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Isolated myocardial relapse of Philadelphia-positive acute lymphoblastic leukaemia causing myocarditis a case report.

Relapse of acute lymphoblastic leukaemia (ALL) causes significant morbidity. Extramedullary relapse is seldom isolated to one site and almost always coexists with extensive marrow disease. Leukaemic infiltration of the myocardium is a well described entity, evident in up to 44% of patients at post-mortem examination however, ante-mortem diagnosis remains difficult and rare. As a result, myocardial involvement in the absence of any other foci of relapse has only seldom been reported. Here, we present an unusual case of isolated gross intracardiac relapse of ALL in a patient presenting with chest pain and fevers. Both cardiac magnetic resonance imaging and endomyocardial biopsy were utilized in the diagnosis and identified leukaemic infiltrate in the absence of peripheral lymphoblasts. Despite evidence supporting a positive correlation between peripheral lymphocyte count and myocardial infiltration, our case highlights the rare and hypothesis-driving occurrence of myocardial infiltration with a complete absence of a peripheral lymphoblastosis. The report highlights the utility of modern histopathological and imaging modalities in the diagnosis of isolated myocardial relapse of ALL and provides insight into the aetiologies driving this process.

Lymphoblastic leukemia following myelodysplastic syndromes or myelodysplasticmyeloproliferative neoplasms.

Lymphoblastic leukemia (ALL) following myelodysplastic syndrome (MDS) or myelodysplasticmyeloproliferative neoplasm (MDSMPN) is very rare. We report five cases four had ALL diagnosed after MDS or MDSMPN and one had ALL and MDS diagnosed simultaneously. At the onset of ALL, all patients showed co-existing MDS or MDSMPN. Map-back FISH was performed in four patients, showing that ALL and MDS were cytogenetically related in two patients and unrelated in the other two patients. All five patients were treated with ALL-based chemotherapies, two patients with ALL clonally related to MDS were refractory to the therapies, whereas the other three patients achieved remission. We conclude that ALL developed after MDS is extremely rare. In some patients, ALL is clonally related to MDS and these patients may be refractory to ALL-based chemotherapies. In other patients who have no evidence of clonal relation between ALL and MDS, these patients more likely respond to ALL-based treatment regimens.

Combination chemotherapy plus dasatinib leads to comparable overall survival and relapse-free survival rates as allogeneic hematopoietic stem cell transplantation in Philadelphia positive acute lymphoblastic leukemia.

The Philadelphia chromosome is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). While hematopoietic stem cell transplantation (HSCT) has been regarded as a favorable treatment option in adult Philadelphia-positive (Ph) ALL, its benefit is less clear in the era of newer generation tyrosine kinase inhibitors (TKIs) like dasatinib. This was a retrospective study that analyzed the outcomes of adult patients with Ph ALL treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib followed by allogeneic HSCT. A total of 70 patients were included 30 (42.9%) underwent allogeneic HSCT while 40 (57.1%) received only chemotherapy plus dasatinib. In comparing overall survival (OS) rates, results between the 2 groups were similar with a 1-year OS of 93.3% versus 100% (P 0.20), 2-year OS of 89.8% versus 86.2% (P 0.72), and 3-year OS of 76% versus 71.3% (P 0.56) in the transplant versus nontransplant groups, respectively. The 3-year relapse-free survival (RFS) rates were also similar at 70.5% in the transplant group and 80.1% in the nontransplant group (P 0.94). Subgroup analyses were performed for patients with specific poor prognostic factors (higher white blood count, older age, positive minimal residual disease status), but results again showed no significant survival difference between transplant and nontransplant patients. While HSCT has historically led to a survival advantage in Ph ALL, the results of our study demonstrate that it may have a less beneficial role in the era of newer generation TKIs such as dasatinib.

Semisynthetic aurones inhibit tubulin polymerization at the colchicine-binding site and repress PC-3 tumor xenografts in nude mice and myc-induced T-ALL in zebrafish.

Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC

OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL.

OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL). We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL OBI-3424 exerted profound

The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice.

PR domain-containing 14 (

Value of S100A8 in evaluating the prognosis of children with acute lymphoblastic leukemia.

To study the association between S100A8 expression and prognosis in children with acute lymphoblastic leukemia (ALL). The clinical data of 377 children with ALL who were treated with the CCLG-2008-ALL regimen were retrospectively reviewed. ELISA and PCR were used to measure serum protein levels and mRNA expression of S100A8. The Kaplan-Meier method was used for survival analysis and a Cox regression analysis was also performed. The children were followed up for 56 months, and the overall survival rate of the 377 children was 89.1%. The prednisone good response group had significantly lower S100A8 protein and mRNA levels than the prednisone poor response group (P<0.01). In the children with standard or median risk, both S100A8 protein and mRNA levels were associated with event-free survival rate (P<0.05). There were significant differences in S100A8 protein and mRNA levels between the children with different risk stratifications (P<0.01). The children who experienced events had significantly higher S100A8 protein and mRNA levels than those who did not (P<0.01). The Kaplan-Meier survival analysis and the Cox regression model suggested that S100A8 overexpression was an independent risk factor for the prognosis of children with ALL. High S100A8 expression may be associated with the poor prognosis of children with ALL and is promising as a new marker for individualized precise treatment of children with ALL. 探讨急性淋巴细胞白血病（ALL）患儿S100A8表达与预后的关系。 回顾性分析CCLG-2008-ALL方案治疗的377例ALL患儿的临床资料。采用ELISA及PCR分别检测患儿血清S100A8蛋白水平及其mRNA的表达，并进行Kaplan-Meier生存分析和Cox回归分析。 随访56个月，377例患儿总生存率为89.1%。激素诱导良好组患儿S100A8蛋白及mRNA表达水平显著低于激素诱导不良组（ S100A8高表达可能与儿童ALL不良预后有关，有望作为儿童ALL个体化精准治疗的新参考因子。

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients recent advances and remaining challenges.

The Philadelphia (Ph) chromosome, resulting from the t(922)(q34q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions. In CML, key molecular response milestones have been defined that draw the ideal trajectory towards optimal long-term outcomes. Treatment discontinuation (treatment-free remission, TFR) has proven feasible in a proportion of patients, and clinical efforts are now focused on how to increase this proportion and how to best select TFR candidates. In Ph ALL, results of trials with second- and third-generation TKIs are challenging the role of intensive chemotherapy and even that of allogeneic stem cell transplantation. Additional weapons are offered by the recently introduced monoclonal antibodies. In patients harboring mutations in the BCR-ABL1 kinase domain, prompt therapeutic reassessment and individualization based on mutation status are important to regain response and prevent disease progression. Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations. In this review, we discuss the latest advances in treatment and monitoring of CML and Ph ALL and the issues that still need to be addressed to make the best use of the therapeutic armamentarium and molecular testing technologies currently at our disposal.

Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group.

Disease recurrence occurs in 20% to 40% of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) who are treated with chemotherapy and tyrosine kinase inhibitors (TKIs). In the current study, the authors report the incidence, treatment, and outcome after first disease recurrence in young and older adults treated in the ALL Ph08 trial (ClinicalTrials.gov identifier NCT01491763). Patients aged 18 to 55 years with de novo Ph ALL were treated with imatinib concurrently with standard-dose induction and consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) when possible. In patients with first disease recurrence, the authors analyzed the type of recurrence, timing, location, presence of kinase domain mutations, type of treatment, and outcomes. Of the 125 patients, 28 patients (22%) developed disease recurrence before (4 patients) or after (24 patients) HSCT, with the recurrences being molecular in 11 patients (39%) and overt in 17 patients (61%). T315I was the most common mutation noted at the time of disease recurrence. Change in TKI was the most frequent treatment for patients with molecular disease recurrence whereas rescue chemotherapy and TKI change followed by second allo-HSCT when possible were performed for the most part in patients with overt disease recurrence. A total of 20 patients (71%) achieved response. The median disease-free survival (DFS) and overall survival (OS) were 8.5 months and 15.3 months, respectively. A trend for better DFS and OS was observed in patients with molecular recurrence compared with those with overt recurrence (median of 16.9 months vs 6.3 months P .05 and 28.7 months vs 11.5 months P .05 for DFS and OS, respectively). Disease recurrence was frequent in young and older adults with Ph ALL who were treated with imatinib and chemotherapy with HSCT. Although the majority of patients responded to rescue therapy, their outcomes were poor, especially with regard to overt disease recurrence.

Preclinical activity of the antibody-drug conjugate denintuzumab mafodotin (SGN-CD19A) against pediatric acute lymphoblastic leukemia xenografts.

Denintuzumab mafodotin (SGN-CD19A) is a CD19-targeting antibody-drug conjugate, comprising a monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin F. Since denintuzumab mafodotin has previously shown activity against B-cell malignancies in early-stage clinical trials, it was of interest to test it against the Pediatric Preclinical Testing Program preclinical models of CD19 Denintuzumab mafodotin was evaluated against eight B-cell lineage ALL patient-derived xenografts (PDXs), representing B-cell precursor ALL, Ph-like ALL, and mixed-lineage leukemia rearranged infant ALL. Denintuzumab mafodotin was administered weekly for 3 weeks at 3 mgkg. It was also tested in combination with an induction-type chemotherapy regimen of vincristine, dexamethasone, and l-asparaginase (VXL) against three PDXs. The relationship between cell surface and gene expression of CD19 and drug activity was also assessed. Denintuzumab mafodotin significantly delayed the progression of seven of eight PDXs tested and achieved objective responses in five of eight. There was no apparent subtype specificity of denintuzumab mafodotin activity. No correlations were observed between CD19 mRNA or cell surface expression and denintuzumab mafodotin activity, perhaps due to small sample size, and denintuzumab mafodotin treatment did not select for reduced CD19 expression. Combining denintuzumab mafodotin with VXL achieved therapeutic enhancement compared to either treatment alone. Denintuzumab mafodotin showed single-agent activity against selected B-lineage ALL PDXs, although leukemia growth was evident in most models at 28 days from treatment initiation. This level of activity for denintuzumab mafodotin is consistent with that observed in adults with ALL.

Venous thromboembolism in a large cohort of children with acute lymphoblastic leukemia Risk factors and effect on prognosis.

Venous thromboembolism (VTE) is relatively common in children with acute lymphoblastic leukemia (ALL). Thrombotic risk factors in ALL are asparaginase and steroids. However, within the ALL populations treated on the same regimen, it is less clear which other risk factors play a role. Furthermore, few data are available on the effect of VTE on ALL outcomes. In 778 children (1-18 years) with newly diagnosed precursor-B-lineage or T-lineage ALL, treated in the Dutch Childhood Oncology Group (DCOG) ALL-10 protocol in the Netherlands (October 2004 to April 2013), we conducted a nested case control study with 59 VTE cases and 118 controls to identify risk factors for VTE. Fifty-nine of 778 ALL patients developed VTE (7.6%), with cerebral venous sinus thrombosis (CVST) in 26 of 59 patients (44.1%). VTE occurred during induction treatment in 59.3% (n 35) and in 40.7% (n 24) during medium risk intensification. Conditional multivariable logistic regression analysis showed that age and ALL subtype were significantly associated with VTE (age ≥7 years OR 2.72, 95% CI 1.33-5.57 ALL subtype T-ALL OR 2.95, 95% CI 1.02-8.57). A multivariable Cox model showed no association between the occurrence of VTE and event free survival. In CVST patients, permanent disability was present in 34.6%. Within this large pediatric ALL cohort, we demonstrated a high morbidity in CVST patients. Age ≥7 years at diagnosis and T-ALL subtype were the main risk factors for VTE, and should be considered in preventive strategies.

Single-Chain Variable Fragment-Based Bispecific Antibodies Hitting Two Targets with One Sophisticated Arrow.

