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Feeding a Lower Versus Higher Intensity, Proportion, or Amount of Human Milk to Mixed-Fed Infants and Childhood Leukemia A Systematic Review

This systematic review was conducted as part of the U.S. Department of Agriculture and Department of Health and Human Services Pregnancy and Birth to 24 Months Project. The goal of this systematic review was to examine the following question What is the relationship between feeding a lower versus higher intensity, proportion, or amount of human milk to mixed-fed infants and childhood leukemia This systematic review examines comparisons of mixed-fed infants fed different intensities, proportions, or amounts of human milk. There is no evidence to determine whether or not there is a relationship between feeding a lower versus higher intensity, proportion, or amount of human milk to mixed-fed infants and childhood leukemia. The systematic review was conducted by a team of staff from the Nutrition Evidence Systematic Review in collaboration with a Technical Expert Collaborative. A single literature search was conducted to identify literature for several related systematic reviews that examined infant milk-feeding practices and different outcomes. The search was conducted in CINAHL, Cochrane, Embase, and PubMed, and used a search date range of January 1980 to March 2016. A manual search was done to identify articles that may not have been included in the electronic databases searched. Articles were screened independently by 2 NESR analysts to determine which articles met predetermined criteria for inclusion. Because no articles were identified that met the inclusion criteria, the conclusion statement and grade reflect the absence of evidence and that no grade was assignable to the strength of the evidence. No articles met the inclusion criteria for this systematic review.

Shorter Versus Longer Durations of Exclusive Human Milk Feeding and Childhood Leukemia A Systematic Review

This systematic review was conducted as part of the U.S. Department of Agriculture and Department of Health and Human Services Pregnancy and Birth to 24 Months Project. The goal of this systematic review was to examine the following question What is the relationship between shorter versus longer durations of exclusive human milk feeding and childhood leukemia This systematic review examines comparisons of infants who were fed human milk exclusively for shorter durations with infants who were fed human milk exclusively for longer durations. There is no evidence to determine whether or not there is a relationship between shorter versus longer durations of exclusive human milk feeding and childhood leukemia. The systematic review was conducted by a team of staff from the Nutrition Evidence Systematic Review in collaboration with a Technical Expert Collaborative. A single literature search was conducted to identify literature for several related systematic reviews that examined infant milk-feeding practices and different outcomes. The search was conducted in CINAHL, Cochrane, Embase, and PubMed, and used a search date range of January 1980 to March 2016. A manual search was done to identify articles that may not have been included in the electronic databases searched. Articles were screened independently by 2 NESR analysts to determine which articles met predetermined criteria for inclusion. Because no articles were identified that met the inclusion criteria, the conclusion statement and grade reflect the absence of evidence and that no grade was assignable to the strength of the evidence. No articles met the inclusion criteria for this systematic review.

Shorter Versus Longer Durations of Any Human Milk Feeding and Childhood Leukemia A Systematic Review

This systematic review was conducted as part of the U.S. Department of Agriculture and Department of Health and Human Services Pregnancy and Birth to 24 Months Project. The goal of this systematic review was to examine the following question What is the relationship between shorter versus longer durations of any human milk feeding and childhood leukemia This systematic review examines comparisons of infants who were fed human milk for shorter durations with infants who were fed human milk for longer durations. Limited but consistent evidence suggests that, among infants fed some amount of human milk, a shorter versus longer duration of any human milk feeding is associated with a slightly higher risk of childhood leukemia. The systematic review was conducted by a team of staff from the Nutrition Evidence Systematic Review in collaboration with a Technical Expert Collaborative. A single literature search was conducted to identify literature for several related systematic reviews that examined infant milk-feeding practices and different outcomes. The search was conducted in CINAHL, Cochrane, Embase, and PubMed, and used a search date range of January 1980 to March 2016. A manual search was done to identify articles that may not have been included in the electronic databases searched. Articles were screened independently by 2 NESR analysts to determine which articles met predetermined criteria for inclusion. Data from each included article were extracted, risks of bias were assessed, and both were checked for accuracy. The body of evidence was qualitatively synthesized, a conclusion statement was developed, and the strength of the evidence (grade) was assessed using pre-established criteria including evaluation of the internal validityrisk of bias, adequacy, consistency, impact, and generalizability of available evidence. Eight articles met the inclusion criteria for this systematic review, which presented evidence from 8 case-control studies. The notable feature of this body of evidence was its consistency in the direction of the associations across most of the studies. Two of the 8 studies reported statistically significant associations that suggested that shorter versus longer durations of any human milk feeding are associated with higher risk of childhood leukemia. Further, the majority of nonsignificant associations, some of which had wide confidence intervals indicative of suboptimal statistical power, were consistent in direction with the significant associations. The ability to draw stronger conclusions was primarily limited by the small number of studies, insufficient sample sizes, and the retrospective collection of exposure data, which increases the risk of misclassification of the exposure.

Never Versus Ever Feeding Human Milk and Childhood Leukemia A Systematic Review

This systematic review was conducted as part of the U.S. Department of Agriculture and Department of Health and Human Services Pregnancy and Birth to 24 Months Project. The goal of this systematic review was to examine the following question What is the relationship between never versus ever feeding human milk and childhood leukemia This systematic review examines comparisons of infants who were never fed human milk with infants who were ever fed human milk (i.e., any amount of human milk feeding). Limited evidence suggests that never versus ever being fed human milk is associated with a slightly higher risk of childhood leukemia. The evidence comparing never being fed human milk with being fed human milk for short durations (i.e., < 6 months) and risk of childhood leukemia is mixed. However, the evidence comparing never being fed human milk with being fed human milk for long durations (i.e., ≥ 6 months) is mostly consistent and is associated with a slightly higher risk of childhood leukemia. The systematic review was conducted by a team of staff from the Nutrition Evidence Systematic Review in collaboration with a Technical Expert Collaborative. A single literature search was conducted to identify literature for several related systematic reviews that examined infant milk-feeding practices and different outcomes. The search was conducted in CINAHL, Cochrane, Embase, and PubMed, and used a search date range of January 1980 to March 2016. A manual search was done to identify articles that may not have been included in the electronic databases searched. Articles were screened independently by 2 NESR analysts to determine which articles met predetermined criteria for inclusion. Data from each included article were extracted, risks of bias were assessed, and both were checked for accuracy. The body of evidence was qualitatively synthesized, a conclusion statement was developed, and the strength of the evidence (grade) was assessed using pre-established criteria including evaluation of the internal validityrisk of bias, adequacy, consistency, impact, and generalizability of available evidence. Nineteen articles met the inclusion criteria for this systematic review, which presented evidence from 15 independent case-control studies and 1 retrospective cohort study. Five of the 16 studies reported statistically significant associations. The evidence from these 5 studies is consistent and suggests that never versus ever being fed human milk is associated with a higher risk of childhood leukemia. Some of the studies in the body of evidence compared never being fed human milk with being fed human milk for specific durations. The evidence comparing never being fed human milk with being fed human milk for shorter-term durations (i.e., < 6 months) and risk of childhood leukemia is mixed. However, the evidence comparing never being fed human milk with being fed human milk for longer-term durations (i.e., ≥ 6 months) is mostly consistent and is associated with a slightly higher risk of childhood leukemia. Further, the majority of nonsignificant associations are consistent in direction with the significant associations and some of the inconsistency in statistical significance is likely due to inadequate statistical power. The ability to draw stronger conclusions was primarily limited by insufficient sample sizes and the retrospective collection of exposure data, which increases the risk of misclassification of the exposure.

