with any VOD over the 100-day postindex period was 26.1%, and the inpatient mortality was even higher for patients with severe VOD (37.0%). Total mean (SD) medical costs per patient during the 100 days post-VOD diagnosis were $55,975 ($160,335) mean (SD) costs per patient were ∼4-fold higher for severe ($86,953 $206,906) versus nonsevere ($22,047 $72,847) VOD. Clinical criteria were used to identify VOD events and thus VOD might be underdiagnosed. The mortality of VOD also might be underestimated because only inpatient deaths are captured in the data. The incidence and mortality of VOD could also be underestimated because we focused on adult patients who might receive reduced-intensity treatment. The economic burden of VOD may be underestimated because the Healthcare Common Procedure Coding System code specific for defibrotide was not available, and thus the cost for defibrotide might not be included. Finally, as the study population consisted of patients with commercial or Medicare supplemental insurance, results may not be generalizable to all patients with VOD in the United States. Although VOD occurred infrequently in adults with B-cell ALL, it was associated with high inpatient mortality and substantial costs. Patients with severe VOD were associated with highest mortality and highest costs. Given the clinical and economic burden associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.

Differential Co-expression and Regulatory Network Analysis Uncover the Relapse Factor and Mechanism of T Cell Acute Leukemia.

The pediatric T cell acute lymphoblastic leukemia (T-ALL) still remains a cancer with worst prognosis for high recurrence. Massive studies were conducted for the leukemia relapse based on diagnosis and relapse paired samples. However, the initially diagnostic samples may contain the relapse information and mechanism, which were rarely studied. In this study, we collected mRNA and microRNA (miRNA) data from initially diagnosed pediatric T-ALL samples with their relapse or remission status after treatment. Integrated differential co-expression and miRNA-transcription factor (TF)-gene regulatory network analyses were used to reveal the possible relapse mechanisms for pediatric T-ALL. We detected miR-12461248 and NOTCH2 served as key nodes in the relapse network, and they combined with TF WT1SOX4REL to form regulatory modules that influence the progress of T-ALL. A regulatory loop miR-429-MYCN-MFHAS1 was found potentially associated with the remission of T-ALL. Furthermore, we proved miR-12461248 combined with NOTCH2 could promote cell proliferation in the T-ALL cell line by experiments. Meanwhile, analysis based on the miRNA-drug relationships demonstrated that drugs 5-fluorouracil, ascorbate, and trastuzumab targeting miR-1246 could serve as potential supplements for the standard therapy. In conclusion, our findings revealed the potential molecular mechanisms of T-ALL relapse by the combination of co-expression and regulatory network, and they provide preliminary clues for precise treatment of T-ALL patients.

Selective reduction in glutaminase activity of l‑Asparaginase by asparagine 248 to serine mutation A combined computational and experimental effort in blood cancer treatment.

Type II l‑asparaginase (l‑ASNase) is an FDA approved enzyme drug with extensive applications for treatment of certain blood cancers. However, the therapeutic efficiency of this enzyme is hampered by its undesirable glutaminase activity. Given the pivotal role of this enzyme against cancer, designing engineered mutants with diminished glutaminase activity would be of great therapeutic interest. To this end, N248S mutation was selected as the potential mutation with beneficial effects. Various in silico analyses including MD simulation, molecular docking and QMMM studies were performed to assess the effects of N248S mutation on the activity of the enzyme. Thereafter, this mutation along with N248A, N248V and N248T mutations as controls were exerted in l‑ASNase gene. The results from in silico analyses and experimental efforts indicated that N248S mutation is associated with the suitable l‑ASNase activity, while the glutaminase activity is disturbed due to impaired interactions. It has been shown that glutamine turnover was affected much more strongly than asparagine hydrolysis. The approach of exploiting in silico tools to design mutated enzymes lead to staggering time and cost reduction. Following this strategy, we have designed a mutant l‑ASNase with diminished glutaminase activity, which could be of interest for improved biomedical applications.

Cancer-related effects on relationships, long-term psychological status and relationship satisfaction in couples whose child was treated for leukemia A PETALE study.

Follow-up studies suggest that the psychosocial impact of pediatric cancer on parents often extends beyond the end of their childs cancer treatments, and parents can continue to experience both individual and relationship effects. In a long-term study of parents of children who were treated for acute lymphoblastic leukemia (ALL), we aimed to 1) describe parents adjustment (psychological distress, relationship satisfaction 2) describe the perceived impact of cancer on couples relationship, and 3) identify to what extent the perceived impact of cancer on the couple is related to both parents long-term adjustment. Parents of childhood ALL survivors (n 103 couples) were surveyed as part of a cohort recall (PETALE cohort). Both parents completed questionnaires exploring adjustment (Brief Symptom Inventory-18, Dyadic Adjustment Scale) and perceived impact of cancer on the relationship (Impact of Cancer on the Couple). Mothers and fathers scores were compared using MANOVAs. We also examined the degree to which a parents perceived changes in relationship dynamics following their childs cancer were associated with their own current adjustment (actor effects), and their partners current adjustment (partner effects) using the Actor-Partner Interdependence Model (APIM). Frequencies of current distress were normative in parents (mothersfathers) general distress (6.87.8%), anxiety (5.86.8%), depression (2.96.8%), somatization (13.69.7%), and relationship distress (21.420.4%). Mothers and fathers typically agreed on their reported relationship satisfaction, and the perceived nature of relationship changes following the illness. Dyadic analyses indicated that whereas mothers adjustment was related to their own perceived relationship changes, fathers adjustment was primarily related to their partners perceptions. In long-term stable couples, mothers may act as an influential bridge connecting the illness experiences of survivors and fathers. This could explain why mothers perceptions of relationship changes were related to their partners long-term adjustment, which was not the case for fathers.

Maternal Red Blood Cell Folate and Infant Vitamin B

Inadequate maternal folate intake is associated with increased childhood acute lymphoblastic leukemia (ALL) risk. Folate provides methyl groups for DNA methylation, which is dramatically disrupted in ALL. Whether or not maternal folate (and related B-vitamin) intake during pregnancy may affect ALL risk via influencing DNA methylation is investigated. Genes in which methylation changes are reported both in response to folate status and in ALL are investigated. Folate-responsive genes (n 526) are identified from mouse models of maternal folate depletion during pregnancy. Using published data, 2621 genes with persistently altered methylation in ALL are identified. Overall 25 overlapping genes are found, with the same directional methylation change in response to folate depletion and in ALL. Hypermethylation of a subset of genes (ASCL2, KCNA1, SH3GL3, SRD5A2) in ALL is confirmed by measuring 20 patient samples using pyrosequencing. In a nested cohort of cord blood samples (n 148), SH3GL3 methylation is inversely related to maternal RBC folate concentrations (p 0.008). Furthermore, ASCL2 methylation is inversely related to infant vitamin B12 levels. (p 0.016). Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B-vitamins during pregnancy may influence ALL risk.

Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing.

To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia. Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n 237), followed by validation in independent replication group (n 405). Minor alleles of rs2781377SYNE2 (p 0.01) and rs10513762MRPL47 (p 0.01) showed increased risk, whereas that of rs3803357BAHD1 had a protective effect (p 0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p 0.003). The addition of rs1135989ACTG1 further enhanced model performance (p 0.0001). Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsedrefractory (rr) B-cell acute lymphoblastic leukemia (B-ALL). We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN). Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders ( Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.

Prognostic implications of additional genomic lesions in adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

To shed light onto the molecular basis of Philadelphia chromosome-positive acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia carry an average of 7.8 lesionscase, with deletions outnumbering gains (88%

Analysis of Mesenchymal Stromal Cell Engraftment After Allogeneic HSCT in Pediatric Patients A Large Multicenter Study.

The mesenchymal stem cell (MSC) role after allogeneic hematopoietic stem cell transplantation (HSCT) is still a matter of debate in particular, MSC engraftment in recipient bone marrow (BM) is unclear. A total of 46 patients were analyzed for MSC and hemopoietic stem cell engraftment after HSCT. The majority of patients had the BM as the stem cell source, and acute leukemia was the main indication for HSCT. Mesenchymal and hematopoietic stem cell chimerism analysis was carried out through specific polymorphic tandemly repeated regions. All patients reached complete donor engraftment no evidence of donor-derived MSC engraftment was noted. Our data indicate that MSCs after HSCT remain of recipient origin despite the following (i) myeloablative conditioning (ii) the stem cell source (iii) the interval from HSCT to BM analysis (iv) the underlying disease before HSCT and (v) the patients or the donors age at HSCT.

Clinicopathologic and genetic spectrum of infantile B-lymphoblastic leukemia a multi-institutional study.

Acute lymphoblastic leukemia (ALL) in infants <1-year-old is biologically different from ALL in older children. Although KMT2A rearrangement is the predominant genetic signature in infantile B-ALL, disease course is heterogenous, behaving more aggressively in younger infants. We investigated clinicopathological differences throughout the first year to understand the transition to pediatric B-ALL. In a multi-institutional review involving four medical institutions, 54 cases of infantile B-ALL were identified. Patients were divided into congenital and non-congenital groups with multiple age subgroups. Male predominance was seen in congenital cases compared to female in non-congenital cases. There were decreasing trends of hyperleukocytosis, central nervous system involvement, KMT2A rearrangements, lineage switch, and mortality, versus increasing trends of CD10 expression and non-KMT2A abnormalities. Statistically significant differences emerged at 3 and 9 months, the latter was not previously described. Poor-prognostic risk factors decreased with age, the last trimester of infantile B-ALL essentially merging with pediatric B-ALL.

Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia.

Autologous CD19 chimeric-antigen receptor (CAR) T cells demonstrated remarkable remission rates in relapsed and refractory acute lymphoblastic leukemia (RR ALL). Here, we report results from a phase 1b2 study of in-house produced CD19 CAR with a CD28 costimulatory domain. Twenty-one patients with RR ALL were enrolled, and 20 infused. The median age was 11 years (range, 5-48). Patients had a median of 4 prior regimens, including blinatumomab in 6 and prior stem-cell transplantation in 10. In total 8 patients had extramedullary (EM) leukemic involvement, and prior to lymphodepletion and CAR 7 had active lesions, a group underrepresented in previous trials. In vivo expansion of CAR T cells was observed in 18 patients. In total 16 patients developed cytokine release syndrome, and 11 patients developed neurotoxicity, with no toxic deaths. All responding patients were referred to an allogeneic hematopoietic stem-cell transplantation. The remission rate was 90%, including resolution of all refractory EM sites. Four responding patients relapsed, 3 who had a PCR-MRD positive remission at 28 days following CAR-T cells and 1 patient 21 months after an MRD-negative response. The estimated 1-year event-free survival and overall survival are 73% and 90%, respectively. Patients with RR EM ALL may also benefit from CAR-T cell therapy.

Sanguinarine suppresses growth and induces apoptosis in childhood acute lymphoblastic leukemia.

Sanguinarine (Sang), a plant-derived compound isolated from the roots of Sanguinaria canadensis was evaluated for its potential pro-apoptotic effects in precursor B acute lymphoblastic leukemia (Pre-ALL) cell lines. Treatment of 697, REH, RS411, and SupB15 cell lines with Sang exhibited significant inhibition of cell viability via induction of apoptotic cell death. Sang-mediated apoptosis was found to be associated with the increased expression of proapoptotic bax with concomitant decrease of Bcl-2 expression leading to depolarization of mitochondria membrane resulting in loss of mitochondrial membrane potential (MMP). The reduced MMP caused the leakage in mitochondrial membrane and release of cytochrome c into the cytosol. The cytochrome c then mediates the activation of caspase-cascade and subsequently PARP cleavage. Furthermore, pretreatment with z-VAD-FMK, a pan-caspase inhibitor, abrogated Sang-induced inhibition of cell viability, induction of apoptosis. Sang treatment also reduced the phosphorylation of AKT and suppressed the expression of a number of anti-apoptotic genes such as cIAP1, cIAP2, and XIAP. Sang mediates its anti-cancer activity by generation of reactive oxygen species (ROS) due to depletion of glutathione level in leukemic cell lines. Pretreatment of these cells with N-acetyl cysteine (NAC) prevented Sang-induced depletion of glutathione level and mitochondrial-caspase-induced apoptosis. Finally, Sang treatment of Pre-ALL cell suppressed colony formation ability of these cells suggesting Sang has an anti-leukemic potential. Altogether, our data suggest that Sang is an efficient inducer of intrinsic apoptotic cell death via generation of ROS and exhibition of anti-leukemic effect in Pre-ALL cells raises the possibility to develop Sang as a therapeutic modality for the treatment and management of Pre-ALL.

Thymus autonomy as a prelude to leukemia.

Cell competition in the thymus promotes turnover and functions as a tumor suppressor by inhibiting leukemia. Using thymus transplantation experiments, we have shown that the presence of T lymphocyte precursors, recently seeding the thymus, promotes the clearance of precursors with a longer time of thymus residency. If cell competition is impaired and no cells seed the thymus, the organ is capable of sustaining T lymphocyte production, a state termed thymus autonomy. However, we observed consistently that prolonged autonomy is permissive to the emergence of T cell acute lymphoblastic leukemia (T-ALL). This resembled the onset of T-ALL in patients treated by gene therapy for X-linked severe combined immunodeficiency (SCID-X1). Following treatment, thymus activity was established, with T lymphocyte production, although no bone marrow contribution was detected. However, some patients developed T-ALL. The favored explanation for malignant transformation was considered to be genotoxicity due to integration of the retroviral vector next to oncogenes, thereby activating them ectopically. Although plausible, we consider an alternative, mutually nonexclusive explanation that any condition enabling prolonged thymus autonomy will promote leukemogenesis. In support of this view, two independent studies have recently shown that the efficacy of reconstitution of the bone marrow in the context of SCID-X1 dramatically influences the outcome of treatment, and that lymphoid malignancies emerge following transplantation of a small number of healthy progenitors. Here, we discuss the most recent data in light of our own studies in thymopoiesis and the conditions that trigger malignant transformation of thymocytes in various experimental and clinical settings.