Despite the success of monoclonal antibodies (mAbs) to treat some disorders, the monospecific molecular entity of mAbs as well as the presence of multiple factors and pathways involved in the pathogenesis of disorders, such as various malignancies, infectious diseases, and autoimmune disorders, and resistance to therapy have restricted the therapeutic efficacy of mAbs in clinical use. Bispecific antibodies (bsAbs), by concurrently recognizing two targets, can partly circumvent these problems. Serial killing of tumor cells by bsAb-redirected T cells, simultaneous blocking of two antigens involved in the HIV-1 infection, and concurrent targeting of the activating and inhibitory receptors on B cells to modulate autoimmunity are part of the capabilities of bsAbs. After designing and developing a large number of bsAbs for years, catumaxomab, a full-length bsAb targeting EpCAM and CD3, was approved in 2009 to treat EpCAM-positive carcinomas besides blinatumomab, a bispecific T cell engager antibody targeting CD19 and CD3, which was approved in 2014 to treat relapsed or refractory acute lymphoblastic leukemia. Furthermore, approximately 60 bsAbs are under investigation in clinical trials. The current review aims at portraying different formats of the single-chain variable fragment (scFv)-based bsAbs and shedding light on the scFv-based bsAbs in preclinical development, different phases of clinical trials, and the market.

Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma.

B cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) frequently express CD19, CD20 and CD22 on the cell surfaces. Immunotherapeutic agents including antibodies and chimeric antigen receptor T cells are widely studied in clinical trials. Several antibody-drug conjugates (ADC) have been approved for clinical use (gemtuzumab ozogamicin in acute myeloid leukemia and brentuximab vedotin in Hodgkin lymphoma as well as CD30 anaplastic large cell lymphoma). Inotuzumab ozogamicin (INO), a CD22 antibody conjugated with calicheamicin is one of the newest ADCs. INO has been approved for treatment of relapsed refractory B cell precursor ALL. Multiple ongoing trials are evaluating its role in the relapsed refractory B cell NHL. This review summarized recent development in INO applications for ALL and NHL.

The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia.

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REHAra-C) as a chemoresistance model. REHAra-C 1) was not crossresistant to vincristine or methotrexate 2) showed a similar proliferation rate and cell surface marker expression as parental REH 3) demonstrated decreased chemotaxis toward bone marrow stromal cells and 4) expressed higher transcript levels of cytidine deaminase (

Mechanisms of extramedullary relapse in acute lymphoblastic leukemia Reconciling biological concepts and clinical issues.

Long-term survival rates in childhood acute lymphoblastic leukemia (ALL) are currently above 85% due to huge improvements in treatment. However, 15-20% of children still experience relapses. Relapses can either occur in the bone marrow or at extramedullary sites, such as gonads or the central nervous system (CNS), formerly referred to as ALL-blast sanctuaries. The reason why ALL cells migrate to and stay in these sites is still unclear. In this review, we have attempted to assemble the evidence concerning the microenvironmental factors that could explain why ALL cells reside in such sites. We present criteria that make extramedullary leukemia niches and solid tumor metastatic niches comparable. Indeed, considering extramedullary leukemias as metastases could be a useful approach for proposing more effective treatments. In this context, we conclude with several examples of potential niche-based therapies which could be successfully added to current treatments of ALL.

Development and Validation of a Sensitive UHPLC-MSMS-Based Method for the Analysis of Folylpolyglutamate Synthetase Enzymatic Activity in Peripheral Blood Mononuclear Cells Application in Rheumatoid Arthritis and Leukemia Patients.

Folylpolyglutamate synthetase (FPGS) is a crucial enzyme in both cellular folate homeostasis and the intracellular retention of folate analogue drugs such as methotrexate (MTX), which is commonly used for the treatment of (pediatric) leukemia and the anchor drug in rheumatoid arthritis (RA) treatment. To date, assessment of FPGS catalytic activity relies on assays using radioactive substrates that are labor-intensive and require relatively large numbers of cells. Here, we describe a nonradioactive, ultra-high-performance liquid chromatography-tandem mass spectrometer (UHPLC-MSMS)-based method allowing for sensitive and accurate measurements of FPGS activity in low cell numbers (ie, 1-2 × 10) of biological specimens, including leukemic blast cells of acute lymphoblastic leukemia patients and peripheral blood mononuclear cells of patients with RA. The UHPLC-MSMS assay was validated with 2 CCRF-CEM human leukemia cells, one proficient and one deficient in FPGS activity. Linearity of time and protein input were tested by measuring FPGS activity at 30-180 minutes of incubation time and 10-300 mcg protein extract. In addition, FPGS enzyme kinetic parameters were assessed. The FPGS enzymatic assay showed a linear relation between FPGS activity and protein input (R ≥ 0.989) as well as incubation time (R ≥ 0.996). Moreover, the UHPLC-MSMS method also allowed for evaluation of FPGS enzyme kinetic parameters revealing Km values for the substrates MTX and L-glutamic acid of 64 µmolL and 2.2 mmolL, respectively. The mean FPGS activity of acute lymphoblastic leukemia blast cells (n 4) was 3-fold higher than that of CCRF-CEM cells and 44-fold and 88-fold higher than that of peripheral blood mononuclear cells from MTX-naive (n 9) and MTX-treated RA patients (n 6), respectively. Collectively, given its sensitivity with low cell numbers and avoidance of radioactive substrates, UHPLC-MSMS-based analysis of FPGS activity may be eligible for routine therapeutic drug monitoring of MTX in RA and leukemia for therapy (non)response evaluations.

A Precocious Presentation of B-cell Acute Lymphoblastic Leukemia as Infiltrated Plaques on the Face.

Leukemia cutis, or infiltration of leukemic cells into the skin, occurs rarely in B-cell acute lymphocytic leukemia (ALL). Herein, we have described a rare, precocious presentation of B-cell ALL presenting as indurated facial plaques in a 69-year-old man. Biopsy of the facial plaques revealed precursor B-cell leukemialymphoma in the skin and prompted urgent hematologic-oncologic evaluation. Bone marrow biopsy yielded a final diagnosis of B-cell ALL. The patient underwent induction therapy, and at the last available follow-up, a matched unrelated donor transplant was planned.

Homozygous mutation in NUDT15 in childhood acute lymphoblastic leukemia with increased susceptibility to mercaptopurine toxicity A case report.

As an essential component of consolidation and maintenance therapy for acute lymphoblastic leukemia (ALL), mercaptopurine (6-MP) causes critical myelosuppression. The current study aimed to clarify the reasons for severe myelosuppression and significant hyperpigmentationin a patient with ALL that received consolidation therapy. The present study performed patient NUDT15 testing with fluorescence

Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects.

Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph ALL).Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and

Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma.

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.

Targeting non-oncogene ROS pathway by alantolactone in B cell acute lymphoblastic leukemia cells.

Alantolactone (ALT) is active component of natural product Inula helenium with a lot of pharmacological effects, including anti-tumor effect. The present work aimed to explore the antitumor effect of ALT in B cell acute lymphoblastic leukemia (B-ALL). B-ALL cells were treated with various concentrations of ALT, and then trypan blue assay, Annexin VPI staining assay, PI staining assay, western blot analysis were employed to measure the effect of ALT on viability, apoptosis and cell cycle in B-ALL cells. In addition, a synthetic bioinformatics method was used to predict the underlying mechanism of antitumor effect of ALT. Then Reactive Oxygen Species (ROS) probe Dihydroethidium (DHE) and 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA) were used to detect accumulation of cellular ROS. Meanwhile, DNA damage was identified by 8-oxoG, p-ATM1987, γ-H2AX and comet assay. In addition, activity of glutathione reductase (GR), thioredoxin reductase (TrxR) and catalase were measured and overexpressed in SEM and RS411 cells to study the inhibition on these enzymes. Finally, B-ALL NOD-SCID mouse model was used to test its performance in vivo. ALT showed good antitumor effect in B-ALL in vivo and in vitro through inducing ROS overload, which led to DNA damage. In addition, we found ROS overload caused by ALT was due to its direct inhibition on reductase. We found that ALT, a natural product, showing a promising tactic in the therapy of B-ALL by targeting ROS pathway.

Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Adolescents and Young Adults.

Hematologic stem cell transplantation (HSCT) is the most potent consolidation therapy for high-risk acute lymphoblastic leukemia (ALL), but their outcomes and complications in adolescent and young adult (AYA) patients remain unclear. We compared outcomes after HSCT for ALL among children (age 1 to 9 years n 607), adolescents (age 10 to 19 years n 783), and young adults (age 20 to 29 years old, n 603), based on Japanese nationwide registry data. The 5-year overall survival (OS) rate among AYA patients was worse than that of children, at 64% (95% confidence interval CI, 60% to 68%). In the AYA, the 5-year treatment-related mortality (TRM) after HSCT was 19% (95% CI, 16% to 22%), significantly higher than that in younger patients. The most common cause of TRM in the AYA was infection. The relapse rate was not different across the 3 age groups. When focusing on older adolescents (age 15 to 19 years), there was no difference in outcomes between those treated in pediatric centers and those treated in adult centers. In conclusion, the AYA had a greater risk of nonrelapse death than younger patients, and infection was the most common cause. Further optimization is required for HSCT in AYAs with ALL.

Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.

Patients with relapsedrefractory (RR) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with RR Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CRCRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CRCRh in the first 2 cycles, and the median overall survival was 8.5 months overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.

Methylation of the promoter region of the MTRR gene in childhood acute lymphoblastic leukemia.

Epigenetic analysis of the association between the methylation status of the promoter region of the MTRR (5‑methyltetrahydrofolate‑homocysteine methyltransferase reductase) gene and the risk of acute lymphoblastic leukemia (ALL) in children plays an important role in the early diagnosis, assessment of the malignant degree, treatment and evaluation of the risk of relapse and prognosis of the disease. In the present study, RT‑qPCR was used to detect the mRNA levels of the MTRR and MTHFR (methylenetetrahydrofolate reductase) genes in the bone marrow of 20 ALL patients and 20 age‑ and sex‑matched controls with normal bone marrow. The methylation pattern of the MTRR promoter region in eligible DNA samples was quantitatively analyzed using MALDI‑TOF MS. The results indicated that the mRNA expression level of MTRR in the bone marrow from children with ALL was lower than that in the control samples (P<0.05), but no significant difference was detected in the MTHFR gene between the two groups (P>0.05). According to the risk classification of ALL in children with high, medium and low risk, the low‑risk group had a higher methylation rate of CpG6 compared to the medium‑risk group. However, the medium‑risk group had a higher CpG46.47 methylation rate compared to the low‑risk group. The methylation rates of CpG26 and CpG46.47 in the high‑risk group were higher than these rates in the low‑risk group, while the CpG42.23.44 methylation rate was lower in the high‑risk group than in the low‑risk group (P<0.05). The methylation rates at CpG1, CpG10, CpG48 sites, score and the average methylation rate in the ALL‑H (high) group (≥50x109l) were lower than these in the ALL‑NH (not high) group (<50x109l) and the control group (P<0.05). We conclude that abnormal MTRR mRNA expression and the methylation of the MTRR promoter can be used to classify the risk of ALL in children.

Histone Modifications Drive Aberrant Notch3 ExpressionActivity and Growth in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer caused by the deregulation of key T-cell developmental pathways, including Notch signaling. Aberrant Notch signaling in T-ALL occurs by

Massive bilateral renomegaly with maintained renal morphology in an infant.

Massive bilateral renomegaly with maintained renal morphology in infants is a rare entity. We present the images of a A 9-month-old female child who presented with massive bilateral renomegaly with maintained renal morphology due to acute lymphoblastic leukemia.

Change of ROCK1 Gene Expression Level in Patients with Acute Lymphoblastic Leukemia and Its Clinical Significance.