CAR-T immunotherapy how will it change treatment for acute lymphoblastic leukemia and beyond

The recent approval of CD19 chimeric antigen receptor (CAR) T cells for refractory or second relapse of B cell acute lymphoblastic leukemia (B-ALL) has led to a paradigm shift. Besides being an alternative to chemotherapy and antibody-based approaches, CAR-T cells have become the first successful example of personalized medicine. In clinical trials, tisagenlecleucel demonstrated higher response rates than prior therapies, and led to durable remissions lasting up to years for some children. Toxicities like cytokine release syndrome and neurotoxicity, while potentially reversible, have limited usage of CAR-T cells at certified centers with expertise in cellular therapy. Strategies to deal with B-ALL relapse after CAR-T remain an open area of research. Going forward, improvements will likely be seen in managing the side effects of CAR-T therapy as well as usage of CAR-T cells upfront as a replacement for chemotherapy or allogeneic bone marrow transplant for B-ALL. Further advances will need to reduce the biomanufacturing time needed to generate CAR-T cells as well as develop biomarkers that predict CAR-T persistence andor toxicities.

Incidence of infections after therapy completion in children with acute lymphoblastic leukemia or acute myeloid leukemia a systematic review of the literature.

Infections are a common complication of treatment for pediatric acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Less is known about infections occurring after treatment. We performed a systematic review of the literature to assess the incidence of infections after therapy completion in children and young adults with ALL or AML. Twenty-eight studies, with 4138 patients, were included. Four studies reported infections in patients who did not undergo hematopoietic stem cell transplant (HSCT). Respiratory tract and urinary tract infections affected 9.9-72.5% and 2.9-19.8% of patients, respectively. Twelve studies reported infections in patients treated with HSCT. Late bacterial, viral and fungal infections affected 3.9-38.5%, 16.1-66.7%, and 0.2-41.7% of patients, respectively. Viral hepatitis affected 0.8-75.4% of patients from 12 studies. Our review suggests that infections are a frequent complication after treatment for leukemia in children, especially after HSCT and identifies several knowledge gaps in the current literature.

Results of endoscopic nasal surgery in the treatment of invasive fungal sinusitis in children with cancer and immunosuppression.

to describe the results of the treatment of invasive fungal sinusitis with nasal endoscopic surgery in an immunocompromised paediatric oncological population. retrospective study of all patients diagnosed with invasive fungal sinusitis operated in the National Paediatric Oncology Unit between 2012 and 2016. Data taken from their medical history included epidemiological characteristics, oncological diagnosis, haematological data, symptoms, tomographic studies, surgical interventions, results of pathology and cultures, medications received, complications, evolution and survival. 18 patients were identified, 7 male and 11 female. The average age was 12 years, 13 had a diagnosis of acute lymphocytic leukemia and 5 of acute myeloid leukemia. Seventeen patients presented severe neutropenia at the time of diagnosis. The most frequently identified aetiological agent was Aspergillus in 13 patients. In 16 patients (89%) the disease was controlled with nasal endoscopic surgery. Ten patients died due to unrelated causes throughout the study. Invasive fungal sinusitis should be considered a medical emergency due to its high mortality. The diagnosis is based on a high index of suspicion in patients with predisposing factors (leukaemia, neutropenia, persistent fever, nasogastric tube) and endoscopic nasal evaluation. Antifungal medical treatment and aggressive nasal endoscopic surgery is indicated regardless of the patients condition to reduce the fungal burden and associated high mortality. The treatment must be provided by a multidisciplinary team that includes paediatrics, haemato-oncology, infectology and otorhinolaryngology.

We describe an unusual case of pre-B lymphoblastic leukaemia presenting with a unilateral maxillary sinus mass in which biopsies of the primary mass and the bone marrow demonstrated conflicting immunophenotyping results. The extramedullary mass was consistent with a precursor B-cell malignancy, while the bone marrow was initially reported as a possible mature B-cell malignancy. The treatments for the two are fundamentally different, which necessitated a delay in the initiation of his chemotherapy until a clear diagnosis was made. Mixed lineage leukaemia gene rearrangement was confirmed by fluorescence in situ hybridisation in both the primary mass and bone marrow, which unified the diagnosis as pre-B acute lymphoblastic leukaemia given the common cytogenetic feature.

Candida Tropicalis renal microabscesses in a child with leukemia confirmed using nucleic acid amplification and recovery after prolonged antifungal and corticosteroid treatment.

We report the first case of microabscesses detected by polymerase chain reaction (PCR) amplification of nucleic acid from ultrasound-guided aspirated fluid in a three-year old boy with acute lymphoblastic leukemia and febrile neutropenia during induction chemotherapy. Fever persisted despite effective antifungal treatment. The addition of corticosteroid therapy successfully controlled the suspected immune reconstitution inflammatory syndrome (IRIS). This case highlights the utility of PCR and adjunctive corticosteroid in the approach of Candida tropicalis renal microabscesses in leukemic patients undergoing chemotherapy.

Is There Etiologic Heterogeneity between Subtypes of Childhood Acute Lymphoblastic Leukemia A Review of Variation in Risk by Subtype.

Although substantial advances in the identification of cytogenomic subtypes of childhood acute lymphoblastic leukemia (ALL) have been made in recent decades, epidemiologic research characterizing the etiologic heterogeneity of ALL by subtype has not kept pace. The purpose of this review is to summarize the current literature concerning subtype-specific epidemiologic risk factor associations with ALL subtype defined by immunophenotype (e.g., B-cell vs. T-cell) and cytogenomics (including gross chromosomal events characterized by recurring numerical and structural abnormalities, along with cryptic balanced rearrangements, and focal gene deletions). In case-control analyses investigating nongenetic risk factors, home paint exposure is associated with hyperdiploid,

Access to Hematopoietic Stem Cell Transplantation among Pediatric Patients with Acute Lymphoblastic Leukemia A Population-Based Analysis.

Access to hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) primarily depends on disease-related factors but may be influenced by social and economic determinants. We included all children aged < 15 years with newly diagnosed ALL in Canada between 2001 and 2018 using the Cancer in Young People in Canada national registry. We examined factors potentially associated with the likelihood of receiving HSCT using univariate and multivariable logistic regression models. A total of 3992 patients with newly diagnosed ALL were included. Three hundred twenty-five (8.1%) received an HSCT and formed the transplant cohort. In multivariable analysis factors independently associated with an increased odds of receiving HSCT were male sex (odds ratio OR, 1.42 95% confidence interval CI, 1.05 to 1.93), initial WBC ≥ 50,000 × 10

Childhood Cancer Symptom Cluster Leukemia and Health-Related Quality of Life.