STAT5 is essential for IL-7-mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells.

T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinaseprotein kinase Bmechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7-mediated T-ALL cell viability, growth, and proliferation. At the molecular level, STAT5 is required for IL-7-induced downregulation of p27

A novel role for

Stem cell leukemia (

Rare diseases mortality in Colombia, 2008-2013.

Introduction Rare diseases are characterized by their low prevalence, often of genetic origin, degenerative and life threatening. Objective To describe mortality by orphan diseases and to analyze its trends in Colombia from 2008 to 2013. Materials and methods We conducted a descriptive study to analyze mortality rate trends from the death certificates between 2008 and 2013. We calculated specific mortality rates and adjusted by age and sex. Results Seven thousand one hundred and thirty five deaths were attributed to orphan diseases, and 51.4 % of them occurred among men of all ages. The mean mortality rate during the study period was 2.53 deaths per 100,000 people. Overall, the trend showed an increasing pattern of mortality although very heterogeneous across the country. Mortality rates were higher in Bogotá (20), and the Andes and the Caribbean regions (5.3 and 3.7 deaths per 100,000 population). The five most important causes of mortality among men were acute lymphoblastic leukemia, muscular dystrophy, bronchopulmonary dysplasia originating in the perinatal period, multiple sclerosis, Guillain-Barré syndrome and gastroschisis, and among women multiple sclerosis, acute lymphoblastic leukemia, gastroschisis, bronchopulmonary dysplasia originating in the perinatal period, Guillain-Barré syndrome and acute myeloid leukemia. The mean mortality rate by acute lymphoblastic leukemia was 0.17 deaths per 100,000 men younger than 15 years and that of multiple sclerosis was 0.16 in women over 40 years of age. Conclusion The causes of death showed a similar pattern in both sexes. However, the burden of mortality was higher among men of all ages in Bogota.

Characteristics of acute lymphoblastic leukemia and febrile neutropenia in children and adolescents cared for in a hospital in Guayaquil, Ecuador.

With the objective of performing a clinical characterization of children and adolescents with acute lymphoblastic leukemia and febrile neutropenia in a hospital in Ecuador, a case series study was carried out, which involved reviewing the clinical records of patients receiving care at Hospital de la Sociedad de Lucha Contra el Cancer in Guayaquil between January 2014 and April 2016. Out of the 101 patients, 51.5% were female mean age was 5.5±2.1 years old 72.3% were at high risk for invasive bacterial infection the most common infections were respiratory with 47.5% 18.8% of bacteria isolated in blood cultures were Gram-positive. Finally, 25.7% of patients died, with chemotherapy resistance as one of the associated factors. Con el objetivo de caracterizar clínicamente a los niños y adolescentes con leucemia linfoblástica aguda y neutropenia febril en un hospital de Ecuador se realizó un estudio de serie de casos revisando historias clínicas de pacientes atendidos en el Hospital de la Sociedad de Lucha Contra el Cáncer de la ciudad de Guayaquil durante enero 2014 y abril 2016. De los 101 pacientes 51,5% eran mujeres, la edad promedio fue 5,5±2,1 años, el 72,3% tenían riesgo alto de infección bacteriana invasora, el foco de origen infeccioso más frecuente fue el respiratorio con 47,5%, el 18,8% de los microorganismos aislados en hemocultivos fueron Gram-positivos. El 25,7% de los pacientes fallecieron, siendo la refractariedad a la quimioterapia uno de los factores asociados (p<0,001). En conclusión, la mortalidad en niños y adolescentes, con leucemia linfoblástica aguda y neutropenia febril fue elevada siendo la refractariedad a la quimioterapia uno de los principales factores asociados.

End-of-Life Care Intensity in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation A Population-Level Analysis.

Intensity of end-of-life care receives much attention in oncology because of concerns that high-intensity care is inconsistent with patient goals, leads to worse caregiver outcomes, and is expensive. Little is known about such care in those undergoing allogeneic hematopoietic cell transplantation (HCT), a population at high risk for morbidity and mortality. We conducted a population-based analysis of patients who died between 2000 and 2013, within 1 year of undergoing an inpatient allogeneic HCT using California administrative data. Previously validated markers of intensity were examined and included hospital death, intensive care unit (ICU) admission, and procedures such as intubation and cardiopulmonary resuscitation at end of life. Multivariable logistic regression models determined clinical and sociodemographic factors associated with hospital death, a medically intense intervention (ICU admission, cardiopulmonary resuscitation, hemodialysis, intubation), and ≥ two intensity markers. Of the 2,135 patients in the study population, 377 were pediatric patients (age ≤ 21 years), 461 were young adults (age 22 to 39 years), and 1,297 were adults (age ≥ 40 years). The most common intensity markers were hospital death (83%), ICU admission (49%), and intubation (45%). Medical intensity varied according to age, underlying diagnosis, and presence of comorbidities at time of HCT. Patients with higher-intensity end-of-life care included patients age 15 to 21 years and 30 to 59 years, patients with acute lymphoblastic leukemia, and those with comorbidities at time of HCT. Patients dying within 1 year of inpatient allogeneic HCT are receiving medically intense end-of-life care with variations related to age, underlying diagnosis, and presence of comorbidities at time of HCT. Future studies need to determine if these patterns are consistent with patient and family goals.

Osteonecrosis in children with acute lymphoblastic leukemia A report from Childrens Cancer Hospital Egypt (CCHE).

As survival rates for children with acute lymphoblastic leukemia (ALL) improve, awareness of treatment complications becomes important. Osteonecrosis (ON) is a serious disabling complication in treated ALL patients. The aim of the study was to define the frequency of ON identified by magnetic resonance imaging (MRI) and to study the risk factors for ON. The frequency of ON was evaluated retrospectively in 858 patients with ALL who were diagnosed at Childrens Cancer Hospital of Egypt from January 2009 to December 2012. Patients were treated with St Jude Total Therapy Study XV. Of 858 patients evaluated, 665 were eligible for the study and 65 (9.7%) developed ON. The cumulative 5-year incidence of ON was 11.96% (SE, 0.131%). Of 154 patients aged 10 years and older, 40 (26%) developed ON. The mean age of patients with ON was 10.7 years. The prognostic factors with a significant relationship with ON were age 10 years and older (P 0.0001) and intermediate-high-risk group (P 0.0001). However, gender did not have a significant relationship. At the onset of ON, the mean cumulative dexamethasone dose was 796 mgm The frequency of ON among the studied patients was 9.7%. Risk factors with a significant association with ON were older age and more intensive corticosteroid therapy.