To investigate the expression change of ROCK1 gene in patients with acute lymphoblastic leukemia (ALL) and its prognostic significance. Sixty patients with ALL were selected in our hospital from April 2017 to April 2018, and 60 healthy persons subjected to physical examination were selected as control. The venous blood was taken from the subjects, and then the mononuclear cells were separated. The ROCK1 gene expression level in the samples was detected by RT-PCR, and the expression level of ROCK1 protein was detected by Western blot. The correlation between ROCK1 gene expression and clinical characteristics of ALL patients was analyzed by using statistical methots. The RT-PCR showed that the relative expression level of ROCK1 gene in ALL patients was 1.37 (1.28-1.46), which was significantly higher than that in the control group (P<0.05). Western blot showed that the protein expression level of ROCK1 in ALL patients was higher than that in the control group (P<0.05). The expression level of ROCK1 gene correlated with age, WBC count, lactate dehydrogenase (LDH) level, peripheral blood immature cell count, and risk stratification of ALL patients (P<0.05). The expression level of ROCK1 gene did not correlate with sex, hemoglobin (Hb) level, platelet count and immunophenotype in ALL patients (P>0.05). The standard risk ratio of B-ALL and T-ALL patients with low ROCK1 expression was significantly higher than that in patients with high ROCK1 expression (P<0.05). The high risk ratio of B-ALL and T-ALL patients with low ROCK1 expression was significantly lower than those with high ROCK1 expression (P<0.05). The ratio of CR in the group with low ROCK1 expression patients was significantly higher than that in patients with high ROCK1 expression (P<0.05). The Relapse rate of the group with low ROCK1 expression was significantly lower than that of the group with high ROCK1 expression (P<0.05). Kaplan-Meier survival analysis showed that OS and DFS in ALL patients with low ROCK1 expression were superior to those in ALL patients with high ROCK1 expression (P<0.05). Multiple factor Cox regression analysis showed that age and ROCK1 gene were independent influencing factors for OS (P<0.05) leukocyte count and ROCK1 gene were independent influencing factors for DFS (P<0.05). The expression level of ROCK1 gene in ALL patients is high, which may stimulate the genesis of ALL, and the down-regulation of ROCK1 gene expression may help improve the therapeutic effect for ALL patients. 急性淋巴细胞白血病患者ROCK1基因表达水平变化及其临床意义. 研究ROCK1基因在急性淋巴细胞白血病（ALL）患者中的表达变化及其临床预后意义. 选择自2017年4月-2018年4月在本院接受治疗的60例ALL患者，同时选取60例健康体检者作为对照，从受试者静脉取血后分离单个核细胞，采用RT-PCR实验检测样本的ROCK1基因表达水平，采用Western blot实验检测ROCK1蛋白表达水平，统计学分析ROCK1基因表达与ALL患者临床特征的相关性. ALL患者ROCK1基因相对表达水平为1.37（1.28-1.46），对照组ROCK1基因相对表达水平为1.06（0.96-1.12），ALL患者ROCK1基因水平显著高于对照组（P<0.05）。ALL患者ROCK1蛋白表达水平高于对照组（P<0.05）。ROCK1基因表达水平与ALL患者的年龄、白细胞计数、乳酸脱氢酶（LDH）水平及外周血幼稚细胞数有显著相关性（P<0.05）。ROCK1基因表达水平与ALL患者的性别、血红蛋白（Hb）水平、血小板数及免疫表型无相关性（P>0.05）。ROCK1低表达的B-ALL和T-ALL患者患者标危比例均显著高于ROCK1高表达的患者（P<0.05）。ROCK1低表达的B-ALL和T-ALL患者极高危比例均显著低于ROCK1高表达的患者（P<0.05）。ROCK1低表达组CR比例显著高于ROCK1高表达的患者（P<0.05）。ROCK1低表达组复发比例显著低于ROCK1高表达的患者（P<0.05）。Kaplan-Meier生存分析表明，ROCK1低表达ALL患者的OS和DFS均优于ROCK1高表达的患者（P<0.05）。多因素 Cox 回归分析结果表明，年龄及ROCK1基因是 OS 独立影响因素（P<0.05）；白细胞计数及ROCK1基因是DFS 独立影响因素（P<0.05）. ROCK1基因在ALL患者中表达水平较高，其高水平表达可能刺激ALL的发生，而下调ROCK1基因表达可能有助于提高ALL的治疗效果.

Clinical Characteristics of Patients with Ph

To investigate the clinical biological characteristics and prognosis of the patients with mixed phenotype acute leukemia with t(922)(q34q11.2) andor BCRABL1 (Ph The morphological, immunological, cytogenetic, and molecular features of 33 in patients with Ph Ph Ph Ph阳性混合表型急性白血病的临床研究. 分析Ph染色体和或BCR-ABL1 依据欧洲白血病免疫分型协作组(EGIL)的积分系统和WHO2008诊断标准回顾性判断并总结2002年6月至2016年6月收治的33例Ph Ph Ph

E-cadherin Expression in Children with Acute Leukemia and Its Clinical Significance.

To investigate the correlation of E-cadherin expression level with the clinical characterastics in children with acute leukemia (AL), and to explore the possible regulatory mechanism. Real-time quantitative RT-PCR was applied to detect the expression level of E-cadherin in bone marrow samples from 135 child patients diagnosed as AL, and its relevance with clinical indicators was statistically analyzed. The expression levels of E-cadherin, β-catenin, and Aktp-Akt were detected by using Western blot. The bone marrow samples from 22 children with non-malignant hematological diseases were used as controls. The expression level of E-cadherin significantly decreased in newly diagnosed patients with all 3 types of AL as compared with bone marrow samples from control group (P<0.01). In B-ALL group, compared with standard risk group, E-cadherin expression level significantly decreased in intermediate risk group (P<0.05). Moreover,the expression level of E-cadherin mRNA was also reduced in splenomegaly group (P<0.01). However, the correlation of E-cadherin level with clinical characteristics was not found in T-ALL and AML (P>0.05). The expression level of E-cadherin in the patients from Common-B-ALL group was higher than B-ALL patients with other immunophenotypes (P<0.01), while no significant difference was found among patients grouped by FAB classification. By the correlation analysis of measured data, lower E-cadherin expression level was found to be related with high WBC count and serum lactic dehydrogenase level (LDH) (r-0.419, r-0.269), but with low blood platelet count in B-ALL (r0.335). In T-ALL, expression of E-cadherin was found to be negatively correlated with LDH and percentage of immature cells in the bone marrow (r-0.567, r-0.557). In addition, the lower expression of E-cadherin was also found to be related with WBC count and percentage of immature cells in the bone marrow in newly diagnosed AML patients (r-0.368, r-0.391). Compared with control group, the expression of E-cadherin was down-regulated significantly (P<0.01), while β-catenin, Akt significantly was up-regulated in 3 types of AL patients (P<0.01). The expression of p-Akt and p-AktAkt was up-regulated significantly in T-ALL (P<0.01). Lower expression of E-cadherin is related factor of unfavourable prognosis in children with acute leukemia. The expression deficiency or down-regulation of E-cadherin may activate Wntβ-catenin and PI3K Akt signaling pathways to promote the genesis and progress of haematological malignancies, thus resulting in a series of malignant biological behaviors in cells. E-cadherin may be a new prognostic indicator for pediatric acute leukemia, thus to guide individualized hemotherapy. E-cadherin基因在儿童急性白血病中的表达及其临床意义. 研究E-cadherin基因在儿童急性白血病（AL）中的表达及其与临床指标的相关性，并探讨其可能的调控机制。. 采用实时荧光定量PCR检测135例初诊AL患儿骨髓单个核细胞中E-cadherin mRNA的表达水平，并分析其表达水平与临床指标的相关性；应用Western blot法检测E-cadherin、β-catenin、Akt、p-Akt信号通路相关蛋白的表达；同时收集22例非恶性血液病患儿的骨髓作为对照。. B-ALL、T-ALL、AML组中E-cadherin mRNA的表达均低于对照组（P＜0.01）。在B-ALL中，中危组患儿E-cadherin基因表达水平较标危组显著下降（P＜0.05）；伴有脾脏浸润的患儿E-cadherin基因表达水平亦显著降低（P＜0.01）；而在T-ALL、AML患儿各临床指标分组中，E-cadherin基因表达水平均无显著差异。在B-ALL患儿中，免疫分型为Common-B-ALL的患儿E-cadherin基因表达水平较其他B-ALL患儿显著升高（P＜0.01）。而在3种AL的FAB分组间均未见E-cadherin表达差异。基于计量资料的相关性分析表明，B-ALL患儿中，随着E-cadherin表达水平的下调，初诊外周血白细胞（WBC）计数、乳酸脱氢酶（LDH）水平有升高趋势（r-0.419，r-0.269），而初诊外周血血小板水平呈下降趋势（r0.335）；在T-ALL患儿中，E-cadherin表达水平与LDH、初诊骨髓幼稚细胞比例呈显著负相关（r-0.567，r-0.557）；而在AML患儿中，随着E-cadherin表达水平下调，初诊WBC计数水平和初诊骨髓幼稚细胞比例呈上升趋势（r-0.368，r-0.391）。与对照组比较，3种AL患儿中E-cadherin表达水平下调（P＜0.001），而β-catenin、Akt则上调（P＜0.01），p-Akt、p-AktAkt表达量在T-ALL中上调（P＜ 0.01）。. E-cadherin基因表达降低或缺失是儿童急性白血病的预后不良相关因素，可能通过激活Wntβ-catenin和PI3KAkt信号通路，促进肿瘤的发生，并引起细胞的一系列恶性生物学行为，E-cadherin有望成为判断预后和指导个性化治疗的指标。.

Detection and Analysis of T Lymphocyte Subsets and B Lymphocytes in Patients with Acute Leukemia.

To investigate the changes of T lymphocyte subsets, B lymphocyte and NK cells in peripheral blood of patients with acute leukemia at different periods and their significance. The peripheral T lymphocyte subsets and B lymphocyte of 95 patients with acute leukemia (43 cases of acute lymphoblastic leukemia (ALL), 52 cases of acute myeloid leukemia (AML) and 50 normal people were detected by flow cytometry respectively. The positive rate of CD3 Changes of T lymphocyte subsets, B lymphocytes and NK cells in the patients with newly diagnosed acute leukemia are significant, thus the detection of T lymphocyte cell subsets, B lymphocytes and NK cells can provide some evidences. for evaluation of the disease severity, curative efficiency and prognosis of patients with acute leukemia. 急性白血病患者T、B淋巴细胞的检测与分析. 探讨不同类型的急性白血病患者外周血T淋巴细胞亚群、B淋巴细胞和NK细胞等在疾病的不同时期的变化及其临床意义。. 采用流式细胞术检测95例初诊白血病患者急性淋巴细胞白血病（ALL）43例，急性髓系白血病（AML）52例诱导治疗前后及50例正常对照者外周血T淋巴细胞亚群、B淋巴细胞、NK细胞及Treg细胞百分比。. 初诊白血病各组CD3 初诊白血病各组T淋巴细胞亚群、B淋巴细胞和NK细胞的变化明显，完全缓解组的上述指标基本恢复正常，说明T淋巴细胞亚群、B淋巴细胞、NK细胞水平检测在评价急性白血病严重程度、疗效及判断患者预后有一定的临床价值。.

The Influence of Proinflammatory Cytokines on Voriconazole Trough Concentration in Patients With Different Forms of Hematologic Disorders.

Even though multiple factors are involved in the high fluctuation of voriconazole (VCZ) plasma concentration, little is known regarding the influence of proinflammatory cytokines on VCZ concentration. The aim of this study was to investigate the influence of proinflammatory cytokines, namely, interleukin (IL)-1β, IL-6, IL-18, interferon-γ, tumor necrosis factor-α, and transforming growth factor (TGF)-β1 on VCZ trough concentration (VCZ-C

Chalcones and Chalcone-mimetic Derivatives as Notch Inhibitors in a Model of T-cell Acute Lymphoblastic Leukemia.

Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were selected as putative Notch inhibitors. The evaluation of the antiproliferative effect combined with the inhibition of Notch1 expression in KOPTK1 cell line identified compound

Therapy of RelapsedRefractory Acute Lymphoblastic Leukemia Today and Tomorrow.

New diagnostics and treatments, including the use of new drugs, have advanced considerably the treatment of acute lymphoplastic leukemia (ALL) in the past few years. Monoclonal antibodies and immunoconjugates targeting antigens CD19 and CD22 show greater efficacy and more favourable toxicity profiles than standard salvage chemotherapeutic protocols. Two of these drugs - blinatumomab and inotuzumab ozogamicin - have already made their way into clinical practice. Ponatinib and other new generation tyrosine kinase inhibitors allow dose reduction of intensive cytostatic regimens in Ph-positive ALL patients and slowly start to overshadow the importance of allogeneic hematopoietic cell transplants. For the time being, their use is reserved for relapsedrefractory ALL, but they are already available as a first line therapy in clinical trials. An entirely new group of living drugs is emerging for the treatment of ALL - chimeric antigen receptor T-cells produced by genetic modification of native human cells. Chimeric antigen receptor T-cells can be looked upon as in vitro trained professional blast killers. They show an efficacy never seen before for the treatment of relapsedrefractory ALL. On the other hand, this treatment still presents significant risks, mainly due to cytokine release syndrome. Ruxolitinib, mTOR inhibitors, bortezomib, and other drugs for targeted treatment of ALL are currently being evaluated in clinical trials. The article focuses on current options and news in the field of relapsed and refractory ALL treatment. This work was created at Masaryk University as part of the project 8220New Approaches in Research, Diagnostics and Therapy of Hematological Malignancies VI8221, number MUNIA11052018, supported by Czech Ministry of Education, Youth and Sports in 2019. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted 28. 8. 2018 Accepted 10. 1. 2019.

Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic LeukemiaLymphoma via Cell-Autonomous AMPK Activation.

AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemialymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.

Steroid-induced Bradycardia During Induction Chemotherapy in Children and Young Adults Diagnosed With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.

Systemic corticosteroids are widely used for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. Anecdotal case reports demonstrate bradycardia in patients receiving corticosteroids however, a more in-depth analysis is lacking. This study aimed to describe the incidence, timing, and outcomes of bradycardia in children with ALL receiving corticosteroids during induction chemotherapy at our center from 2010 to 2016. A total of 153 children were included, with 150 (98%) demonstrating decreased heart rate following steroid administration with a median HR decrease of 23 beats per minute. Bradycardia ≤first percentile for age developed in 90 (59%) patients, with nadir occurring, on average, 7 doses into treatment, corresponding to 79 hours after initiation of therapy. No patient experienced adverse events related to bradycardia. Resolution of bradycardia at outpatient follow-up occurred in 62 of 71 (87%). Examination of nadir heart rate during subsequent hospitalizations in which steroids were not being administered did not demonstrate a significant incidence of bradycardia. Corticosteroid-induced bradycardia is common in children with ALL receiving induction chemotherapy. It was not associated with clinical adverse events and self-resolved without intervention. Therefore, further cardiac assessment may not be warranted in the presence of asymptomatic bradycardia suspected to be secondary to steroid administration.

Bacterial l-asparaginases for cancer therapy Current knowledge and future perspectives.

l-Asparaginases hydrolyzing plasma l-asparagine and l-glutamine has attracted tremendous attention in recent years owing to remarkable anticancer properties. This enzyme is efficiently used for acute lymphoblastic leukemia (ALL) and lymphosarcoma and emerged against ALL in children, neoplasia, and some other malignancies. Cancer cells reduce the expression of l-asparaginase leading to their elimination. The l-asparaginase anticancerous application approach has made incredible breakthrough in the field of modern oncology through depletion of plasma l-asparagine to inhibit the cancer cells growth particularly among children. High level of l-asparaginase enzyme production by Escherichia coli, Erwinia species, Streptomyces, and Bacillus subtilis species is highly desirable as bacterial alternative enzyme sources for anticancer therapy. Thermal or harsh conditions stability of those from the two latter bacterial species is considerable. Some enzymes from marine bacteria have conferred stability in adverse conditions being more advantageous in cancer therapy. Several side effects exerted by l-asparaginases such as hypersensitivity should be hindered or decreased through alternative therapies or use of immune-suppressor drugs. The l-asparaginase from Erwinia species has displayed remarkable traits in children with this regard. Noticeably, Erwinia chrysanthemi l-asparaginase exhibited negligible glutaminase activity representing a promising efficiency mitigating related side effects. Application of software such as RSM would optimize conditions for higher levels of enzyme production. Additionally, genetic recombination of the encoding gene would indisputably help improving enzyme traits. Furthermore, the possibility of anticancer combination therapy using two or more l-asparaginases from various sources is plausible in future studies to achieve better therapeutic outcomes with lower side effects.

Engineered Bcor mutations lead to acute leukemia of progenitor B-1 lymphocyte origin in a sensitized background.

Approximately 10% of

Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy.

Micafungin is a well-tolerated and effective prophylactic antifungal agent used in hematologic diseases. In this prospective trial, we evaluated the efficacy and safety of prophylactic micafungin during first induction chemotherapy in patients with acute leukemia. We also compared outcomes of prophylactic micafungin with those of prophylactic posaconazole in acute myeloid leukemia (AML). Medically fit patients with newly diagnosed acute leukemia received 50 mg micafungin intravenously once daily from the initiation of first induction chemotherapy to recovery of neutrophil count, suspected fungal infection, or unacceptable drug-related toxicity ( Clinicaltrials.gov number, NCT02440178). The primary end point was incidence of invasive fungal infection, and the secondary end points were adverse events of prophylactic micafungin and mortality during induction therapy. The 65 patients (median age 51 years, malefemale 3431) enrolled in this study had diagnoses of AML (33, 50.8%), acute lymphoblastic leukemia (31, 47.7%), and acute biphenotypic leukemia (1, 1.5%). Median duration of micafungin treatment was 24 days (range 1-68), with proven invasive fungal disease in one patient (1.5%) and possible fungal infection in two patients (3.1%). Three of the patients (4.6%) experienced the following adverse events, but all events were tolerable liver function abnormality (Grade 2, n 1 Grade 3, n 1) and allergic reaction (Grade 2, n 1). Three patients died during induction therapy, and invasive aspergillosis pneumonia was the cause of death for one of those patients. Overall, 19 patients (29.2%) discontinued prophylactic micafungin, and 18 (27.7%) patients switched to another antifungal agent. We observed no fungal infections caused by amphotericin B-resistant organisms. In AML patients, outcomes of prophylactic micafungin during induction chemotherapy did not differ significantly with those of prophylactic posaconazole with regard to incidence of fungal infections, rate of discontinuation, or safety. Our study demonstrates that prophylactic micafungin is safe and effective in patients with acute leukemia undergoing induction chemotherapy. Outcomes in patients with AML were similar to those of prophylactic posaconazole, indicating the usefulness of micafungin as a prophylactic antifungal agent during induction chemotherapy for AML. Clinicaltrials.gov NCT02440178, registered May 12th 2015.

γ-Catenin-Dependent Signals Maintain BCR-ABL1

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1

L-Asparaginase from

L-Asparaginase (L-ASNase) is an important enzyme used to treat acute lymphoblastic leukemia, recombinantly produced in a prokaryotic expression system. Exploration of alternatives production systems like as extracellular expression in microorganisms generally recognized as safe (such as

Efficacy and association analysis of high-dose methotrexate in the treatment of children with acute lymphoblastic leukemia.

Effect of high-dose methotrexate (MTX) on children with acute lymphoblastic leukemia (ALL) with different subtypes and disease courses was investigated. A retrospective analysis of 207 children with ALL who were admitted to the Peoples Hospital of Pingyi County from March 2014 to June 2017 was carried out. According to the subtype of the disease, the children were divided into two groups. B-lineage group ALL occurred in B-lineage lymphocytes (n128) T-lineage group ALL occurred in T-lineage lymphocytes (n79). According to the disease course, the children were divided into three groups. High-risk group disease course >15 days (n67) moderate-risk group disease course >8 and <15 days (n58) low-risk group disease course <8 days (n82). The plasma concentration, calcium formyltetrahydrofolate (CF) rescue times and adverse reactions were compared at 12 h (T1), 48 h (T2), and 72 h (T3) after MTX infusion. The plasma concentration in B-lineage group was significantly higher than that in the T-lineage group at T2 and T3 (P<0.05). The incidence of adverse reactions in children with ALL in the B-lineage group was significantly higher than that in the T-lineage group (P<0.05). The CF rescue times in high-risk group were more than that in moderate- and low-risk groups (P<0.05). The incidence of adverse reactions in the high-risk group was significantly higher than that in the moderate- and low-risk groups (P<0.05), and in the moderate-risk group was significantly higher than that in the low-risk group (P<0.05). Compared with T-lineage ALL children, high-dose MTX causes more toxic injury to B-lineage ALL children. During clinical application of MTX in the treatment of ALL, close attention should be paid to the changes of the vital signs of patients, and timely CF rescue should be performed.

Delayed remission following sequential infusion of humanized CD19- and CD22-modified CAR-T cells in a patient with relapsedrefractory acute lymphoblastic leukemia and prior exposure to murine-derived CD19-directed CAR-T cells.

CD19-modified CAR-T cells greatly influence responses in patients with relapsedrefractory acute lymphoblastic leukemia (ALL). However, recurrence remains a challenge, and reinfusion of CAR-T cells is not always effective. Sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells may overcome this issue and induce remission. We examined treatment with sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells in a patient with relapsed ALL previously exposed to murine-derived anti-CD19 CAR-T cells. At 6 weeks after treatment, repeated bone marrow smear and flow cytometry analysis revealed no lymphoblasts. Our results suggest that sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells is a valuable option for relapsed patients with prior infusion of murine-derived, CD19-directed CAR-T cells.

Outcome of Philadelphia Positive Acute Lymphoblastic Leukemia With or Without Allogeneic Stem Cell Transplantation in a Retrospective Study.

Philadelphia positive ALL (Ph ALL) is an aggressive leukemia associated with lower remission rates and poor survival. Current treatment approach for Ph ALL is chemotherapy along with TKI and CNS directed therapy followed by Allogeneic stem cell transplantation (Allo-SCT). To analyze outcome of Ph ALL with or without Allo-SCT in the era of universal TKI uses. Retrospectively reviewed medical records of 267 patients who were diagnosed and treated for ALL during study period at our centre. Fifty-one Ph ALL patients (males 31, females 20) out of a total of 267 ALL patients were eligible for the study. Post induction 48 patients achieved complete remission while 1 died during induction. Forty-six patients received further treatment with TKI CNS directed therapy and thereafter the consolidation therapy with Allo-SCT (n 16) or chemotherapy TKI (n 30).Overall mortality was 751 (13.9%) (616 transplant related mortalities due to GVHD and infections and 1 induction death). Fifteen out of 46 patients (32.6%) had relapse (110 relapse after Allo-SCT vs. 1424 after chemotherapy) on or after consolidation therapy. At a median follow-up of 17.5 months (2-58 months) of cohort, the median EFS was 22 months (95% CI 10.4-33.5 months). The estimated 4 year EFS and PFS in Allo-SCT versus chemotherapy only group was 36.0 ± 17.9 versus 27.3 ± 9.1% (

ETV6-RUNX1 interacts with a region in SPIB intron 1 to regulate gene expression in pre-B-cell acute lymphoblastic leukemia.

The most frequently occurring genetic abnormality in pediatric B-lymphocyte-lineage acute lymphoblastic leukemia is the t(1221) chromosomal translocation that results in a ETV6-RUNX1 (also known as TEL-AML1) fusion gene. Expression of ETV6-RUNX1 induces a preleukemic condition leading to acquisition of secondary driver mutations, but the mechanism is poorly understood. SPI-B (encoded by SPIB) is an important transcriptional activator of B-cell development and differentiation. We hypothesized that SPIB is directly transcriptionally repressed by ETV6-RUNX1. Using chromatin immunoprecipitation, we identified a regulatory region in the first intron of SPIB that interacts with ETV6-RUNX1. Mutation of the RUNX1 binding site in SPIB intron 1 prevented transcriptional repression in transient transfection assays. Next, we sought to determine to what extent gene expression in REH cells can be altered by ectopic SPI-B expression. SPI-B expression was forced using CRISPR-mediated gene activation and also using a retroviral vector. Forced expression of SPI-B resulted in altered gene expression and, at high levels, impaired cell proliferation and induced apoptosis. Finally, we identified CARD11 and CDKN1A (encoding p21) as transcriptional targets of SPI-B involved in regulation of proliferation and apoptosis. Taken together, this study identifies SPIB as an important target of ETV6-RUNX1 in regulation of B-cell gene expression in t(1221) leukemia.

Inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-HCVD) with or without blinatumomab versus standard intensive chemotherapy (HCVAD) as frontline therapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukemia A propensity score analysis.

The outcome of older patients with newly diagnosed, Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) is poor. The combination of targeted therapy with low-intensity chemotherapy is safe and effective. The objective of the current analysis was to compare the outcome of patients who received a combination of inotuzumab ozogamicin plus low-intensity chemotherapy (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone mini-HCVD) with or without blinatumomab versus the outcome of those who received the standard, intensive, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) regimen. The authors analyzed 135 older patients with newly diagnosed, Ph-negative ALL who were treated prospectively with standard HCVAD (n 77) or with the combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab (n 58). A propensity score analysis was conducted using 11 matching using the nearest neighbor matching method. Propensity score matching identified 38 patients in each cohort. The antibody plus low-intensity chemotherapy combination induced higher response rates (98% vs 88%), with lower rates of early death (0% vs 8%) and lower rates of death in complete remission (5% vs 17%). With propensity score matching, the 3-year event-free survival rates for patients who received HCVAD and those who received the combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab were 34% and 64%, respectively (P .003), and the 3-year overall survival rates were 34% and 63%, respectively (P .004). By multivariate analysis, age (P .019 hazard ratio, 1.045) and the combination of inotuzumab plus mini-HCVD with or without blinatumomab (P .020 hazard ratio, 0.550) were identified as independent prognostic factors for survival. The combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab is safe and effective in older patients with newly diagnosed, Ph-negative ALL and confers a better outcome compared with standard HCVAD chemotherapy.