To examine the relationship of the Childhood Cancer Symptom Cluster-Leukemia (CCSC-L) with health-related quality of life (HRQOL). 327 children receiving treatment for acute lymphoblastic leukemia from four pediatric oncology programs across the United States. Participants completed fatigue, sleep disturbance, pain, nausea, and depression symptom questionnaires at four time points these symptoms comprised the CCSC-L. HRQOL was measured at the start of postinduction therapy and then at the start of maintenance therapy. Relationships between the CCSC-L and HRQOL scores were examined with longitudinal parallel-process modeling. The mean HRQOL significantly increased over time (p < 0.001). The CCSC-L had a significant negative association with HRQOL scores at the start of postinduction therapy (beta -0.53, p < 0.005) and the start of maintenance therapy (beta -0.33, p < 0.015). Participants with more severe symptoms in the CCSC-L over time had significantly lower HRQOL at the start of maintenance therapy (beta -0.42, p < 0.005). Nurses are pivotal in providing management strategies to minimize symptom severity that may improve HRQOL.

Clinical trials of dual-target CAR T cells, donor-derived CAR T cells, and universal CAR T cells for acute lymphoid leukemia.

The current treatment for pediatric acute lymphoblastic leukemia (ALL) is highly successful with high cure rate. However, the treatment of adult ALL remains a challenge, particularly for refractory andor relapsed (RR) ALL. The advent of new targeted agents, blinatumomab, inotuzumab ozogamycin, and chimeric antigen receptor (CAR) T cells, are changing the treatment paradigm for ALL. Tisagenlecleucel (kymriah, Novartis) is an autologous CD19-targeted CAR T cell product approved for treatment of RR B cell ALL and lymphoma. In an attempt to reduce the relapse rate and treat those relapsed patients with antigen loss, donor-derived CAR T cells and CD19CD22 dual-target CAR T cells are in clinical trials. Gene-edited off-the-shelf universal CAR T cells are also undergoing active clinical development. This review summarized new clinical trials and latest updates at the 2018 ASH Annual Meeting on CAR T therapy for ALL with a focus on dual-target CAR T and universal CAR T cell trials.

Comprehensive Investigation of miRNome Identifies Novel Candidate miRNA-mRNA Interactions Implicated in T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors. The genetic landscape of T-ALL has been largely characterized by next-generation sequencing. Yet, the transcriptome of miRNAs (miRNome) of T-ALL has been less extensively studied. Using small RNA sequencing, we characterized the miRNome of 34 pediatric T-ALL samples, including the expression of isomiRs and the identification of candidate novel miRNAs (not previously annotated in miRBase). For the first time, we show that immunophenotypic subtypes of T-ALL present different miRNA expression profiles. To extend miRNome characteristics in T-ALL (to 82 T-ALL cases), we combined our small RNA-seq results with data available in Gene Expression Omnibus. We report on miRNAs most abundantly expressed in pediatric T-ALL and miRNAs differentially expressed in T-ALL versus normal mature T-lymphocytes and thymocytes, representing candidate oncogenic and tumor suppressor miRNAs. Using eight target prediction algorithms and pathway enrichment analysis, we identified differentially expressed miRNAs and their predicted targets implicated in processes (defined in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of potential importance in pathogenesis of T-ALL, including interleukin-6-mediated signaling, mTOR signaling, and regulation of apoptosis. We finally focused on hsa-mir-106a-363 cluster and functionally validated direct interactions of hsa-miR-20b-5p and hsa-miR-363-3p with 3 untranslated regions of their predicted targets (PTEN, SOS1, LATS2), overrepresented in regulation of apoptosis. hsa-mir-106a-363 is a paralogue of prototypic oncogenic hsa-mir-17-92 cluster with yet unestablished role in the pathogenesis of T-ALL. Our study provides a firm basis and data resource for functional analyses on the role of miRNA-mRNA interactions in T-ALL.

Acute Lymphoblastic Leukemia in the Older Adult.

Acute lymphoblastic leukemia (ALL) in older adults presents a real challenge as a result of adverse disease biology and comorbidities that preclude delivering curative regimens. Conventional chemotherapy approaches have generally yielded unsatisfactory results in older patients with ALL as a result of excessive induction mortality, chemotherapy resistance of the leukemia, and the need to omit or dose reduce key drugs during the course of therapy because of adverse effects. Philadelphia chromosome-positive ALL represents about a quarter of newly diagnosed older adults, and the striking single-agent activity and excellent safety profile of tyrosine kinase inhibitors has allowed incorporation of these agents into therapy, significantly improving the outcome of older adults with Philadelphia chromosome-positive ALL. Allogeneic hematopoietic cell transplantation using reduced-intensity conditioning is a potentially curative approach in the older adult with ALL, and ironically, it may be better tolerated than intensive combination chemotherapy in a subset of older patients with ALL. Immunotherapies such as chimeric antigen receptor-modified T-cells, the bispecific T-cell-engaging antibody targeting CD19 (blinatumomab), and the antibody-drug conjugate targeting CD22 (inotuzumab) have shown safety and exceptional activity even in advanced ALL, and the efficacy of these agents has been observed irrespective of patient age. Several promising studies tailored specifically toward older adults with ALL are ongoing, with the majority of them incorporating novel immunotherapies, targeted therapies, or third-generation tyrosine kinase inhibitors into the front-line treatment regimen.

Allogeneic blood transfusion in 163 children with acute lymphocytic leukemia (a STROBE-compliant article).

Little research has been done about the effects of allogeneic blood transfusion (ABT) on the recurrence and prognosis in the cases with childhood acute lymphocytic leukemia (cALL). In order to provide a basis for clinical safe blood transfusion, the data of 163 cases with cALL were retrospectively analyzed to explore the issue.The data of 163 cases with cALL between 2006 and 2011 were retrospectively analyzed. According to the frequency of blood transfusion, the 163 cases were divided into 4 groups including non-transfusion group, 1 to 10-time transfusion group, 11 to 25-time transfusion group, and >25-time transfusion group. Survival rates were compared with Log-Rank test. Cox regression analysis was used in the effects of risk factors on recurrence and death.ABT was performed in 152 cases with cALL (93.25%). In low-risk and intermediate-and-high risk cALL, the survival rate significantly decreased in all transfusion groups compared with that in non-transfusion group (all P < .01). Cox regression analysis showed that >25-time transfusion was an independent prognosis index of recurrence (odds ratio OR 3.015, 95% confidence interval CI 1.368-6.646) and death (OR 3.979, 95% CI 1.930-8.207) in cALL.Frequency of ABT appears to affect the recurrence and death in cALL. We should be careful with blood transfusion and avoid unnecessary blood transfusion as far as possible in the cases with cALL.

Genotoxic activity of L-asparaginase produced by Streptomyces ansochromogenes UFPEDA 3420.