The biological basis and clinical symptoms of CAR-T therapy-associated toxicites.

Currently, immunotherapy is attracting a lot of attention and may potentially become a leading approach in the treatment of cancer. One emerging therapeutic, the chimeric-antigen receptor T-cell adoptive immunotherapy (CAR-T) is showing remarkable efficacy in the treatment of several B-cell malignancies. The popularity of CAR-T has been founded on two CAR T-cell products recently approved by FDA (during 2017) in the treatment of relapsedrefractory B-cell acute lymphoblastic leukemia and B-cell lymphoma. However, their toxicities observed in clinical trials were extremely significant and in some cases even fatal with no approved algorithms for toxicity prediction being available to date. A deeper understanding of the biological basis of such complications is the key to prompt and comprehensive clinical management. Here we review the wide spectrum of effects associated with CAR T cell therapy with a major focus on the pathogenesis of cytokine release syndrome and neurotoxicity as the most common, potentially life-threatening effects of this treatment. We discuss the basis of clinical management and the existing models that predict the severity of toxicity, as well as the key factors that modulate this event. Finally, we will summarize the literature detailing universal allogenic CAR T-cells and their toxicity profile.

High-grade B-cell lymphomas with TdT expression a diagnostic and classification dilemma.

Mature B-cell neoplasms and immature or precursor B-cell neoplasms need to be distinguished because these patients usually require different therapeutic approaches. B-cell neoplasms that express TdT without unequivocal other features of immaturity may therefore present a diagnostic challenge. We describe 13 patients with TdT-positive aggressive B-cell lymphoma. The clinicopathologic features of these patients were highly heterogeneous, but for the purpose of this study we grouped these cases as follows (1) de novo high-grade B-cell lymphoma with MYC, BCL2, andor BCL6 rearrangements (double-hit or triple-hit lymphoma) with TdT expression. In this group we included two cases of de novo composite lymphoma in which there were components of diffuse large B-cell lymphoma and TdT-positive blastic B-cell lymphoma (2) TdT-positive aggressive B-cell lymphoma arising in patients who previously had follicular lymphoma (3) initial relapse of TdT-negative aggressive B-cell lymphoma in patients who previously had follicular lymphoma, followed by relapses in which the neoplasm acquired TdT expression and (4) mature B-cell lymphomas that acquired TdT expression at relapse. This group included one case of EBV-positive diffuse large B-cell lymphoma and one case of pleomorphic variant mantle cell lymphoma. All patients in this study had an aggressive clinical course and a dismal outcome despite appropriate therapy. Rather than squeezing these cases into current World Health Organization classification categories, we suggest the use of a descriptive term such as high-grade B-cell lymphoma with TdT expression. In these tumors, the cytogenetic findings and poor prognosis of this patient subgroup suggest that these neoplasms need to be distinguished from B-lymphoblastic leukemialymphoma. Segregation of these neoplasms also may foster additional research on these neoplasms.

Chimeric Antigen Receptor T-Cell Therapy.

Patients with relapsed or refractory (RR) cancers have a poor prognosis and limited treatment options. The recent approval of 2 chimeric antigen receptor (CAR) autologous T-cell products for RR B-cell acute lymphoblastic leukemia and non-Hodgkins lymphoma treatment is setting the stage for what is possible in other diseases. However, there are important factors that must be considered, including patient selection, toxicity management, and costs associated with CAR T-cell therapy. To begin to address these issues, NCCN organized a task force consisting of a multidisciplinary panel of experts in oncology, cancer center administration, and health policy, which met for the first time in March 2018. This report describes the current state of CAR T-cell therapy and future strategies that should be considered as the application of this novel immunotherapy expands and evolves.

Genomic Landscape of Adult and Pediatric

BCR-ABL1-like B-Acute Lymphoblastic Leukemia (B-ALL) is a subset of B-ALL with a poor prognosis that is found in all age groups. Definitive identification of these patients is difficult in routine clinical practice as gene expression profiling, the gold standard test, is not widely available. Comprehensive genomic profiling performed on 450 patients with extensive fusion profiling revealed a wide range of genomic alterations which were consistent with a classification of BCR-ABL1-like B-ALL in 29% of cases. This manuscript highlights a clinically available alternative method for identifying a large subset of patients with BCR-ABL1-like B-ALL.

Genetic Mutations in B-Acute Lymphoblastic Leukemia Among African American and European American Children.

The survival of patients with B-acute lymphoblastic leukemia (B-ALL) is significantly lower in African American (AA) children compared with European American children (EA). Here, we present a whole exome sequencing (WES) study showing race-specific genetic variations that may play a role on the disparate outcomes among AA and EA children with B-ALL. Five AA and 15 EA patients ranging in age from 1 to 18 years were enrolled. The median blast percentage was 94.8% (range, 64.5%-99.9%). Frozen bone marrow aspirate was used to extract DNA, and WES was performed, focusing on race and B-ALL-specific germline mutations. Most genetic variants (n 339) were shared between AA and EA children. Some genetic aberrations were only uniquely identified in AA (n 58) and others in EA (n 52) In AA, the genetic aberrations clustered in canonical pathways related to telomerase signaling and cancer signaling. In EA, the unique genetic aberration clustered in pathways related to stem cell pluripotency and hereditary cancer. Our study revealed aberrant genetic aberrations in signaling networks that may contribute to race-specific aspects of leukemogenesis. Our results suggest the value of WES as a tool for development of individual gene signatures and gene scores for AA and EA children afflicted by B-ALL. These findings may ultimately impact disease management and contribute to the elimination of disparate outcomes in AA children with B-ALL.

Comparison of efficacy of first-line administration of generic dasatinib or imatinib in patients with Philadelphia chromosome positive acute lymphoblastic leukemia treated by hematopoietic stem cell transplantation.

Management of toxicities associated with pegaspargase in treatment of patients with lymphoid malignancy experience from 443 cases in a single center.

Treatment of central nervous system leukemia with CD19-chimeric antigen receptor T-cell immunotherapy two cases report and literature review.

Intravitreal Methotrexate for Iris and Ciliary Body Relapse in Acute Lymphoblastic Leukemia.

The authors report a rare unilateral iris and ciliary body relapse in acute lymphoblastic leukemia. Ophthalmologic examination showed reduced visual acuity, pseudohypopyon, and iris irregularity. Ultrasound biomicroscopy and aqueous humor cytology confirmed leukemic infiltration. Lesions were treated with intravitreal methotrexate, which has not been described previously for acute lymphoblastic leukemia. J Pediatr Ophthalmol Strabismus. 201855e16-e19..

Lactic Acidosis in a Critically Ill Patient Not Always Sepsis.