CD20-negative primary middle ear diffuse large B-cell lymphoma coexpressing MYC and BCL-2 secondary to acute lymphoblastic leukemia A case report.

Second diffuse large B-cell lymphoma (DLBCL) after treatment of acute lymphoblastic leukemia (ALL) is uncommon. To our knowledge, primary middle ear DLBCL which presents CD20-negative and coexpression of MYC and BCL-2 has not been reported yet. A 20-year-old Chinese man complained fever and weakness for 2 months. Subsequently bone marrow morphology and flow cytometry immunophenotype suggested ALL. Administrated with 9 cycles of multiagent combined chemotherapy, he felt right ear progressive hearing loss, otalgia, aural fullness. Otoendoscopic examination revealed a pitchy mass obstructing the right external auditory canal. Then the mass resection was performed for biopsy and immunohistochemistry examination. The mass was diagnosed as DLBCL which was negative for CD20 and double expression of MYC and BCL-2. Chemotherapy. The patient eventually gave up and died of severe infection. Although intensive chemotherapy has markedly improved the survival of ALL, more and more secondary cancers have been reported. In addition, primary middle ear lymphoma is much rare hence, it is easy to be misdiagnosed. Furthermore, DLBCL with negative CD20 and double expression of MYC and BCL-2 is aggressive, which is characterized by chemotherapy resistance and inferior survival rates. We discuss this case aiming at raising awareness of tumors secondary to ALL and exploring the appropriate treatment options for the rare DLBCL.

Trends in International Incidence of Pediatric Cancers in Children Under 5 Years of Age 1988-2012.

Pediatric cancer incidence has been steadily increasing over the last several decades with the largest increases reported in infants. Few evaluations have looked at international pediatric cancer incidence trends in the youngest children. The aim of this analysis was to evaluate trends in cancer incidence in children under 5 years of age, overall and by type, using data from Rates of cancers in children ages 0-4 years were extracted from registries available in Overall, in children under 5 years, increasing incidence was seen in multiple regions for acute lymphoblastic leukemia, acute myeloid leukemia, ependymal tumors, neuroblastoma, and hepatoblastoma. Hepatoblastoma had the largest AAPC in 11 out of 15 regions and showed an increase in all regions except southern Asia. Astrocytic tumors were the only cancer that decreased over the time period. We evaluated 25 years of cancer incidence in children ages 0-4 years and observed increases in incidence for hepatoblastoma, leukemia, neuroblastoma, and ependymal tumors. Further etiologic evaluation will be required to explain these increases in incidence.

Three-Dimensional Printed Patient Models for Complex Pediatric Spinal Surgery.

Identification of a single-nucleotide polymorphism within

Infant milk-feeding practices and childhood leukemia a systematic review.

During the Pregnancy and Birth to 24 Months Project, the US Departments of Agriculture and Health and Human Services initiated a review of evidence on diet and health in these populations. The aim of these systematic reviews was to examine the relation of 1) never versus ever feeding human milk, 2) shorter versus longer durations of any human milk feeding, 3) shorter versus longer durations of exclusive human milk feeding, and 4) feeding a lower versus higher intensity of human milk to mixed-fed infants with acute childhood leukemia, generally, and acute lymphoblastic leukemia, specifically. The Nutrition Evidence Systematic Review team conducted systematic reviews with external experts. We searched CINAHL, Cochrane, Embase, and PubMed for articles published January 1980 to March 2016, dual-screened the results using predetermined criteria, extracted data from and assessed risk of bias for each included study, qualitatively synthesized the evidence, developed conclusion statements, and graded the strength of the evidence. We included 24 articles from case-control or retrospective studies. Limited evidence suggests that never feeding human milk versus 1) ever feeding human milk and 2) feeding human milk for durations ≥6 mo are associated with a slightly higher risk of acute childhood leukemia, whereas evidence comparing never feeding human milk with feeding human milk for durations <6 mo is mixed. Limited evidence suggests that, among infants fed human milk, a shorter versus longer duration of human milk feeding is associated with a slightly higher risk of acute childhood leukemia. None of the included articles examined exclusive human milk feeding or the intensity of human milk fed to mixed-fed infants. Feeding human milk for short durations or not at all may be associated with slightly higher acute childhood leukemia risk. The evidence could be strengthened with access to broadly generalizable prospective samples therefore, we recommend linking surveillance systems that collect infant feeding and childhood cancer data.

Catheter-related bloodstream infection by Microbacterium paraoxydans in a pediatric patient with B-cell precursor acute lymphocytic leukemia A case report and review of literature on Microbacterium bacteremia.

Microbacterium species are coryneform gram-positive rods that are widely distributed in the environment and have been recently recognized as rare pathogens in humans. However, information about the epidemiologic and clinical characteristics of Microbacterium species is scarce. We herein reported an 11-year-old girl with acute leukemia who was found to have catheter-related bloodstream infection in her neutropenic phase. Gram-positive bacilli repeatedly grew on the blood cultures and were later confirmed by 16S rRNA analysis as Microbacterium paraoxydans. A literature review found available clinical courses in 21 cases (7 pediatric cases) of Microbacterium spp. bacteremia. Our case and those in literature suggested that Microbacterium spp. bacteremia often occurs in patients with indwelling central venous catheters the literature review further suggested that removal of central venous catheters is required in most cases and that 16S rRNA sequence was useful in identifying in detail the species of Microbacterium.

Tisagenlecleucel for the Treatment of Relapsed or Refractory B-cell Acute Lymphoblastic Leukaemia in People Aged up to 25 Years An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellences (NICEs) Single Technology Appraisal (STA) process, Novartis submitted evidence on the clinical effectiveness and cost-effectiveness of tisagenlecleucel for treating paediatric and young adult patients (under the age of 25 years) with relapsed or refractory (rr) B-cell acute lymphoblastic leukaemia (ALL). This article presents a summary of the Evidence Review Groups (ERGs) independent review of the evidence submission, the committees deliberations, and the subsequent development of NICE guidance for the use of tisagenlecleucel on the National Health Service (NHS) in England. Tisagenlecleucel is a chimeric antigen receptor-modified T-cell (CAR-T) product, the first of this emerging therapeutic class to be considered by NICE in this indication. The companys evidence submission was based upon three single-arm, phase II studies ELIANA, ENSIGN, and B2101J. These trials demonstrated a beneficial effect of tisagenlecleucel, with significant extensions in event-free survival (EFS) and overall survival (OS) compared to historical control datasets on blinatumomab and salvage chemotherapy. Adverse events were common 77% of patients suffered from cytokine release syndrome (CRS), 56% of whom required intensive care unit-level care. The ERG did not consider clofarabine monotherapy an appropriate proxy for salvage chemotherapy. The company presented a hybrid cost-effectiveness model, combining a decision tree and three-state partitioned survival model structure. The majority of quality-adjusted life-years (QALYs) gained were generated through additional life-years in the extrapolated long-term survival phase of the model, where patients were assumed to be cured. The ERG considered the results to be subject to substantial uncertainty, due in part to immature trial data, unresolved long-term treatment effects, and a lack of appropriate comparator data. The ERG implemented a number of changes to the companys model in an alternative base case, producing deterministic incremental cost-effectiveness ratios (ICERs) of £45,397 per QALY gained versus salvage chemotherapy, and £27,732 versus blinatumomab. The probabilistic model produced ICERs of £48,265 per QALY gained versus salvage chemotherapy, and £29,501 versus blinatumomab. The committee considered the ERGs analysis to be most closely aligned with their preferred assumptions, and did not consider tisagenlecleucel to meet both of the end-of-life (EoL) criteria. In recognition of the innovative nature of tisagenlecleucel, and the present immaturity of ongoing clinical trials, the committee considered further data collection would be valuable in resolving uncertainties around OS, the technologys novel mechanism of action, and the management of CRS and B-cell aplasia. The committee therefore recommended tisagenlecleucel for use in the Cancer Drugs Fund (CDF) until the conclusion of the ELIANA study (June 2023). This appraisal highlighted the difficulty of interpreting EoL criteria in the context of curative therapies and the valuation of cure versus extension of life. Further clarification of NICEs position in these situations may be necessary to ensure consistency and equity in their decision-making.

Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma.

T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsedrefractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19

Survivorship care plan experiences among childhood acute lymphoblastic leukemia patients and their families.

As survivorship care plan (SCP) use among childhood cancer survivors and their families has not been extensively researched, we report on their experiences with receiving an SCP after the completion of therapy. Eligible patients had acute lymphoblastic leukemia, completed therapy, and had no evidence of disease at enrollment. Patients aged 7 or older (N 13) and at least one parent (N 23 for 20 total patients) were surveyed and completed assessments at enrollment (Time 1, T1), SCP delivery (Time 2, T2), and follow-up (Time 3, T3) (retention 90.9%). Surveys assessed the delivery process and SCP format. McNemar tests were used to assess change from T2-T3. Satisfaction with the SCP was generally high among parents. At T1 the majority of parents (69.6%) thought the SCP should be delivered after treatment but by T3 most preferred the plan to be delivered before the end of treatment (60.9%). While 95.7% of parents intended to share their childs SCP with another provider, family, or school at T2, only 60.9% had done so by T3 (P < 0.01). At both T2 and T3, 100% of parents agreed that the SCP would help make decisions about their childs future health care. Most patients at T3 (83.3%) felt they had learned something new from their SCP. Pediatric oncology patients and families feel SCPs are useful and will help them make decisions about health care in the future.

Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities A NOPHO ALL2008 Randomized Study.

Asparaginase is an essential drug in childhood acute lymphoblastic leukemia (ALL) therapy and is frequently given for months to obtain continuous asparagine depletion. We randomly assigned patients to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there would be decreased toxicity with unchanged efficacy. Children (median age, 4.2 years) treated for non-high-risk ALL according to the Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol received five intramuscular PEG-asp injections (1,000 IUm After a median follow-up of 4.1 years, the 5-year disease-free survival was 92.2% (95% CI, 88.6 to 95.8) and 90.8% (95% CI, 87.0 to 94.6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity n 13 osteonecrosis n 29 pancreatitis n 24 thromboembolism n 17) was 9.3% in the experimental arm and 18.1% in the standard arm ( The excellent cure rates and reduced toxicity risk support the use of intermittent PEG-asp therapy after the first 10 weeks in future childhood ALL trials that apply prolonged PEG-asp therapy.

IKZF1 Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico.

The IKZF1 gene is formed by 8 exons and encodes IKAROS, a transcription factor that regulates the expression of genes that control cell cycle progression and cell survival. In general, 15-20% of the patients with preB acute lymphoblastic leukemia (preB ALL) harbor IKZF1 deletions, and the frequency of these deletions increases in BCR-ABL1 or Ph-like subgroups. These deletions have been associated with poor treatment response and the risk of relapse. The aim of this descriptive study was to determine the frequency of IKZF1 deletions and the success of an induction therapy response in Mexican pediatric patients diagnosed with preB ALL in 2 hospitals from 2017 to August 2018. Thirty-six bone marrow samples from patients at the Instituto Nacional de Pediatría in Mexico City and the Centro Estatal de Cancerología in Tepic were analyzed. The IKZF1 deletion was identified by MLPA using the SALSA MLPA P335 ALL-IKZF1 probemix. Deletions of at least 1 IKZF1 exon were observed in 734 samples (20.6%) 3 with 1 exon deleted 1 with 2 exons, 1 with 5 exons, 1 with 6 exons, and 1 patient with a complete IKZF1 deletion. This study was descriptive in nature we calculated the frequency of the IKZF1 gene deletion in a Mexican pediatric population with preB ALL as 20.6%.

Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia.

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.