L-asparaginase is an enzyme capable of hydrolyzing the substrate asparagine in aspartic acid and ammonia. Due to this mechanism of action observed, L-asparaginase is widely used in the treatment of Acute Lymphoblastic Leukemia, since these cells use asparagine for their survival. Because it is frequently used as an antineoplastic, it is necessary to evaluate its genotoxic effects. The aim of the present study was to evaluate cellular DNA damage after exposure to L-asparaginase produced by Streptomyces ansochromogenes UFPEDA 3420. NCIH-292, MCF-7 and MOLT-4 neoplastic cell lines and normal PBMC cells were used. L-Asparaginase used in this study was produced by actinobacteria S. ansochromogenes UFPEDA 3420, isolated and purified by chromatographic methods. L-Asparaginase induced micronucleus formation in PBMC cells and tumor lines when compared to the negative control. These data suggest that L-Asp appears to have a genotoxic effect very close to the positive control in normal cells (p < 0.05). The level of genomic damage measured by DNA breaks in alkaline SCGE assay was detected from the lowest concentration (12.5 µgmL) to the highest concentration (50 µgmL) for tumor cell lines and PBMC. In view of the above, new genotoxic studies will be carried out to better elucidate L-Asparaginase and its mutagenic potential, still unknown, enough for this drug to be safely used in conventional antineoplastic therapies.

Phenotype and Function of Activated Natural Killer Cells From Patients With Prostate Cancer Patient-Dependent Responses to Priming and IL-2 Activation.

Successful use of blinatumomab in a patient with acute lymphoblastic leukemia and severe hepatic dysfunction.

Relapsedrefractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, with survival rates of less than a year, even with novel therapies. Patients frequently experience toxicities from induction chemotherapy such as hepatotoxicity, which can limit therapeutic options upon relapse. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsedrefractory acute lymphoblastic leukemia however, there are limited data on use of this agent in patients with significant organ dysfunction. In this report, we describe the safe and effective use of blinatumomab in an adult patient with refractory Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia in the setting of severe hepatic dysfunction. Blinatumomab may represent a viable option to treat relapsedrefractory acute lymphoblastic leukemia in patients with significant hepatic dysfunction.

Matching-Adjusted Indirect Comparison of Blinatumomab vs. Inotuzumab Ozogamicin for Adults with RelapsedRefractory Acute Lymphoblastic Leukemia.

In the absence of head-to-head trials, this analysis aimed to provide a fair indirect comparison of the efficacy between blinatumomab and inotuzumab ozogamicin (InO), two treatments for adult patients with relapsed or refractory acute lymphoblastic leukemia (RR ALL) who received no more than one prior salvage therapy, by adjusting for cross-trial differences. Patient-level data from the Phase 3 blinatumomab trial TOWER and published aggregated data from the Phase 3 InO trial INO-VATE-ALL were used to conduct matching-adjusted indirect comparisons. Patients with 2 prior salvage therapies from TOWER were excluded because such patients were not included in INO-VATE-ALL. To ensure balance in the remaining patients, baseline characteristics for the TOWER patients were weighted to match the average baseline characteristics in INO-VATE-ALL, including sex, age, race, performance status, bone marrow blast, previous salvage therapy, previous allogeneic transplantation, complete remission with complete hematologic recovery (CR) to most recent induction therapy, and duration of first remission. Overall survival (OS), including median and restricted mean survival time (RMST) at 12 and 20.7 months, and CR were estimated and compared. A total of 310 patients in TOWER were included (blinatumomab, n 203 standard of care chemotherapy, n 107). After matching the listed baseline characteristics, the median OS was 9.3 months for blinatumomab and 7.7 months for InO (weighted log-rank test p 0.4). The relative RMST at 12 months was 1.6 months longer for blinatumomab than for InO 95% CI (0.1, 3.2) p 0.04 at 20.7 months the RMST was not significantly different. The CR rates were similar anchor-based difference - 2.8%, 95% CI (- 17.5%, 11.9%) p 0.71. After adjusting for cross-trial differences, blinatumomab demonstrated a similar CR rate and potential OS benefit versus InO among adult patients with RR ALL who received no more than one prior salvage therapy. Further studies are suggested to confirm this finding. Amgen.

Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated. Patients with ALL on St. Jude Total Therapy XV (n 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institutes Common Terminology for Adverse Events (version 3.0). In a preclinical model, BalbcJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy. We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR 1.88 95% CI, 1.03-3.41, P 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P 0.00086) and arteriopathy (P 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P 0.00045) and arteriopathy (P 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS. These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.

Minimal residual disease level predicts outcome in adults with Ph-negative B-precursor acute lymphoblastic leukemia.

Detectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. This study evaluated outcomes of patients with B-cell precursor ALL with MRD of ≥10 Of 272 patients in CR1, baseline MRD was ≥10 In conclusion, RFS, DoR, and OS are relatively short in patients with MRD-positive ALL, particularly at higher MRD levels. AlloHSCT may improve survival but has limitations. Alternative approaches are needed to improve outcomes in MRD-positive ALL.

A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies however, designing CARs for T-cell based diseases remain a challenge since most target antigens are shared between normal and malignant cells, leading to CAR-T cell fratricide. CD7 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL), but it is not expressed in one small group of normal T lymphocytes. Here, we constructed monovalent CD7-CAR-NK-92MI and bivalent dCD7-CAR-NK-92MI cells using the CD7 nanobody VHH6 sequences from our laboratory. Both CD7-CAR-NK-92MI and dCD7-CAR-NK-92MI cells consistently showed specific and potent anti-tumor activity against T-cell leukemia cell lines and primary tumor cells. We observed robust cytotoxicity of the bivalent mdCD7-CAR-NK-92MI monoclonal cells against primary T-ALL samples. In agreement with the enhanced cytotoxicity of mdCD7-CAR-NK-92MI cells, significant elevations in the secretion of Granzyme B and interferon γ (IFN-γ) were also found in mdCD7-CAR-NK-92MI cells in response to CD7-positive primary T-ALL cells compared with NK-92MI-mock cells. Furthermore, we also demonstrated that mdCD7-CAR-NK-92MI cells significantly inhibited disease progression in xenograft mouse models of T-ALL primary tumor cells. Our data suggest that CD7-CAR-NK-92MI cells can be used as a new method or a complementary therapy for treating T-cell acute lymphocytic leukemia.

Fibroblast growth factor receptor signaling in pediatric B-cell precursor acute lymphoblastic leukemia.

The FGF receptor signaling pathway is recurrently involved in the leukemogenic processes. Oncogenic fusions of FGFR1 with various fusion partners were described in myeloid proliferative neoplasms, and overexpression and mutations of FGFR3 are common in multiple myeloma. In addition, fibroblast growth factors are abundant in the bone marrow, and they were shown to enhance the survival of acute myeloid leukemia cells. Here we investigate the effect of FGFR stimulation on pediatric BCP-ALL cells in vitro, and search for mutations with deep targeted next-generation sequencing of mutational hotspots in FGFR1, FGFR2, and FGFR3. In 481 primary BCP-ALL cases, 28 samples from 19 unique relapsed BCP-ALL cases, and twelve BCP-ALL cell lines we found that mutations are rare (4481 0.8%, 028 and 012) and do not affect codons which are frequently mutated in other malignancies. However, recombinant ligand FGF2 reduced the response to prednisolone in several BCP-ALL cell lines in vitro. We therefore conclude that FGFR signaling can contribute to prednisolone resistance in BCP-ALL cells, but that activating mutations in this receptor tyrosine kinase family are very rare.