Lactic acidosis in the emergency department and other hospital settings is typically due to tissue hypoxia with sepsis being the most common cause. However, in patients with persistently elevated lactate without evidence of inadequate oxygen delivery, type B lactic acidosis should be considered. We report the case of a 12-year-old boy with relapsed and refractory pre-B-cell acute lymphoblastic leukemia who presented in distress with tachycardia, history of fever, and diffuse abdominal tenderness. The patient had severe metabolic acidosis with elevated lactate upon arrival to the emergency department. Despite aggressive fluid resuscitation and intravenous antibiotics, the patients acidosis worsened. Serial blood cultures were negative, and he was eventually diagnosed with type B lactic acidosis secondary to relapsed acute lymphoblastic leukemia.

Successful pregnancies in patients with BCR-ABL-positive leukemias treated with interferon-alpha therapy during the tyrosine kinase inhibitors era.

Management of pregnant patients with BCR-ABL-positive leukemia is challenging. Managing a patient who has been diagnosed while pregnant requires a different approach as compared to a patient who plans to become pregnant while on the treatment with tyrosine kinase inhibitor (TKI). Interferon (IFN)-alpha is a useful option in both situations due to teratogenic potential of TKIs. We presented a series of 12 successful pregnancies in 11 women with BCR-ABL-positive leukemia, whose leukemia was managed with IFN-alpha throughout their pregnancy. All children have normal growth and development. All patients remained at least in hematological response and could start or resume TKI after delivery or breastfeeding. Because of the increased risk of teratogenicity and spontaneous abortion in female patient with pregnancy, when receiving TKI, IFN-alpha can be considered a safe drug to be administered throughout pregnancy and could represent the drug of choice in this situation during the era of TKI therapy.

A successful multidisciplinary approach for treatment and for preserving the reproductive potential in a rare case of acute lymphocytic leukemia during pregnancy.

Leukemia in pregnancy is a rare condition with the prevalence of 1 in 75,000-100,000 pregnancies. In this case report, we present a successful multidisciplinary management strategy for treatment and for preserving the reproductive potential in a rare case of acute lymphocytic leukemia (ALL) during pregnancy. Several complex challenges existed and necessitated a multidisciplinary approach with strong coordination and collaboration between oncologists, gynecologists, reproductive cryobiologists, obstetricians, and neonatologists in order to improve the maternal and fetal outcome. Pregnancy in the second trimester is neither a contraindication for ALL treatment nor for emergency fertility preservation via ovarian tissue extraction and further cryopreservation.

BCL6 promotes the methotrexate-resistance by upregulating ZEB1 expression in children with acute B lymphocytic leukemia.

To investigate the effect of BCL6 on methotrexate-resistant children with acute B lymphoblastic leukemia (B-ALL) and its underlying mechanism. Bone marrow samples of B-ALL children diagnosed at The Children Womens Healthcare of Laiwu City from June 2014 to February 2017 were collected. Subjects were assigned into methotrexate-resistant group (n8) and non-resistant group (n32) according to the follow-up outcome. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was performed to detect expressions of BCL6 and E-cadherin in bone marrow tissues. Cell cycle and apoptosis of methotrexate-resistant B-ALL cells (BALL-1MTXR cells) were detected after overexpression or inhibition of BCL6, respectively. Western blot was performed to determine the protein levels of E-cadherin and BCL6. The direct binding of BCL6 in the ZEB1 promoter region was verified by the ChIP (chromatin immunoprecipitation) assay. QRT-PCR showed a higher BCL6 expression in bone marrow samples of methotrexate-resistant group than that of the non-resistant group. Moreover, BCL6 was upregulated in BALL-1MTXR cells than that of untreated B-ALL cells. After knockdown of BCL6 expression, we observed a decreased IC50, increased apoptosis, and arrested the cell cycle in BALL-1MTXR cells. In addition, increased expression of E-cadherin was found in BALL-1MTXR cells, which could be reversed by ZEB1 overexpression. ChIP assay suggested that BCL6 bound to the promoter region of ZEB1, so as to promote ZEB1 expression. BCL6 is overexpressed in the bone marrow of methotrexate-resistant children with B-ALL, which is capable of attenuating the sensitivity of B-ALL to methotrexate via promoting ZEB1 expression.

Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene.

In acute lymphoblastic leukemia (ALL), high ABCB1 gene expression has been associated with treatment resistance, which affects patient prognosis. Many preclinical reports and retrospective population studies have shown an anti-cancer effect of metformin. Therefore, the objective of this study was to assess the effect of metformin on the treatment regimen in patients with ALL who exhibited high levels of ABCB1 gene expression and to determine its impact on overall survival. A total of 102 patients with ALL were recruited one group (n 26) received metformin, and the other received chemotherapy (n 76). Measurement of ABCB1 transcript expression was performed using qRT-PCR prior to treatment initiation. Survival analysis was performed using Kaplan-Meier curves. The impact of both the type of treatment and the level of expression on the response (remission or relapse) was analyzed by calculating the odds ratio. The survival of patients with high ABCB1 expression was lower than those with low or absent ABCB1 gene expression (p 0.030). In the individual analysis, we identified a benefit to adding metformin in the group of patients with high ABCB1 gene expression (p 0.025). In the metformin user group, the drug acted as a protective factor against both therapeutic failure (odds ratio OR 0.07, 95% confidence interval CI 0.0037-1.53) and early relapse (OR 0.05, 95% CI 0.0028-1.153). The combined use of metformin with chemotherapy is effective in patients with elevated levels of ABCB1 gene expression. Trial registration NCT 03118128 NCT.

Total-body irradiation using linac-based volumetric modulated arc therapy Its clinical accuracy, feasibility and reliability.

To report the feasibility, accuracy, and reliability of volumetric modulated arc therapy (VMAT)-based total-body irradiation (TBI) treatment in patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). From 2015 to 2018, 30 patients with AML or ALL were planned and treated with VMAT-based TBI, which consisted of three isocenters and three overlapping arcs. TBI dose was prescribed to 90% of the planning treatment volume (PTV) receiving 12 Gy in six fractions, at two fractions per day. Mean lung and kidney doses were restricted less than 10 Gy, and maximum lens dose less than 6 Gy. Quality assurance (QA) comprised the verification of the irradiation plans via dose-volume histogram (DVH) based 3D patient QA system. Average mean lung dose was 9.7 ± 0.2 Gy, mean kidney dose 9.6 ± 0.2 Gy, maximum lens dose 4.5 ± 0.4 Gy, mean PTV dose 12.7 ± 0.1 Gy, and heterogeneity index of PTV was 1.16 ± 0.02 in all patients. Grade 3 or more acute radiation toxicity was not observed. When comparing plan and DVH-based 3D patient QA results, average differences of 3.3% ± 1.3 in mean kidney doses, 1.1% ± 0.7 in mean lung doses, and 0.9% ± 0.4 in mean target doses were observed. Linac-based VMAT increased the dose homogeneity of TBI treatment more than extended SSD techniques. Partial cone-beam CT and optical surface-guided system assure patient positioning. DVH-based 3D patient dose verification QA was possible with linac-based VMAT showing small differences between planned and delivered doses. It is feasible, accurate, and reliable.