What is the Role of Hematopoietic Cell Transplantation (HCT) for Pediatric Acute Lymphoblastic Leukemia (ALL) in the Age of Chimeric Antigen Receptor T-Cell (CART) Therapy

CD19 chimeric antigen receptor T-cell (CART) therapy has revolutionized the treatment of patients with relapsedrefractory hematologic malignancies, especially B-cell acute lymphoblastic leukemia. As CART immunotherapy expands from clinical trials to FDA-approved treatments, a consensus among oncologists and hematopoietic cell transplant (HCT) physicians is needed to identify which patients may benefit from consolidative HCT post-CART therapy. Here, we review CD19 CART therapy and the outcomes of published clinical trials, highlighting the use of post-CART HCT and the pattern of relapse after CD19 CART. At this time, the limited available long-term data from clinical trials precludes us from making definitive HCT recommendations. However, based on currently available data, we propose that consolidative HCT post-CART therapy be considered for all HCT-eligible patients and especially for pediatric patients with KMT2A-rearranged B-cell acute lymphoblastic leukemia.

Most Variable Genes and Transcription Factors in Acute Lymphoblastic Leukemia Patients.

Acute lymphoblastic leukemia (ALL) is a hematologic tumor caused by cell cycle aberrations due to accumulating genetic disturbances in the expression of transcription factors (TFs), signaling oncogenes and tumor suppressors. Though survival rate in childhood ALL patients is increased up to 80% with recent medical advances, treatment of adults and childhood relapse cases still remains challenging. Here, we have performed bioinformatics analysis of 207 ALL patients mRNA expression data retrieved from the ICGC data portal with an objective to mark out the decisive genes and pathways responsible for ALL pathogenesis and aggression. For analysis, 3361 most variable genes, including 276 transcription factors (out of 16,807 genes) were sorted based on the coefficient of variance. Silhouette width analysis classified 207 ALL patients into 6 subtypes and heat map analysis suggests a need of large and multicenter dataset for non-overlapping subtype classification. Overall, 265 GO terms and 32 KEGG pathways were enriched. The lists were dominated by cancer-associated entries and highlight crucial genes and pathways that can be targeted for designing more specific ALL therapeutics. Differential gene expression analysis identified upregulation of two important genes, JCHAIN and CRLF2 in dead patients cohort suggesting their possible involvement in different clinical outcomes in ALL patients undergoing the same treatment.

The mechanisms of taxodione-induced apoptosis in BCR-ABL-positive leukemia cells.

Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are caused by a fusion protein, BCR-ABL, which induces cellular transformation by activating the signaling molecules, STAT5 and Akt. The specific BCR-ABL inhibitors including imatinib, nilotinib, and dasatinib, are clinically utilized in the treatment with CML and ALL patients. Although these BCR-ABL inhibitors are initially successful in the treatment of leukemia, many patients develop drug resistance due to the appearance of the gatekeeper mutation of BCR-ABL, T315I. Recently, we found that taxodione, a quinone methide diterpene isolated from a conifer, Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which is positive for the bcr-abl gene. Taxodione reduced the activities of mitochondrial respiratory chain complex III, leading to the production of reactive oxygen species (ROS). An antioxidant agent, N-acetylcysteine (NAC), canceled taxodione-induced ROS production and apoptotic cell death, suggesting that taxodione induced apoptosis through ROS accumulation. Furthermore, in K562 cells treated with taxodione, BCR-ABL, STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation. Strikingly, NAC canceled these taxodione-caused inhibition of BCR-ABL, STAT5 and Akt. In addition, taxodione significantly induced apoptosis in transformed BaF3 cells by not only BCR-ABL but also T315I-mutated BCR-ABL through the generation of ROS, suggesting that taxodione has potential as anti-tumor drug with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells. Its also expected that these knowledge becomes an important clue in the development of anti-cancer drugs against the broad range of tumors.

Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells.

Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T- acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS411) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with 10 μM up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to 1.94 μM. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3KAKT, MAPK and JAKSTAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.

Treatment of relapsedrefractory acute lymphoblastic leukemia.

Patients with relapsed or refractory acute lymphoblastic leukemia (RR ALL) have dismal outcomes, with survival of less than 6 months, and treatment options in the salvage setting have been limited to conventional cytotoxic chemotherapy with minimal activity. Advances in the development of novel targeted therapies have significantly improved outcomes in RR ALL. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy constitute new treatment modalities that are challenging the historical regimens and paving a new path for treating patients with RR ALL.

Psychological intervention based on psychoneuroimmunology improves clinical evolution, quality of life, and immunity of children with leukemia A preliminary study.

We conducted a non-randomized, open-label clinical trial to assess whether a psychoneuroimmunology-based intervention enhanced immunity in children with acute lymphoblastic leukemia undergoing chemotherapy. In total, 16 children (44% female) received psychoneuroimmunology-based intervention, whereas 12 (50% female) received health psychoeducation (controls). The primary outcome was immunity markers, being clinical conditions the secondary outcome. Psychoneuroimmunology-based intervention increased immune markers (CD8 T, B, and natural killer cells, serum immunoglobulin A, and immunoglobulin M) and quality of life, whereas it shortens the duration of fever and use of antipyretics, antibiotics, analgesics, and respiratory therapy. Immunity markers correlated with clinical conditions. Thus, psychoneuroimmunology-based intervention could reduce hospital cost and increase patient well-being.

The anti-malarial drug chloroquine sensitizes oncogenic NOTCH1 driven human T-ALL to γ-secretase inhibition.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from T-cell progenitors. Although current treatments, including chemotherapy and glucocorticoids, have significantly improved survival, T-ALL remains a fatal disease and new treatment options are needed. Since more than 60% of T-ALL cases bear oncogenic NOTCH1 mutations, small molecule inhibitors of NOTCH1 signalling γ-secretase inhibitors (GSI), are being actively investigated for the treatment of T-ALL. Unfortunately, GSI have shown limited clinical efficacy and dose-limiting toxicities. We hypothesized that by combining known drugs, blocking NOTCH activity through another mechanism, may synergize with GSI enabling equal efficacy at a lower concentration. Here, we show that the clinically used anti-malarial drug chloroquine (CQ), an inhibitor of lysosomal function and autophagy, decreases T-ALL cell viability and proliferation. This effect of CQ was not observed in GSI-resistant T-ALL cell lines. Mechanistically, CQ impairs the redox balance, induces ds DNA breaks and activates the DNA damage response. CQ also interferes with intracellular trafficking and processing of oncogenic NOTCH1. Interestingly, we show for the first time that the addition of CQ to γ-secretase inhibition has a synergistic therapeutic effect on T-ALL and reduces the concentration of GSI required to obtain a reduction in cell viability and a block of proliferation. Overall, our results suggest that CQ may be a promising repurposed drug in the treatment of T-ALL, as a single treatment or in combination with GSI, increasing the therapeutic ratio.

CAR T Cell Immunotherapy in Human and Veterinary Oncology Changing the Odds Against Hematological Malignancies.

The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkins lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.

Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation.

The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.

An age-based, RNA expression paradigm for survival biomarker identification for pediatric neuroblastoma and acute lymphoblastic leukemia.

Pediatric cancer survival rates overall have been improving, but neuroblastoma (NBL) and acute lymphoblastic leukemia (ALL), two of the more prevalent pediatric cancers, remain particularly challenging. One issue not yet fully addressed is distinctions attributable to age of diagnosis. In this report, we verified a survival difference based on diagnostic age for both pediatric NBL and pediatric ALL datasets, with younger patients surviving longer for both diseases. We identified several gene expression markers that correlated with age, along a continuum, and then used a series of age-independent survival metrics to filter these initial correlations. For pediatric NBL, we identified 2 genes that are expressed at a higher level in lower surviving patients with an older diagnostic age and 4 genes that are expressed at a higher level in longer surviving patients with a younger diagnostic age. For pediatric ALL, we identified 3 genes expressed at a higher level in lower surviving patients with an older diagnostic age and 17 genes expressed at a higher level in longer surviving patients with a younger diagnostic age. This process implicated pan-chromosome effects for chromosomes 11 and 17 in NBL and for the X chromosome in ALL.

Osteomyelitis Caused by Carbapenemase-Producing Klebsiella Pneumoniae A Diagnosis to Consider in Patients with Hematologic Malignancies and Stem Cell Transplant Recipients.

BACKGROUND Osteomyelitis (OM) due to carbapenemase-producing Klebsiella pneumoniae (CPKp) is a very rare but severe condition, particularly among patients with hematologic malignancies and stem cell transplant recipients, who are especially at risk of developing nosocomial infections caused by this bacterium. CASE REPORT We describe 2 cases of acute and chronic OM by CPKp in adults with hematologic disorders. Patient 1, with acute lymphoblastic leukemia, developed bacteremia due to multidrug CPKp after induction chemotherapy. Despite pathogen-directed antibiotic treatment, blood cultures remained positive for CPKp, with an increase in its resistance pattern, and worsening of clinical condition. A pelvic computed tomography revealed air bubbles in the femoral head and ilium, suggestive of OM, and bone culture was positive for pandrug-resistant CPKp. The clinical condition deteriorated rapidly and the patient died. Patient 2, with aplastic anemia, developed multidrug CPKp bacteremia after immunosuppressive therapy, with good response to pathogen-directed antibiotic treatment. Ten months later, she underwent a hematopoietic stem cell transplant, and at the time of neutrophil engraftment, an abscess developed in the right thigh. An extensively drug-resistant CPKp was isolated from the pus, and antibiotics were started, without clinical improvement. A magnetic resonance of the thigh revealed an intraosseous abscess, suggestive of OM, and after debridement surgery and 6 weeks of parenteral antibiotics, she was successfully discharged home. CONCLUSIONS OM due to CPKp is uncommonly reported. These 2 cases illustrate the complex management of OM by CPKp in immunocompromised hematologic patients, and the importance of clinical suspicion for a prompt diagnosis, early treatment, and successful outcome.

Cutting Edge Lymphomyeloid-Primed Progenitor Cell Fates Are Controlled by the Transcription Factor Tal1.

Lymphoid specification is the process by which hematopoietic stem cells (HSCs) and their progeny become restricted to differentiation through the lymphoid lineages. The basic helix-loop-helix transcription factors E2A and Lyl1 form a complex that promotes lymphoid specification. In this study, we demonstrate that Tal1, a Lyl1-related basic helix-loop-helix transcription factor that promotes T acute lymphoblastic leukemia and is required for HSC specification, erythropoiesis, and megakaryopoiesis, is a negative regulator of murine lymphoid specification. We demonstrate that Tal1 limits the expression of multiple E2A target genes in HSCs and controls the balance of myeloid versus T lymphocyte differentiation potential in lymphomyeloid-primed progenitors. Our data provide insight into the mechanisms controlling lymphocyte specification and may reveal a basis for the unique functions of Tal1 and Lyl1 in T acute lymphoblastic leukemia.

Correction to socioeconomic inequalities in survival of children with acute lymphoblastic leukemia insured by social security in Mexico a study of the 2007-2009 cohorts.

Following publication of the original article 1, the author reported her name has been erroneously spelled as Blanca E. Pelcastre. The full name is Blanca E. Pelcastre-Villafuerte.

Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway.

Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure. LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis. We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71. The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.

Case report on hypersensitivity to methotrexate infusion in a pediatric acute lymphoblastic leukaemia patient.

Methotrexate is extensively used in the treatment of various malignancies and autoimmune conditions. Methotrexate is associated with several toxicities, while hypersensitivity reactions to methotrexate are unusual, but have been reported in adult cancer patients. Hereby, we detail the case of a child with acute lymphoblastic leukaemia who developed a hypersensitivity reaction to high-dose methotrexate infusion (HDMTX) during the fourth cycle of HDMTX. The child was rechallenged with another brand of methotrexate she started complaining of itching on trunk within 5 min of infusion. Few studies have reported that desensitization has been helpful in children with hypersensitivity reactions allowing the continuation of HDMTX. However, it was decided to omit parenteral methotrexate for this child. Cranial radiotherapy was given for CNS prophylaxis. In conclusion, unexpected hypersensitivity with methotrexate should be kept in mind during the treatment especially with high-dose infusion.

Suppression of c-Myc using 10058-F4 exerts caspase-3-dependent apoptosis and intensifies the antileukemic effect of vincristine in pre-B acute lymphoblastic leukemia cells.