Long-Term Risk of Hospitalization Among Five-Year Survivors of Childhood Leukemia in the Nordic Countries.

Adverse effects from childhood leukemia treatment may persist or present years after cure from cancer. We provide a comprehensive evaluation of subsequent hospitalization in five-year survivors of childhood acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). In the Adult Life after Childhood Cancer in Scandinavia Study, we identified 4003 five-year survivors diagnosed with childhood leukemia 1970-2008 in Denmark, Sweden, Iceland, and Finland. Survivors and 129 828 population comparisons were followed for first-time nonpsychiatric hospitalizations for 120 disease categories in the hospital registries. Standardized hospitalization rate ratios and absolute excess rates were calculated. All statistical tests were two-sided. Survivors of ALL (n 3391), AML (n 389), and CML (n 92) had an increased overall hospitalization rate compared with population comparisons. The rate ratio for any hospitalization was 1.95 (95% confidence interval CI 1.83 to 2.07) in ALL, 3.09 (95% CI 2.53 to 3.65) in AML, and 4.51 (95% CI 3.03 to 6.00) in CML survivors and remained increased even 20 years from leukemia diagnosis. Corresponding absolute excess rates per 1000 person-years were 28.48 (95% CI 24.96 to 32.00), 62.75 (95% CI 46.00 to 79.50), and 105.31 (95% CI 60.90 to 149.72). Leukemia survivors have an increased rate of hospitalization for medical conditions. We provide novel insight into the relative and absolute rate of hospitalization for 120 disease categories in survivors of ALL, AML, and CML, which are likely to be informative for both survivors and healthcare providers.

Novel site-specific PEGylated L-asparaginase.

L-asparaginase (ASNase) from Escherichia coli is currently used in some countries in its PEGylated form (ONCASPAR, pegaspargase) to treat acute lymphoblastic leukemia (ALL). PEGylation refers to the covalent attachment of poly(ethylene) glycol to the protein drug and it not only reduces the immune system activation but also decreases degradation by plasmatic proteases. However, pegaspargase is randomly PEGylated and, consequently, with a high degree of polydispersity in its final formulation. In this work we developed a site-specific N-terminus PEGylation protocol for ASNase. The monoPEG-ASNase was purified by anionic followed by size exclusion chromatography to a final purity of 99%. The highest yield of monoPEG-ASNase of 42% was obtained by the protein reaction with methoxy polyethylene glycol-carboxymethyl N-hydroxysuccinimidyl ester (10kDa) in 100 mM PBS at pH 7.5 and PEGASNase ratio of 251. The monoPEG-ASNase was found to maintain enzymatic stability for more days than ASNase, also was resistant to the plasma proteases like asparaginyl endopeptidase and cathepsin B. Additionally, monoPEG-ASNase was found to be potent against leukemic cell lines (MOLT-4 and REH) in vitro like polyPEG-ASNase. monoPEG-ASNase demonstrates its potential as a novel option for ALL treatment, being an inventive novelty that maintains the benefits of the current enzyme and solves challenges.

Microstructural white matter alterations associated to neurocognitive deficits in childhood leukemia survivors treated with cranial radiotherapy - a diffusional kurtosis study.

Long Non-Coding RNA and Acute Leukemia.

Acute leukemia (AL) is the main type of cancer in children worldwide. Mortality by this disease is high in developing countries and its etiology remains unanswered. Evidences showing the role of the long non-coding RNAs (lncRNAs) in the pathophysiology of hematological malignancies have increased drastically in the last decade. In addition to the contribution of these lncRNAs in leukemogenesis, recent studies have suggested that lncRNAs could be used as biomarkers in the diagnosis, prognosis, and therapeutic response in leukemia patients. The focus of this review is to describe the functional classification, biogenesis, and the role of lncRNAs in leukemogenesis, to summarize the evidence about the lncRNAs which are playing a role in AL, and how these genes could be useful as potential therapeutic targets.

Hematopoietic Stem-Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia A Report From Childrens Oncology Group.

Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem-cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Childrens Oncology Group (COG) trials to evaluate the impact of HSCT on outcome. Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 andor DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort. Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier NCT00482352). Hypodiploidy occurred in 1.5% of patients (n 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes. Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.

Downregulation of specific FBXW7 isoforms with differential effects in T-cell lymphoblastic lymphoma.

FBXW7 is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, β and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7 in a panel of primary T-cell lymphoblastic lymphomas characterised by the absence of mutations in its sequence. We observed that decreased expression mainly affected the FBXW7β isoform and to a lesser extent FBXW7α and may be attributed to the combined effect of epigenetic changes, alteration of upstream factors and upregulation of miRNAs. Transient transfections with miRNA mimics in selected cell lines resulted in a significant decrease of total FBXW7 expression and its different isoforms separately, with the consequent increment of critical substrates and the stimulation of cell proliferation. Transient inhibition of endogenous miRNAs in a T-cell lymphoblastic-derived cell line (SUP-T1) was capable of reversing these proliferative effects. Finally, we show how FBXW7 isoforms display different roles within the cell. Simultaneous downregulation of the α and γ isoforms modulates the amount of CCNE1, whilst the β-isoform alone was found to have a prominent role in modulating the amount of c-MYC. Our data also revealed that downregulation of all isoforms is a sine qua non condition to induce a proliferative pattern in our cell model system. Taking these data into account, potential new treatments to reverse downregulation of all or a specific FBXW7 isoform may be an effective strategy to counteract the proliferative capacity of these tumour cells.

CD9 in acute myeloid leukemia Prognostic role and usefulness to target leukemic stem cells.

CD9 is a cell surface protein and belongs to the tetraspanin family. Its role in carcinomagenesis has been widely studied in solid tumors but remains controversial, depending on the cancer type. Although CD9 seems to be associated with unfavorable outcome and disease progression in acute lymphoblastic leukemia (ALL), this marker has not yet been studied in acute myeloid leukemia (AML). First, we explored its prognostic role and its association with biological factors in a cohort of 112 AML patients treated with intensive chemotherapy. CD9 was expressed in 40% of AML and was associated with a favorable outcome (event-free survival and relapse-free survival) in univariate (P 0.009 and P 0.048, respectively) and multivariate (P 0.004 and P 0.039, respectively) analyses. Interestingly, CD9 expression was different between the more immature physiologic and AML cells (CD34CD38-) as it was also expressed in AML on putative leukemic stem cells (LSCs) but not on hematopoietic stem cells (HSCs). Hence, CD9 could be a very relevant marker for minimal residual disease (MRD) monitoring in AML based on LSC targeting.

Exploring a potential mechanistic role of DNA methylation in the relationship between in utero and post-natal environmental exposures and risk of childhood acute lymphoblastic leukaemia.