An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia.

NSD2, a histone methyltransferase specific for methylation of histone 3 lysine 36 (H3K36), exhibits a glutamic acid to lysine mutation at residue 1099 (E1099K) in childhood acute lymphocytic leukemia (ALL), and cells harboring this mutation can become the predominant clone in relapsing disease. We studied the effects of this mutant enzyme in silico, in vitro, and in vivo using gene edited cell lines. The E1099K mutation altered enzymesubstrate binding and enhanced the rate of H3K36 methylation. As a result, cell lines harboring E1099K exhibit increased H3K36 dimethylation and reduced H3K27 trimethylation, particularly on nucleosomes containing histone H3.1. Mutant NSD2 cells exhibit reduced apoptosis and enhanced proliferation, clonogenicity, adhesion, and migration. In mouse xenografts, mutant NSD2 cells are more lethal and brain invasive than wildtype cells. Transcriptional profiling demonstrates that mutant NSD2 aberrantly activates factors commonly associated with neural and stromal lineages in addition to signaling and adhesion genes. Identification of these pathways provides new avenues for therapeutic interventions in NSD2 dysregulated malignancies.

Clinical and molecular characteristics of

Fusion genes involving

The telomerase inhibitor MST-312 synergistically enhances the apoptotic effect of doxorubicin in pre-B acute lymphoblastic leukemia cells.

There have been consistent efforts in concomitant administration of chemotherapeutic agents such as doxorubicin beside other more tumor-specific drugs in order to increase sensitivity of tumor cells to the cytotoxicity of doxorubicin and reduce necessary chemotherapeutic dosage. Telomerase-targeted therapy for cancer has received great attention because telomerase is expressed in almost all cancer cells but is inactive in most normal somatic cells. The present study was aimed to investigate the effect of telomerase inhibitor MST-312, a chemically modified derivative of epigallocatechin gallate (EGCG), on doxorubicin-induced apoptosis in pre-B acute lymphoblastic leukemia cells. The pre-B ALL cell lines (NALM-6 and REH) were cultured and treated with MST-312 and doxorubicin, separately and in combination. Cell viability was measured by trypan blue staining and MTT assay. Annexin-V7-AAD staining by flow cytometry was used for evaluation of apoptosis. Gene expression of hTERT, c-Myc, Bax and Bcl-2, was detected by the quantitative Real-Time PCR. Our results showed that MST-312 exerted dose-dependent short-term cytotoxic and apoptotic effects on pre-B ALL cells. Combination of MST-312 and doxorubicin synergistically enhanced the cytotoxicity and apoptosis of both NALM-6 and REH cells. Consistently, apoptosis induction by the combined treatment was associated with significant reduction of Bcl-2, c-Myc and hTERT, and a marked increase of Bax mRNA expression levels, compared with the single treatments. Our data suggest that the synergistic anticancer effect induced by combination of MST-312 and doxorubicin represents a novel treatment strategy for pre-B ALL.

Acute lymphoid leukemia (ALL) is a malignant proliferation of abnormal lymphoid precursors in the bone marrow. It is the most common acute leukemia in childhood, accounting for only 20% of acute leukemia in adults. The clinical presentation is heterogeneous including pallor, fatigue and weakness. Diagnosis is performed through myelogram, bone marrow biopsy and immunophenotyping. Chemotherapy and, in some cases, bone marrow transplantation (BMT) are used to treat the disease. However, the efficacy of treatment in adult patients is still below expected and therapeutic innovations have not increased disease-free survival. In addition, about 20% of patients have relapse, usually generalized, of the disease. This article aims to report the case of a patient previously treated for ALL B presenting localized medullar relapse or

Global efforts toward the cure of childhood acute lymphoblastic leukaemia.

Improvements in risk-directed treatment and supportive care, together with increased reliance on both national and international collaborative studies, have made childhood acute lymphoblastic leukaemia (ALL) one of the most curable human cancers. Next-generation sequencing studies of leukaemia cells and the host germline provide new opportunities for precision medicine and thus potential improvements in the cure rate and quality of life of patients. Efforts are underway to assess the global impact of childhood ALL and develop initiatives that can meet the long-term challenge of providing quality care to children with this disease worldwide and improving cure rates globally. This ambitious task will rely on increased collaborative research and international networking so that the therapeutic gains in high-income countries can be translated to patients in low-income and middle-income countries. Ultimately, the greatest obstacle to overcome will be to fully understand leukaemogenesis, enabling measures to decrease the risk of leukaemia development and thus close the last major gap in offering a cure to any child who might have the disease.

Assessing the feasibility and validity of the Toronto Childhood Cancer Stage Guidelines a population-based registry study.

Cancer stage at diagnosis is crucial for assessing global efforts to increase awareness of childhood cancer and improve outcomes. However, consistent information on childhood cancer stage is absent from population cancer registries worldwide. The Toronto Childhood Cancer Stage Guidelines, compiled through an international consensus process, were designed to provide a standard framework for collection of information on stage at diagnosis of childhood cancers. We aimed to assess the feasibility of implementing the Toronto Guidelines within a national population cancer registry. We did a population-based registry study using data from the Australian Childhood Cancer Registry and included data from children aged 0-14 years diagnosed between Jan 1, 2006, and Dec 31, 2010 with one of 16 childhood cancers listed in the Toronto Guidelines (acute lymphoblastic leukaemia, acute myeloid leukaemia, Hodgkins lymphoma, non-Hodgkin lymphoma, neuroblastoma, Wilms tumour, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, Ewings sarcoma, retinoblastoma, hepatoblastoma, testicular cancer, ovarian cancer, medulloblastoma, and ependymoma). We extracted data from medical records, and assigned stage according to the Tier 1 criteria (basic) and Tier 2 criteria (more detailed, requiring data from cytology, imaging, and other diagnostic tests, where available) using computer algorithms derived from the Toronto Guidelines. Additionally, expert reviewers independently assigned Tier 2 stage to a random subsample of 160 cases (ten per malignancy type). Feasibility of the guidelines was assessed on the percentage of cases that could be staged, agreement between stage assigned by the algorithms and the expert reviewers, and the mean time (min) taken to collect the required data. We obtained data for 1412 eligible children. Stage could be assigned according to Tier 2 criteria for 1318 (93%) cases, ranging from 48 (84%) of 57 cases of non-rhabdomyosarcoma soft tissue sarcoma to 46 (100%) cases of hepatoblastoma. According to Tier 1 criteria, stage could be assigned for 1329 (94%) cases, ranging from 131 (87%) of 151 cases of acute myeloid leukaemia to 46 (100%) cases of hepatoblastoma. By contrast, stage at diagnosis was recorded by the treating physician for 555 (39%) of the 1412 cases. The computer algorithm assigned the same stage as did one or more independent expert reviewers in 155 (97%) of the 160 cases assessed. The mean time taken to review medical records and extract the required data was 18·0 min (SD 9·5 per case). The Toronto Guidelines provide a highly functional framework that can be used to assign cancer stage at diagnosis using data routinely available in medical records for most childhood cancers. Data on staging have the potential to inform interventions targeting improved diagnosis and survival. Cancer Australia.