Despite an old history behind the identification of the leading role of c-Myc in leukemogenesis, the road to constructing a therapeutic perspective for this molecule in acute lymphoblastic leukemia (ALL) is yet mesmerizing. This study was designed to provide a better outlook for the anticancer property of 10058-F4, an appealing inhibitor of c-Myc, in pre-B ALL cell lines either in the context of monotherapy or in combination with chemotherapeutic drugs. Our results declared that abrogation of c-Myc decreased the proliferative capacity of pre-B ALL-derived cells through halting the transition of the cells from G1 phase, and reducing the replicative potential of both REH and Nalm-6 cells, at least partly, through c-Myc-mediated suppression of human telomerase reverse transcriptase. Moreover, 10058-F4 potently induced a caspase-3-dependent apoptosis in pre-B ALL cells via shifting the balance between pro- and anti-apoptotic target genes. Although the inhibition of PI3Kδ using Idelalisib upregulated the messenger RNA expression of autophagy-related genes in 10058-F4-treated cells, treatment with autophagy inhibitor chloroquine decreased viability of the cells, either as a single agent or in combination with Idelalisib andor 10058-F4 suggesting that the activation of autophagy in pre-B ALL cells could blunt apoptotic events and attenuate anticancer effect of both c-Myc and PI3K inhibitors. Finally, the results of our synergistic experiments delineated that 10058-F4 produced a synergistic effect with vincristine and provided an enhanced therapeutic efficacy in ALL cells, highlighting that c-Myc oncoprotein could be a bona fide target for the treatment of ALL.

Bortezomib reinduction chemotherapy in high-risk ALL in first relapse a report from the Childrens Oncology Group.

While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Childrens Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18-36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFSOS of 0-3% (P 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFSOS 58-65% vs. MRDpos 10-19%, EFS P 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at httpwww.clinical.trials.gov as NCT00873093.

Outcome and prognostic factors of children with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib followed by allogeneic hematopoietic cell transplantation in first remission.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) is a subset of ALL with poor prognosis. Here, we analyzed the outcomes and prognostic factors of children with Ph ALL who received imatinib and chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR). Thirty-one Ph ALL patients (female 10) diagnosed from January 2005 to December 2016 were included in the study. All patients were treated with imatinib and chemotherapy before HCT. Bone marrow (BM) evaluations included real-time quantitative polymerase chain reaction (RQ-PCR) study of the Compared to values at diagnosis, the median decrement of RQ-PCR value post-consolidation, and prior to HCT was -3.7 Log and -4.8 Log, respectively. The 5-year event-free survival (EFS) and overall survival of the patients were 64.5±9.4% (2031) and 75.0±8.3% (2331) respectively. Events included relapse (N5) and death in CR post-HCT (N6). The 5-year incidence of molecular relapse was 30.9±9.1% (931). An RQ-PCR decrement of at least -4 Log post-consolidation significantly predicted lower incidence of molecular relapse 7.7±7.7% for ≥-4 Log decrement, 50.0±13.8% for <-4 Log decrement ( Decrement in RQ-PCR for the

Cancer survival trends in Kuwait, 2000-2013 A population-based study.

To examine population-based cancer survival trends in Kuwait to facilitate public assessment of cancer control. Data were obtained from the Kuwait Cancer Registry for Kuwaiti adults (15-99 years) and children (0-14 years) diagnosed with one of 18 common cancers during 2000-2013 and followed up to 31 December 2014. Net survival was estimated at 1, 3, and 5 years by sex. To control for background mortality, life tables of all-cause mortality in the general population were constructed by single year of age, sex, and calendar year of death (complete life tables). Net survival estimates were age-standardised using the International Cancer Survival Standard weights. Cancers with the highest net survival throughout the 14-year period were prostate, breast (women) and rectum in adults, and lymphoma in children. Survival was lowest for liver, pancreas and lung cancer in adults, and brain tumours in children. During 2010-2013, one year survival was over 80% for cancers of the prostate, breast, rectum, cervix and colon. Five-year survival was above 80% only for prostate cancer. For children, one and five-year survival was above 80% only for acute lymphoblastic leukaemia (ALL) and lymphoma. Survival was generally higher for women than men, and declined faster in women than men between 1 and 3 years after diagnosis. Differences between boys and girls were small. Cancer survival improved for most Kuwaiti adults and children over the 14-year period, with women generally having a more favourable prognosis than men. Continuous surveillance is required to monitor cancers for which survival did not improve, and to dissect the underlying causes for the differences in survival between Kuwait and other countries.

Strong expression of p53 protein in bone marrow samples after hematopoietic stem cell transplantation indicates risk of relapse in pediatric acute lymphoblastic leukemia patients.

For pediatric ALL patients that relapse or respond poorly to conventional chemotherapy treatment, HSCT is one treatment option. Still, relapse occurs in 30% of the children after HSCT. Mutations in the tumor suppressor gene TP53 which can lead to an altered p53 protein expression are rare at time of diagnosis of ALL, yet occur more frequent at relapse indicating a more aggressive disease. Our aim was to evaluate if alterations in the expression of the tumor suppressor protein p53 signaled a relapse in pediatric ALL patients post-HSCT and could guide for preemptive immunotherapy. Paraffin-embedded bone marrow samples from 46 children diagnosed with ALL between 1997 and 2010, and transplanted at Karolinska University Hospital, were analyzed for p53 by IHC. Samples were analyzed independently at diagnosis, before HSCT, and after HSCT 0-3 months, 3-6 months, and 6-12 months. Strong expression of p53 in the bone marrow at 0-3-months after HSCT was associated with increased risk of relapse, odds ratio 2.63 (confidence interval 1.08-6.40) P 0.033. Evaluation of p53 protein expression in bone marrow from pediatric ALL patients that undergo HSCT may be a potential, additional prognostic marker for predicting relapse after HSCT.

A multicentre retrospective cohort study of ovarian germ cell tumours Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice.

Adult guidelines recommend BEP (bleomycin, etoposide, cisplatin) for all ovarian germ cell tumours, causing debilitating toxicities in young patients who will survive long term. Paediatricians successfully reduce toxicities by using lower bleomycin doses and substituting carboplatin for cisplatin, while testicular and paediatric immature teratomas (ITs) are safely managed with surgery alone. The aim was to determine whether reduced-toxicity treatment could rationally be extended to patients older than 18 years. Multicentre cohort study was carried out in four large UK cancer centres over 12 years. One hundred thirty-eight patients were enrolled. Overall survival was 93%, and event-free survival (EFS) was 72%. Neoadjuvantadjuvant chemotherapy (82% BEP) caused 27 potentially chronic toxicities, and one patient subsequently died from acute lymphoblastic leukaemia. There was no difference in histology, stage or grade in patients ≤>18 years, and EFS was not different in these age groups (≤1828% and >1828% log-rank P 0.96). Histological subtype powerfully predicted EFS (log-rank P 4.9 × 10 Survival was excellent but chemotherapy toxicities were severe, implying significant overtreatment. Our data support the extension of reduced-toxicity, paediatric regimens to adults. Our practice-changing findings that IT was chemotherapy resistant and pathological grade uninformative strongly endorse exclusive surgical management of ovarian ITs at all ages.

Prognostic and predictive value of a microRNA signature in adults with T-cell lymphoblastic lymphoma.

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n 75) and fetal thymus tissues (n 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression lower risk was associated with better prognosis (disease-free survival (DFS) hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001 overall survival (OS) HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n 106) and the independent external set (n 304). High risk was associated with more favorable response to HSCT (DFS HR 1.675, 95% CI 1.127-2.488, p 0.011 OS HR 1.602, 95% CI 1.055-2.433, p 0.027). When combined with ECOG-PS andor NOTCH1FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS HR 2.088, 95% CI 1.290-3.379, p 0.003 OS HR 1.996, 95% CI 1.203-3.311, p 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.

Complete Blood Count Score Model Integrating Reduced Lymphocyte-Monocyte Ratio, Elevated Neutrophil-Lymphocyte Ratio, and Elevated Platelet-Lymphocyte Ratio Predicts Inferior Clinical Outcomes in Adult T-Lymphoblastic Lymphoma.

T-lymphoblastic lymphoma (T-LBL) is a highly aggressive neoplasm of lymphoblasts of T-cell origin. Although promising improvements have been recently achieved, one third of patients experience relapse or refractory T-LBL. Therefore, optimal strategies for identifying high-risk patients are urgently needed. In the present study, 75 newly diagnosed adult patients (aged ≥15 years) with T-LBL were identified and the predictive value of complete blood count (CBC) abnormalities, including lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) on clinical outcomes, was analyzed. Using the receiver operating characteristic curve to determine the best cutoff values based on survival, it was found that patients with T-LBL with LMR ≤2.8, NLR ≥3.3, and PLR ≥200 had both inferior progression-free survival (PFS) and inferior overall survival (OS), in which the differences were much more remarkable in the international prognostic index score 0-2 subgroup. In the multivariable analysis, NLR ≥3.3 together with age >40 years and central nervous system (CNS) involvement were identified to be independently associated with shortened PFS, whereas PLR ≥200 and CNS involvement were identified to be independent risk factors for OS. LMR, NLR, and PLR were integrated to generate a CBC score model, which well separated adult patients with T-LBL into three risk groups, and the 3-year OS was 84%, 53%, and 30% for low-, intermediate-, and high-risk patients, respectively. Overall, a CBC score model was initially promoted for stratification in adult patients with T-LBL using simple, widely available, and easy to interpret parameters in the largest adult T-LBL cohort to date. Optimal strategies for identifying high-risk patients with T-lymphoblastic lymphoma (T-LBL) are urgently needed. In the largest adult T-LBL cohort to date, simple, inexpensive, widely available parameters were applied and revealed that patients with lymphocyte-monocyte ratio (LMR) ≤2.8, neutrophil-lymphocyte ratio (NLR) ≥3.3, and platelet-lymphocyte ratio (PLR) ≥200 had both inferior progression-free survival and inferior overall survival (OS), in which the differences were much more remarkable in the international prognostic index score 0-2 subgroup. LMR, NLR, and PLR were integrated to generate a complete blood count score model, in which the 3-year OS was 84%, 53%, and 30% for low-, intermediate-, and high-risk patients, respectively.

Effect of Stem Cell Transplant on Survival in Adult Patients With Acute Lymphoblastic Leukemia NCDB Analysis.

A retrospective analysis was performed to investigate the survival outcomes in adult acute lymphoblastic leukemia (ALL) based on treatment received. Data from 17,504 men and women (≥18 years of age) registered in the National Cancer Database who were diagnosed with ALL between 2004 and 2013 and had follow-up to the end of 2014, were analyzed. The primary predictor variable was treatment received, and overall survival was the outcome variable. Additional variables addressed and adjusted included gender, age, race, Charleston Comorbidity Index, level of education, income, insurance, distance traveled, facility type and diagnosingtreating facility. The mean age of patients was 48.8 years with a standard deviation of 19.3 years. In multivariate analysis, after adjusting for secondary predictor variables, treatment modality was a statistically significant predictor of overall survival from ALL. Relative to patients who were treated with chemotherapy only, the patients who got chemotherapy and stem cell transplant had a decreased risk of mortality by 39%. Of the 5,409 patients between the ages of 18 and 39 years i.e. adolescent and young adults (AYA), no statistically significant survival difference was found between patients treated with stem cell transplant and those not. Stem cell transplant led to improved survival for all age groups except the AYA.

Alternative splicing of the tumor suppressor ASPP2 results in a stress-inducible, oncogenic isoform prevalent in acute leukemia.

Apoptosis-stimulating Protein of TP53-2 (ASPP2) is a tumor suppressor enhancing TP53-mediated apoptosis via binding to the TP53 core domain. TP53 mutations found in cancers disrupt ASPP2 binding, arguing for an important role of ASPP2 in TP53-mediated tumor suppression. We now identify an oncogenic splicing variant, ASPP2κ, with high prevalence in acute leukemia. An mRNA screen to detect ASPP2 splicing variants was performed and ASPP2κ was validated using isoform-specific PCR approaches. Translation into a genuine protein isoform was evaluated after establishing epitope-specific antibodies. For functional studies cell models with forced expression of ASPP2κ or isoform-specific ASPP2κ-interference were created to evaluate proliferative, apoptotic and oncogenic characteristics of ASPP2κ. Exon skipping generates a premature stop codon, leading to a truncated C-terminus, omitting the TP53-binding sites. ASPP2κ translates into a dominant-negative protein variant impairing TP53-dependent induction of apoptosis. ASPP2κ is expressed in CD34 leukemic progenitor cells and functional studies argue for a role in early oncogenesis, resulting in perturbed proliferation and impaired induction of apoptosis, mitotic failure and chromosomal instability (CIN) - similar to TP53 mutations. Importantly, as expression of ASPP2κ is stress-inducible it defines a novel class of dynamic oncogenes not represented by genomic mutations. Our data demonstrates that ASPP2κ plays a distinctive role as an antiapoptotic regulator of the TP53 checkpoint, rendering cells to a more aggressive phenotype as evidenced by proliferation and apoptosis rates - and ASPP2κ expression results in acquisition of genomic mutations, a first initiating step in leukemogenesis. We provide proof-of-concept to establish ASPP2κ as a clinically relevant biomarker and a target for molecule-defined therapy. FUND Unrestricted grant support from the Wilhelm Sander Foundation for Cancer Research, the IZKF Program of the Medical Faculty Tübingen, the Brigitte Schlieben-Lange Program and the Margarete von Wrangell Program of the State Ministry Baden-Wuerttemberg for Science, Research and Arts and the Athene Program of the excellence initiative of the Eberhard-Karls University, Tübingen.