The aetiology of childhood acute lymphoblastic leukaemia (ALL) is unclear. Genetic abnormalities have been identified in a number of ALL cases, although these alone are not sufficient for leukaemic transformation. Various in utero and post-natal environmental exposures have been suggested to alter risk of childhood ALL. DNA methylation patterns can be influenced by environmental exposures, and are reported to be altered in ALL, suggesting a potential mediating mechanism between environment and ALL disease risk. To investigate this, we used a meet in the middle approach, investigating the overlap between exposure-associated and disease-associated methylation change. Genome-wide DNA methylation changes in response to possible ALL-risk exposures (i.e. breast feeding, infection history, day care attendance, maternal smoking, alcohol, caffeine, folic acid, iron and radiation exposure) were investigated in a sub-population of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort using an epigenome-wide association study (EWAS) approach (n 861-927), and compared to a list of ALL disease-associated methylation changes compiled from published data. Hypergeometric probability tests suggested that the number of directionally concordant gene methylation changes observed in ALL disease and in response to the following exposures maternal radiation exposure (p 0.001), alcohol intake (p 0.006) sugary caffeinated drink intake during pregnancy (p 0.045) and infant day care attendance (p 0.003), were not due to chance. Data presented suggests that DNA methylation may be one mediating mechanism in the multiple hit pathway needed for ALL disease manifestation.

Impact of Videotaped Information on the Experience of Parents of Children with Acute Lymphoblastic Leukemia.

Videotaped information has been shown to be effective in reducing parental anxiety and facilitating knowledge transfer in various clinical settings. There is lack of literature on the use of videotaped information during the pediatric oncology initial family disclosure meeting. The purpose of this study was to deliver an informative DVD, highlighting information on childhood acute lymphoblastic leukemia (ALL), to parents of children with newly diagnosed ALL and to assess if the DVD provided increased levels of satisfaction and decreased levels of anxiety in parents around the time of diagnosis. We surveyed 24 parents of children on active treatment for ALL, diagnosed between the ages of 1 and 18 years from 2008 to 2016 at The Hospital for Sick Children, Toronto, Canada. Parents were provided a survey questionnaire assessing levels of satisfaction with information communicated by the healthcare team and anxiety following verbal disclosure and were asked to report satisfaction and anxiety levels immediately following viewing the DVD intervention. Twenty-three24 (95.8%) parents surveyed reported seeking information from additional resources after disclosure. Of the 24 parents who watched the DVD, 12 (50.0%) watched it once, while 12 (50.0%) watched it twice or more. All parents were satisfied with DVD information, and there was a significant decrease in anxiety after viewing (P 0.03). All 24 parents felt that the DVD was a useful educational tool. Videotaped information after verbal disclosure is an effective educational resource and is associated with reduced anxiety among parents of children with ALL.

Expression of Ikaros and FUT4 in Childrens Acute Lymphoblastic Leukemia and Their Relationship.

To explore the possible molecular mechanism of Ikaros regulation on FUT4 expression by analyzing the correlation of the functional state of Ikaros with level of FUT4 expression, so as to provide the theoretical basis for personalized treatment in children with ALL. The subtypes of Ikaros were identified by nested PCR and sequencing. The expression level of FUT4 was detected by quantitative PCR and analyzed by ΔΔCt method in the early stage of treatment, remission and relapse of ALL. Ik1 and Ik2 were the main functional subtypes, and the dominant negative Ikaros was Ik6 the Ik6 was detected in 23 patients with ALL. It was found that 2.73% patients expressing Ik6 alone and 18.18% patients with heterozygous expression were detected. The expression of FUT4 in the newly diagnosed ALL was higher than that in the control group, and the functional Ikaros negatively correlated with the FUT4 expression(r-0.6329). Dominant negative Ikaros closely correlated with the relapse of acute lymphoblastic leukemia in children. The functional Ikaros negatively correlated with FUT4 expression. Ikaros inhibit the transcriptional activity of FUT4, that may be the molecular mechanism of Ikaros regulating the expression of FUT4.

FLT3, a prognostic biomarker for acute myeloid leukemia (AML) Quantitative monitoring with a simple anti-FLT3 interaction and flow cytometric method.

Overexpression of fms-like tyrosine kinase 3 (FLT3) protein in leukemia is highly related to poor prognosis and reduced survival rate in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Simple but efficient quantification of FLT3 protein levels on the leukemic cell surface using flow cytometry had been developed for rapid determination of FLT3 on intact cell surface. Quantitation protocol for FLT3 biomarker in clinical samples was developed and validated. Cell model selection for calibration curve construction was identified and evaluated. Selected antibody concentrations, cell density, and incubation time were evaluated for most appropriate conditions. Comparison of the developed FLT3 determination protocol with the conventional Western blot analysis was performed. EoL-1 cell line was selected for using as positive control cells. Calibration curve (20%-120% of FLT3 positive cells) and quality control (QC) levels were constructed and evaluated. The results demonstrated good linearity (r The effective, reliable, rapid, and economical analytical technique using the developed flow cytometric method was demonstrated for FLT3 protein determination on leukemic cell surface. This method provided a practical analysis of FLT-3 biomarker levels which is valuable for physician decision in acute leukemia treatment.

Clinical trial update on bispecific antibodies, antibody-drug conjugates, and antibody-containing regimens for acute lymphoblastic leukemia.

The relapse rate remains high after chemotherapy for adult patients with acute lymphoblastic leukemia (ALL). With better molecular diagnosis and classification as well as better assessment for minimal residual disease, major progress in the treatment for refractory andor relapsed ALL is being made. In addition to the tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome-positive ALL, immunotherapeutic agents, blinatumomab, inotuzumab ozogamicin (INO), and chimeric antigen receptor (CAR) T cells, are changing the treatment paradigm for ALL. Blinatumomab and INO are being incorporated into induction chemotherapy regimens and combined with TKIs for ALL therapy. A novel low-intensity regimen, miniHCVD-INO-blinatumomab, appears to be less toxic and more effective than conventional intensive chemotherapy regimens. This review summarized new therapeutic researches of ALL and updated latest progress in clinical trials on bispecific antibodies, antibody-drug conjugates, and new regimens incorporating these novel antibodies.

Chimeric Antigen Receptor T-Cells The Future is Now.

The immune system acting via cancer immune-surveillance is considered a potential target for improving outcomes among some malignancies. The ability to harness immune cells, engineer them and educate them to target cancer cells has changed the paradigm for treating non-Hodgkins lymphomas (NHL) and acute lymphoblastic leukemia (ALL). Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable anti-tumor activity against refractory B cell malignancies. Ongoing research aims to expand the scope of this adoptive cell therapy, understanding mechanisms of resistance and reducing toxicity. In this review, we will discuss the current scope of CAR T-cell therapy and ongoing future applications.

Synthesis and bioevaluation of 6-chloropyridazin-3-yl hydrazones and 6-chloro-3-substituted-1,2,4triazolo4,3-bpyridazines as cytotoxic agents.

An efficient synthesis of a series of 6-chloro-3-substituted-1,2,4triazolo4,3-bpyridazines is described via intramolecular oxidative cyclization of various 6-chloropyridazin-3-yl hydrazones with iodobenzene diacetate. The structures of the newly synthesized compounds were assigned on the basis of elemental analysis, IR, NMR (

CRISPRCas9-based genome editing in the era of CAR T cell immunotherapy.