Clinical and clinicopathological characteristics of acute lymphoblastic leukaemia in six cats.

To investigate the clinical characteristics of feline acute lymphoblastic leukaemia patients diagnosed according to the recent diagnostic criteria for the equivalent canine condition. The medical records of six cats diagnosed with acute lymphoblastic leukaemia were retrospectively reviewed to extract data on clinicopathological characteristics and outcomes. The lymphoid origin of the tumour cells was confirmed by polymerase chain reaction for antigen receptor gene rearrangement, flow cytometry or immunohistochemistry. Non-specific clinical signs such as lethargy and anorexia were common, and anaemia and thrombocytopenia were also commonly identified. Leucocytosis was observed in four cats and leucopenia was observed in two the number of lymphoblasts in the peripheral blood samples varied among the cases. Lymphoblasts originated from B-cell lineage in four cats and T-cell lineage in one, and those of another cat were positive for both B-cell marker CD21 and T-cell marker CD8. Five of the six cats were treated with cytotoxic chemotherapy, and a partial response was obtained in two. The median overall survival was 55 days (range 1 to 115). Acute lymphoblastic leukaemia should be considered if lymphoblasts are observed in peripheral blood, even if their number is small. The prognosis for cats that have acute lymphoblastic leukaemia is as poor as that for dogs, and further studies are needed to develop effective treatment.

A triple-probe FISH screening strategy for risk-stratified therapy of acute lymphoblastic leukaemia in low-resource settings.

Karyotyping along with a 3-probe fluorescence in situ hybridization (FISH) strategy was used to risk stratify therapy in 303 children with B-cell precursor acute lymphoblastic leukaemia. Of the 166 patients risk stratified, karyotype identified 91 (55%). FISH identified all karyotypes accurately, with the exception of hypodiploidy, and risk stratified an additional 75 patients. The frequency of ETV6-RUNX1 is lower and high hyperdiploidy, higher than reported in the west. An adapted 3-probe FISH strategy identified two patients with ETV6-ABL1 fusion who received imatinib. In limited-resource settings, a 3-probe FISH approach provides a practical approach for risk-stratified therapy in childhood ALL.

Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells.

Pre-leukemic stem cells (pre-LSCs) give rise to leukemic stem cells through acquisition of additional gene mutations and are an important source of relapse following chemotherapy. We postulated that cell-cycle kinetics of pre-LSCs may be an important determinant of clonal evolution and therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia to study cell cycle in vivo, we show that self-renewal, clonal evolution and therapeutic resistance are limited to a rare population of pre-LSCs with restricted cell cycle. We show that proliferative pre-LSCs are unable to return to a cell cycle-restricted state. Cell cycle-restricted pre-LSCs have activation of p53 and its downstream cell-cycle inhibitor p21. Furthermore, absence of p21 leads to proliferation of pre-LSCs, with clonal extinction through loss of asymmetric cell division and terminal differentiation. Thus, inducing proliferation of pre-LSCs represents a promising strategy to increase cure rates for acute leukemia.

Fludarabine, busulfan, and low-dose TBI conditioning versus cyclophosphamide and TBI in allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia.

The optimal conditioning regimen for adults undergoing transplantation for acute lymphoblastic leukemia (ALL) remains undetermined. Cyclophosphamide and total body irradiation (CyTBI) has emerged as a standard myeloablative regimen but is associated with significant toxicity. We compared outcomes between patients undergoing transplant for ALL at centers using CyTBI as standard of care and another center using fludarabine, busulfan, and low-dose TBI (400 cGy) in combination with anti-thymocyte globulin as its standard. Among 146 patients (74 CyTBI and 72 FluBuTBI) there were no significant differences in overall or progression-free survival between groups. Non-relapse mortality was similar (12% vs. 16.7% for CyTBI and FluBuTBI, respectively, p .62) despite the FluBuTBI group having significantly worse performance status. FluBuTBI resulted in significantly lower cumulative incidence of relapse compared with CyTBI (2-year point estimate 18.5% vs. 31.5%, p .05). These results demonstrate similar outcomes for patients receiving FluBuTBI versus CyTBI. FluBuTBI may allow the possibility of providing myeloablative conditioning to patients with poor performance status.

Dysregulated transcriptional networks in

For children and young adults with T-lineage acute lymphoblastic leukemia (T-ALL), event free survival following relapse is < 10%. We recently showed that rearrangements of the mixed lineage leukemia gene (

Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia.

Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear. We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry. The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs. Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.

Disseminated fusariosis with cutaneous involvement in hematologic malignancies report of six cases with high mortality rate.

Fusariosis is due to inhalation or direct contact with conidia. Clinical presentation depends on hosts immunity and can be localized, focally invasive or disseminated. Given the severity of this infection and the possibility for the dermatologist to make an early diagnosis, we report six cases of patients with hematologic malignancies, who developed febrile neutropenia an skin lesions suggestive of cutaneous fusariosis. All patients had skin cultures showing growth of Fusarium solani complex, and they received amphotericin B and voriconazole. As this infection can quickly lead to death, dermatologists play a crucial role in diagnosing this disease.

A critical analysis of L-asparaginase activity quantification methods-colorimetric methods versus high-performance liquid chromatography.

L-asparaginase or ASNase (L-asparagine aminohydrolase, E.C.3.5.1.1) is an enzyme clinically accepted as an antitumor agent to treat acute lymphoblastic leukemia (ALL) and lymphosarcoma through the depletion of L-asparagine (L-Asn) resulting in cytotoxicity to leukemic cells. ASNase is also important in the food industry, preventing acrylamide formation in processed foods. Several quantification techniques have been developed and used for the measurement of the ASNase activity, but standard pharmaceutical quality control methods were hardly reported, and in general, no official quality control guidelines were defined. To overcome this lack of information and to demonstrate the advantages and limitations, this work properly compares the traditional colorimetric methods (Nessler L-aspartic acid β-hydroxamate (AHA) and indooxine) and the high-performance liquid chromatography (HPLC) method. A comparison of the methods using pure ASNase shows that the colorimetric methods both overestimate (Nessler) and underestimate (AHA and indooxine) the ASNase activity when compared to the values obtained with HPLC, considered the most precise method as this method monitors both substrate consumption and product formation, allowing for overall mass-balance. Correlation and critical analysis of each method relative to the HPLC method were carried out, resulting in a demonstration that it is crucial to select a proper method for the quantification of ASNase activity, allowing bioequivalence studies and individualized monitoring of different ASNase preparations. Graphical abstract ᅟ.