Gene mutations and pretransplant minimal residual disease predict risk of relapse in adult patients after allogeneic hematopoietic stem-cell transplantation for T cell acute lymphoblastic leukemia.

We retrospectively analyzed outcomes of 120 hematopoietic stem cell transplantation (HSCT) patients with T cell acute lymphoblastic leukemia (T-ALL), with emphases on gene mutations and pre-transplant minimal residual disease (MRD). Patients with NOTCH1FBXW7 (NF) mutations but no RAS or PTEN abnormalities were considered genetic low risk (gLoR), whereas those with RASPTEN alterations or no NF mutations were considered high risk (gHiR). The gLoR and gHiR groups differed significantly in 3-year CIR (gLoR 12.4%, gHiR 41.2%,

Early T-cell precursor acute lymphoblastic leukemia with

Early T-cell precursor acute lymphoblastic leukemialymphoma (ETP-ALL) is a recently recognized subgroup of T lymphoblastic leukemialymphoma thought to be derived from lymphocytes at the ETP differentiation stage that have not irreversibly committed to the T-cell lineage. The definition of ETP-ALL is based on a unique immunophenotype that also expresses at least one myeloid or stem cell marker other than myeloperoxidase and monocytic markers. Correspondingly, ETP-ALLs are often found to express myeloid-associated mutations and have stem cell gene expression profiles. Because its morphology is nonspecific, recognizing the immunophenotype of this uncommon entity is important to separate it from other closely related acute leukemias. We report a case of ETP-ALL with

First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia.

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes

Extensive intracranial haemorrhage as a complication of acute lymphoblastic leukaemia with hyperleukocytosis.

We report a rare case of distinctive extensive punctate intracranial haemorrhage associated with acute lymphoblastic leukaemia with hyperleukocytosis. A 7-year-old girl presented with hyperleukocytosis (white cell count 788.7 × 10

Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer A Systematic Review and Meta-Analysis.

Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception - November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% 95% CI, 42.5%-65.9% experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% 95% CI, 9.4%-50.3% experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% 95% CI, 40.3%-69.4% of patients and neurotoxicity 37.2% 95% CI, 28.6%-46.8% of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% 95% CI, 1.6%-10.6% experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19 hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.

Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cell precursor acute lymphoblastic leukemia.

Outcomes for adults with relapsedrefractory acute lymphoblastic leukemia (ALL) are poor with chemotherapy, particularly in later salvage. The TOWER study examined survival, remission, bridge to allogeneic hematopoietic stem cell transplantation (HSCT), and safety with blinatumomab versus chemotherapy. This report examined outcomes separately for study treatment as first or later salvage. Adults with Philadelphia chromosome-negative B-cell precursor ALL relapsedrefractory to chemotherapy were randomly assigned 21 to receive blinatumomab by continuous infusion for 4 weeks in 6-week cycles, or standard salvage chemotherapy. Overall survival for blinatumomab versus chemotherapy was higher both in first salvage and in later salvage. Safety was similar between patients in first salvage and those in later salvage. Blinatumomab as later salvage was associated with higher complete remission rates and served as a bridge to allogeneic HSCT, supporting the use of blinatumomab in both settings. This study is registered at www.clinicaltrials.gov as NCT02013167.

CD4

Regulatory T-cells (Tregs) are a very important subtype of lymphocytes when it comes to self-control in the human immunological system. Tregs are decisive not only in the protection against destruction of own tissues by autoimmune immunocompetent cells but also in the immunological answer to developing cancers. On the other hand, Tregs could be responsible for the progression of acute and chronic leukemias. In our study, we review publications available in the PUMED database concerning acute leukemia, with a particular emphasis on childs leukemias. The percentage of regulatory T-lymphocytes in peripheral blood and bone marrow was elevated compared to those in healthy individuals and correlated with progressive disease. Regulatory T-cells taken from children diagnosed with leukemia showed a higher suppressive capability, which was confirmed by detecting elevated levels of secreted IL-10 and TGF-beta. The possibility of pharmacological intervention in the self-control of the immunological system is now under extensive investigation in many human cancers. Presumably, Treg cells could be a vital part of targeted therapies. Routine Treg determination could be used to assess the severity of disease and prognosis in children with acute lymphoblastic leukemia. This proposition results from the fact that in some studies, higher percentage of Treg cells in peripheral blood was demonstrated. However, observations confirming these facts are scarce thus, extrapolating them to the population of children with hematological malignancies needs to be verified in additional studies.

Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.

Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 24 cases displayed a clear loss of TAD boundary strength and 34 showed reduced insulation at TAD borders, with putative leukemogenic effects.

Effect and changes in PD‑1 expression of CD19 CAR‑T cells from T cells highly expressing PD‑1 combined with reduced‑dose PD‑1 inhibitor.

CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsedrefractory B‑cell leukemia and lymphoma. However, its efficacy in patients with relapsedrefractory non‑Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death‑1programmed death‑ligand 1 (PD‑1PD‑L1) inhibitors in numerous malignancies, but the immune‑associated adverse events of PD‑1PD‑L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR‑T cells with a reduced dose of PD‑1 inhibitor. This method is expected to overcome the side-effects of PD‑1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD‑1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR‑T cells. An interesting finding of the present study was that the number of PD‑1‑positive cells CAR‑T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co‑culture time of CD19 CAR‑T cells with lymphoma cells however, there was no change in the mRNA expression of T cells and CAR‑T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR‑T cells on B‑cell lymphoma is unsatisfactory compared with B‑cell leukemia. The synergistic effect of a reduced‑dose PD‑1 inhibitor combined with CD19 CAR‑T cells from T cells highly expressing PD‑1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR‑T cells and the level of interleukin‑6 were higher compared with those in the CAR‑T cell group. In conclusion, a reduced dose of a PD‑1 inhibitor combined with CD19 CAR‑T cells appears to be a promising treatment option for relapsedrefractory B‑NHL exhibiting high PD‑1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD‑1 inhibitors.

Exploiting Necroptosis for Therapy of Acute Lymphoblastic Leukemia.

Escape from chemotherapy-induced apoptosis is a hallmark of drug resistance in cancer. The recent identification of alternative programmed cell death pathways opens up for possibilities to circumvent the apoptotic blockade in drug resistant cancer and eliminate malignant cells. Indeed, we have recently shown that programmed necrosis, termed necroptosis, could be triggered to induce cell death in a subgroup of primary acute lymphoblastic leukemia (ALL) including highly refractory relapsed cases. In this review we focus on molecular mechanisms that drive drug resistance in ALL of childhood and discuss the potential of necroptosis activation to eradicate resistant disease.

Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia.

Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.

Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice.

Insertional mutagenesis is a powerful means of identifying cancer drivers in animal models. We used the Sleeping Beauty (SB) transposontransposase system to identify activated oncogenes in hematologic cancers in wild-type mice and mice that express a stabilized cyclin E protein (termed cyclin ET74AT393A). Cyclin E governs cell division and is misregulated in human cancers. Cyclin ET74AT393A mice develop ineffective erythropoiesis that resembles early-stage human myelodysplastic syndrome, and we sought to identify oncogenes that might cooperate with cyclin E hyperactivity in leukemogenesis. SB activation in hematopoietic precursors caused T-cell leukemialymphomas (T-ALL) and pure red blood cell erythroleukemias (EL). Analysis of >12,000 SB integration sites revealed markedly different oncogene activations in EL and T-ALL Notch1 and Ikaros were most common in T-ALL, whereas ETS transcription factors (Erg and Ets1) were targeted in most ELs. Cyclin E status did not impact leukemogenesis or oncogene activations. Whereas most SB insertions were lost during culture of EL cell lines, Erg insertions were retained, indicating Ergs key role in these neoplasms. Surprisingly, cyclin ET74AT393A conferred growth factor independence and altered Erg-dependent differentiation in EL cell lines. These studies provide new molecular insights into erythroid leukemia and suggest potential therapeutic targets for human leukemia.

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically. AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized. We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.

Germline deletion of

Recent studies have identified germline mutations in

Cost-effectiveness analysis of rasburicase over standard of care for the prevention and treatment of tumor lysis syndrome in children with hematologic malignancies in China.

Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. A novel risk locus in the USP7 gene (rs74010351, odds ratio OR 1.44, 95% confidence interval CI 1.27 to 1.65, P 4.51 × 10-8) reached genome-wide significance in the discovery cohort, with independent validation (OR 1.51, 95% CI 1.03 to 2.22, P .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this raceethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

BCR-ABL1-like B-Lymphoblastic LeukemiaLymphoma with FOXP1-ABL1 Rearrangement Comprehensive Laboratory Identification Allowing Tyrosine Kinase Inhibitor Use.

B-lymphoblastic leukemialymphoma (B-ALL) is the most common type of childhood cancer it also occurs in teenagers and adults, in whom the prognosis is generally less favorable. Therapeutic and molecular advances have substantially improved the treatment for subtypes of B-ALL, such that subclassification by cytogenetic and molecular alterations is critical for risk stratification and management. Novel rearrangements involving ABL1, JAK2, EPO, and other kinases have been identified that may respond to inhibition akin to BCR-ABL1. This diverse group of leukemias has been recognized as a provisional entity in the 2016 revision of the World Health Organization (WHO) Classification of the Hematopoietic Neoplasms as B-lymphoblastic leukemialymphoma, BCR-ABL1-like (Ph-like B-ALL). Herein, we present cytogenetic and molecular analysis of a case of B-ALL in a 16-year-old Caucasian boy with t(39) FOXP1-ABL1 rearrangement and concurrent loss of IKZF1, CDKN2A, and RB1 gene loci, meeting WHO criteria for Ph-like ALL. This case highlights diagnostic, prognostic, and therapeutic considerations of this recently recognized entity.

Antithrombin and fibrinogen levels as predictors for plasma L-asparaginase activity in children with acute lymphoblastic leukemia.

L-asparaginase is a cornerstone treatment for children with acute lymphoblastic leukemia (ALL). However, immune reaction to the drug may increase the clearance or impair the function of L-asparaginase and reduces its therapeutic efficacy. The objective of this study was to identify potential plasma proteins that could be used as proxies for L-asparaginase activity. Fibrinogen, von Willebrand factor antigen (VWFAg), total protein, and albumin levels as well as antithrombin (AT) and L-asparaginase activities were measured in 97 children with ALL treated for prolonged period of time with L-asparaginase. Binary logistic regression and a receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive value of plasma proteins for L-asparaginase activity. Median E. coli L-asparaginase activity was 220 IUL (range, 0-1308) throughout the treatment period. L-asparaginase activity was below 100 IUL in 23% of measured samples. L-asparaginase activity was inversely associated with AT activity, fibrinogen, total protein, and albumin levels (r -0.63, -0.62, -0.57, and -0.45, respectively P < 0.0001), but not with VWFAg. ROC curve analyses showed an intermediate accuracy of AT activity (area under the ROC curve AUC 0.77) to detect specimens with subtherapeutic level of L-asparaginase. An optimal accuracy was found when AT and fibrinogen were combined (AUC 0.82 sensitivity 75% specificity 82% positive predictive value 55% negative predictive value 92%) with cutoff values of 0.73 IUmL and 1.85 gL, respectively. AT combined with fibrinogen levels could be used as a proxy to identify patients with therapeutic level of L-asparaginase activity in the absence of real-time asparaginase measurement during prolonged exposure to L-asparaginase.