The advent of engineered T cells as a form of immunotherapy marks the beginning of a new era in medicine, providing a transformative way to combat complex diseases such as cancer. Following FDA approval of CAR T cells directed against the CD19 protein for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma, CAR T cells are poised to enter mainstream oncology. Despite this success, a number of patients are unable to receive this therapy due to inadequate T cell numbers or rapid disease progression. Furthermore, lack of response to CAR T cell treatment is due in some cases to intrinsic autologous T cell defects andor the inability of these cells to function optimally in a strongly immunosuppressive tumor microenvironment. We describe recent efforts to overcome these limitations using CRISPRCas9 technology, with the goal of enhancing potency and increasing the availability of CAR-based therapies. We further discuss issues related to the efficiencyscalability of CRISPRCas9-mediated genome editing in CAR T cells and safety considerations. By combining the tools of synthetic biology such as CARs and CRISPRCas9, we have an unprecedented opportunity to optimally program T cells and improve adoptive immunotherapy for most, if not all future patients.

Early (Day 15 Post Diagnosis) Peripheral Blood Assessment of Measurable Residual Disease in Flow Cytometry is a Strong Predictor of Outcome in Childhood B-Lineage Lymphoblastic Leukemia.

In children with acute lymphoblastic leukemia (ALL) low levels of minimal residual disease (MRD) after induction, essentially assessed in the bone marrow, have been shown to be of good prognosis. However, only few studies have tested the peripheral blood for MRD. Here, we report the impact on survival of peripheral blood (PB) MRD assessment by multiparameter flow cytometry (MFC) at early time points of treatment in 125 B-ALL children, compared to Day 35 molecular bone marrow (BM) MRD. Patients were sampled for MFC one week postdiagnosis after a pre-phase of corticotherapy (Day 8), then after one week of chemotherapy (Day 15). The study enrolled 67 boys and 58 girls with a median follow-up of 52 months. Over the duration of the study, 20 patients relapsed and eight died. MFC was performed based on the leukemia-associated immunophenotype at diagnosis, using panels of 10 antibodies. Although, PB MFC-MRD had no prognostic impact at Day 8, Day 15 MRD negativity was associated with a significantly better 4 years DFS (91.6 ± 3% vs. 67.6 ± 9% P 0.0013). Furthermore, while MFC and molecular data were concordant in most cases, patients with detectable PB MRD on Day 15, yet negative in BM on Day 35 had a significantly lower DFS (P < 0.0001). This study demonstrates that the less invasive procedure of MFC-MRD assessment in PB can be informative for childhood ALL patients at the early point of Day 15 of the treatment schedule. © 2019 International Clinical Cytometry Society.

Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells.

The cell of origin, defined as the normal cell in which the transformation event first occurs, is poorly identified in leukemia, despite its importance in understanding of leukemogenesis and improving leukemia therapy. Although hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were used for leukemia models, whether their self-renewal and differentiation potentials influence the initiation and development of leukemia is largely unknown. In this study, the self-renewal and differentiation potentials in 2 distinct types of HSCs (HSC1 CD150

Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia.

Glucocorticoids (GCs) are used in combination chemotherapies as front-line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although effective, many patients relapse and become resistant to chemotherapy and GCs in particular. Why these patients relapse is not clear. We took a comprehensive, functional genomics approach to identify sources of GC resistance. A genome-wide shRNA screen identified the transcriptional coactivators EHMT2, EHMT1, and CBX3 as important contributors to GC-induced cell death. This complex selectively supports GC-induced expression of genes contributing to cell death. A metaanalysis of gene expression data from B-ALL patient specimens revealed that Aurora kinase B (AURKB), which restrains GC signaling by phosphorylating EHMT1-2, is overexpressed in relapsed B-ALL, suggesting it as a potential contributor to relapse. Inhibition of AURKB enhanced GC-induced expression of cell death genes, resulting in potentiation of GC cytotoxicity in cell lines and relapsed B-ALL patient samples. This function for AURKB is distinct from its canonical role in the cell cycle. These results show the utility of functional genomics in understanding mechanisms of resistance and rapidly identifying combination chemotherapeutics.

The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models.

Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked

Flow cytometric predictive scoring systems for common fusions ETV6RUNX1, BCRABL1, TCF3PBX1 and rearrangements of the KMT2A gene, proposed for the initial cytogenetic approach in cases of B-acute lymphoblastic leukemia.

In B-acute lymphoblastic leukemia (B-ALL), the identification of cytogenetic prognostic factors is important for stratifying patients into risk groups and tailoring treatment accordingly. The purpose of this study was to propose flow cytometric (FCM) scoring systems (SSs) for predicting t(1221)(p13q22), t(922)(q34q11), t(11q23), and t(119)(q23p13.3) translocations. We analyzed retrospectively the FCM immunophenotype of 377 patients with B-ALL with regard to the major cytogenetic findings revealed by interphase fluorescence in situ hybridization (i-FISH). Comparing descriptive data on the expression of each antigen and performing receiver operating characteristic (ROC) analysis, we identified the most reliable predictive markers for each translocation and sought to establish a specific SS for each translocation, based on specific antibody panels. CD27, CD9, CD66c, CD10, CD25, and CD34 were employed for the prediction of t(1221), CD25, CD38, CD34, and CD66c for t(922), NG2, CD10, CD15, CD34, and CD20 for t(11q23), and CD34, cμ, CD123, and CD66c for t(119). The sensitivity and specificity, respectively, of each predictive score were 89.29% and 96.15% for t(1221), 75.00% and 88.19% for t(922), 84.21% and 99.04% for t(11q23), and 85.71% and 92.71% for t(119). Four highly specific and significantly sensitive FCM-obtained SSs are proposed for the prediction of the four major translocations observed in patients with B-ALL. Prospective evaluation of the proposed SSs could lead to a better targeted cytogenetic investigation and therefore to more cost-effective laboratory practice.

Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies.

The clinical and procedural parameters that affect the optimal collection of lymphocytes for the production of chimeric antigen receptor (CAR) T cells remain undefined but are increasingly important, as commercial products are now available. We evaluated determinants of low lymphocyte collection efficiency (CE) and the rate of successful CAR T-cell manufacture in middle-aged and older adults with advanced B-cell malignancies. Mononuclear cell collections using two apheresis platforms (COBE Spectra and Spectra Optia, Terumo BCT) from patients participating in a CD19-directed CAR T-cell therapy trial were reviewed. Patient- and disease-specific factors, peripheral blood counts, apheresis parameters, and product cell counts were analyzed to determine effects on lymphocyte CE. Ninety-two apheresis events from patients with acute lymphocytic leukemia (ALL) (n 28), chronic lymphocytic leukemia (n 18), and non-Hodgkin lymphoma (n 46) were available for analysis. Forty-one collections (45%) had a lymphocyte CE of <40%. On multivariable analysis, age (every 10-year increase, odds ratio OR 1.51 p 0.034), disease type (chronic lymphocytic leukemia vs. ALL, OR 0.24 p 0.052 non-Hodgkin lymphoma vs. ALL, OR 0.20 p 0.009) and precollection platelets (every 10 × 10 Lymphocyte collection at our center was well tolerated and 100% successful in manufacturing CD19-directed CAR T cells from adult patients with B-cell malignancies despite low CE in some patients. A diagnosis of ALL, advancing age, and higher preapheresis platelet counts were observed to be associated with low CE.