Joint Modeling of Immune Reconstitution Post Haploidentical Stem Cell Transplantation in Pediatric Patients With Acute Leukemia Comparing CD34

Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemiatumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34

Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment.

Glucocorticoids (GCs) are metabolic hormones with immunosuppressive effects that have proven effective drugs against childhood acute lymphoblastic leukemia (ALL). Yet, the role of metabolic reprogramming in GC-induced ALL cell death is poorly understood. GCs efficiently block glucose uptake and metabolism in ALL cells, but this does not fully explain the observed induction of autophagy and cell death. Here, we have performed parallel time-course proteomics, metabolomics, and isotope-tracing studies to examine in detail the metabolic effects of GCs on ALL cells. We observed metabolic events associated with growth arrest, autophagy, and catabolism prior to onset of apoptosis nucleotide de novo synthesis was reduced, while certain nucleobases accumulated polyamine synthesis was inhibited and phosphatidylcholine synthesis was induced. GCs suppressed not only glycolysis but also entry of both glucose and glutamine into the TCA cycle. In contrast, expression of glutamine-ammonia ligase (GLUL) and cellular glutamine content was robustly increased by GC treatment, suggesting induction of glutamine synthesis, similar to nutrient-starved muscle. Modulating medium glutamine and dimethyl-α-ketoglutarate (dm-αkg) to favor glutamine synthesis reduced autophagosome content of ALL cells, and dm-αkg also rescued cell viability. These data suggest that glutamine synthesis affects autophagy and possibly onset of cell death in response to GCs, which should be further explored to understand mechanism of action and possible sources of resistance.

Targeting STAT5 or STAT5-Regulated Pathways Suppresses Leukemogenesis of Ph Acute Lymphoblastic Leukemia.

Combining standard cytotoxic chemotherapy with BCR-ABL1 tyrosine kinase inhibitors (TKI) has greatly improved the upfront treatment of patients with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL). However, due to the development of drug resistance through both BCR-ABL1-dependent and -independent mechanisms, prognosis remains poor. The STAT5 transcription factor is activated by BCR-ABL1 and by JAK2-dependent cytokine signaling therefore, inhibiting its activity could address both mechanisms of resistance in Ph ALL. We show here that genetic and pharmacologic inhibition of STAT5 activity suppresses cell growth, induces apoptosis, and inhibits leukemogenesis of Ph cell lines and patient-derived newly diagnosed and relapsedTKI-resistant Ph ALL cells

Comparative Analysis of Calcineurin Inhibitor-Based Methotrexate and Mycophenolate Mofetil-Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation.

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor MRD) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk RR, 1.78 P < .001) and grade III to IV acute GVHD (RR, 1.93 P .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48 P .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results.

Establishing the cost of implementing a performance-based, managed entry agreement for a hypothetical CAR T-cell therapy.

Non-typhoidal

Non-typhoidal

An Adult Patient with Early Pre-B Acute Lymphoblastic Leukemia with t(1217)(p13q21)ZNF384-TAF15.

This is a case report of a 46-year-old man diagnosed with early pre-B acute lymphoblastic leukemia (ALL), bearing the translocation t(1217)(p13q21) as the sole chromosomal abnormality. This is a rare chromosomal abnormality that has been reported in approximately 25 cases worldwide. FISH analysis revealed a rearrangement of ZNF384 (12p13) and TAF15 (17q12) genes, which is usually associated with a pre-B ALL phenotype with co-expression of the myeloid markers CD13 andor CD33. ZNF384 encodes a zinc finger protein, which acts as a transcription factor, regulating the expression of several matrix metalloproteinases and TAF15 belongs to the FET (FUS, EWS, and TAF15) family, consisting of RNA and DNA-binding proteins. Unlike most of the cases where CD10 expression was absent or weak, in our case CD10 was highly expressed. The prognostic significance of ZNF384TAF15 fusion is not very clear since several reports support a generally good prognosis, while others support a poor clinical outcome. Our patient was treated with the German multicenter ALL (GMALL) protocol for B-ALL, but experienced a fulminant gram-negative sepsis and eventually died during induction therapy.

Spinal subacute combined degeneration after intrathecal chemotherapy. Report of two cases.

Intrathecal chemotherapy may be complicated with the development of myelopathies or toxic radiculopathies. This myeloradicular involvement, of toxic character, is unpredictable, since these patients have repeatedly received Intrathecal chemotherapy with the same drugs without apparent injury. The toxic effect should be mainly attributed to Cytarabine and not to methotrexate, since the central nervous system lacks Cytidine deaminase, the enzyme that degrades Cytarabine. We report two patients, an 18-year-old woman and a 16 years old male, who received systemic and intrathecal chemotherapy (methotrexate, cytarabine) for the treatment of an acute lymphoblastic leukemia and developed, in relation to this procedure, a spinal subacute combined degeneration. They had a proprioceptive and motor alteration of the lower extremities and neuroimaging showed selective rear and side spinal cord hyper intensity produced by central axonopathy. Two weeks later the woman developed a quadriplegia and the young man a flaccid paraplegia due to added root involvement.

Oncogenic transcriptional program driven by TAL1 in T-cell acute lymphoblastic leukemia.

TAL1SCL is a prime example of an oncogenic transcription factor that is abnormally expressed in acute leukemia due to the replacement of regulator elements. This gene has also been recognized as an essential regulator of hematopoiesis. TAL1 expression is strictly regulated in a lineage- and stage-specific manner. Such precise control is crucial for the switching of the transcriptional program. The misexpression of TAL1 in immature thymocytes leads to a widespread series of orchestrated downstream events that affect several different cellular machineries, resulting in a lethal consequence, namely T-cell acute lymphoblastic leukemia (T-ALL). In this article, we will discuss the transcriptional regulatory network and downstream target genes, including protein-coding genes and non-coding RNAs, controlled by TAL1 in normal hematopoiesis and T-cell leukemogenesis.

The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models.

The CNOT3 protein is a subunit of the CCR4-NOT complex, which is involved in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL). Here, we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, and other members of the CCR4-NOT complex. Our data show that knockdown of Not3, the structural components Not1Not2, and the deadenylases twinPop2 all result in increased tumor formation. In addition, overexpression of Not3 could reduce tumor formation. Not3 downregulation has a mild but broad effect on gene expression and leads to increased levels of genes involved in DNA replication and ribosome biogenesis. CycB upregulation also contributes to the Not3 tumor phenotype. Similar findings were obtained in human T-ALL cell lines, pointing out the conserved function of Not3. Together, our data establish a critical role for Not3 and the entire CCR4-NOT complex as tumor suppressor.