Impact of NUDT15 genetics on severe thiopurine-related hematotoxicity in patients with European ancestry.

Severe hematotoxicity in patients with thiopurine therapy has been associated with genetic polymorphisms in the thiopurine S-methyltransferase (TPMT). While TPMT genetic testing is clinically implemented for dose individualization, alterations in the nudix hydrolase 15 (NUDT15) emerged as independent determinant of thiopurine-related hematotoxicity. Because data for European patients are limited, we investigated the relevance of NUDT15 in Europeans. Additionally to TPMT phenotypinggenotyping, we performed in-depth Sanger sequencing analyses of NUDT15 coding region in 107 European patients who developed severe thiopurine-related hematotoxicity as extreme phenotype. Moreover, genotyping for NUDT15 variants in 689 acute lymphoblastic leukemia (ALL) patients was performed. As expected TPMT was the main cause of severe hematotoxicity in 31% of patients, who were either TPMT deficient (10%) or heterozygous carriers of TPMT variants (21%). By comparison, NUDT15 genetic polymorphism was identified in 14 (13%) patients including one novel variant (p.Met1Ile). Six percent of patients with severe toxicity carried variants in both TPMT and NUDT15. Among patients who developed toxicity within 3 months of treatment, 13% were found to be carriers of NUDT15 variants. Taken together, NUDT15 and TPMT genetics explain 50% of severe thiopurine-related hematotoxicity, providing a compelling rationale for additional preemptive testing of NUDT15 genetics not only in Asians, but also in Europeans.

Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy.

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative (MRD-negative) complete remission (CR) rates in patients with relapsedrefractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsedrefractory B-ALL enrolled in a phase 12 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months

Downregulation of TdT Expression through Splicing Modulation by Antisense Peptide Nucleic Acid (PNA).

Antisense oligonucleotides are able to modulate splicing patterns and offer therapeutic intervention for cancer and other diseases. Considering TdT potential as a target in cancer therapy, the present study aimed to investigate splicing alteration of TdT pre-mRNA in Molt-4 cells using peptide nucleic acid (PNA) octaarginine and cholic acid conjugates. We examined 16 mer PNAs targeting 5 and 3 junctions of intron 7 and addressed their mRNA splicing modulation effects using RT-PCR analysis. We also tested corresponding 2-base mismatch PNAs to confirm the sequence specificity. In addition, protien level of TdT, apoptosis induction and cell viability rate were analysed. PCR analysis showed that full match PNAs could modulate the splicing process, thereby producing a longer mRNA still including intron 7. PCR results also implied exon 7 skipping. In addition, reduced level of TdT protein in Molt-4 cells was observed. Downregulation of TdT level in PNA treated cells was accompanied by an increased rate of apoptosis and decreased the level of cell survival. PNA-mediated splicing modulation can specifically downregulate TdT expression. TdT dowregulation results in apoptosis induction and reduced cell survival in Molt-4 cells. These observations could draw more attentions to develop PNA based strategies for TdT suppression and consequent apoptosis induction in acute lymphoblastic leukemia.

Sustained Response to Imatinib in a Pediatric Patient with Concurrent Myeloproliferative Disease and Lymphoblastic Lymphoma Associated with a CCDC88C-PDGFRB Fusion Gene.

The WHO defined myeloid and lymphoid neoplasms (MLN) with eosinophilia associated with PDGFRB, PDGFRA, FGFR1 rearrangements as a new entity in 2016. PDGFRB-rearranged MLN sensitive to imatinib were described in adult patients. We report the first pediatric patient with PDGFRB-rearranged myeloproliferative disorder associated with T-lymphoblastic lymphoma bearing the t(5 14)(q33q32) translocation who was successfully treated with imatinib only. MethodsAims Analysis of bone marrow and peripheral blood cells by fluorescent in situ hybridization identified the PDGFRB partner as CCDC88C. Whole genome sequencing of the patients DNA identified the exact junction site, confirmed by PCR amplification and Sanger sequencing. A real-time quantitative PCR assay was designed to quantify the fused CCDC88C-PDGFRB product. A 2.5-year-old boy was diagnosed with myeloproliferative disorder and eosinophilia associated with lymphoblastic lymphoma both bearing the CCDC88C-PDGFRB fusion. Imatinib therapy resulted in rapid clinical, hematological, and cytogenetic response. Molecular response to treatment was monitored by a real-time PCR assay specific for the CCDC88C- PDGFRB fusion. This is the first description of MLN with eosinophilia in the pediatric age group. Response to treatment with imatinib only was monitored by specific quantitative PCR assay with sustained remission lasting 5.5 years from diagnosis.

Bone Marrow Mesenchymal Stromal Cell-Derived Periostin Promotes B-ALL Progression by Modulating CCL2 in Leukemia Cells.

Periostin (POSTN) is a multifunctional extracellular component that regulates cell-matrix interactions and cell-cell crosstalk. POSTN deletion significantly decreases leukemia burden in mice however, the underlying mechanisms by which POSTN promotes B cell acute lymphoblastic leukemia (B-ALL) progression remain largely unknown. Here, we demonstrate that bone marrow (BM)-derived mesenchymal stromal cells (BM-MSCs) express higher levels of POSTN when co-cultured with B-ALL cells in vitro and in vivo. POSTN deficiency in BM-MSCs significantly decreases CCL2 expression in co-cultured B-ALL cells in vitro and in vivo. Moreover, POSTN treatment increases expression of CCL2 in B-ALL cells by activating the integrin-ILK-NF-κB pathway. Conversely, CCL2 treatment upregulates expression of POSTN in BM-MSCs via STAT3 activation. Furthermore, there is a positive correlation between POSTN expression and CCL2 level in the BM of mice and patients with B-ALL. These findings suggest that B-ALL cell-derived CCL2 contributes to the increased leukemia burden promoted by BM-MSC-derived POSTN.

Port-a-cath and ventriculoatrial shunt at the same atrium technical note.

Hydrocephalus is a rare complication of brain involving acute lymphoblastic leukemia (ALL). The standard treatment is ventriculoperitoneal (VP) shunting, while ventriculoatrial (VA) shunting is the second option in a case of VP shunt failure in young children. But the presence of port catheter at the right atrium restricts and makes a VA shunt difficult to place in the same atrium. We presented a 4-year-old boy who had the diagnoses of ALL and underwent chemotherapy through a port-a-cath. He also had hydrocephalus due to the brain invasion of the ALL. He firstly underwent VP shunting for the treatment of hydrocephalus, but it failed due to an intraabdominal cyst. Then, he underwent VA shunting through the left internal jugular vein. This is the first case in the literature showing both catheters in the right atrium.

Variants in vincristine pharmacodynamic genes involved in neurotoxicity at induction phase in the therapy of pediatric acute lymphoblastic leukemia.

Vincristine is an important drug of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LALSHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. A genetic variant in CEP72, a gene involved in vincristine pharmacodynamics, was recently associated with neurotoxicity after prolonged vincristine treatment. This association was not replicated in our Spanish population during induction phase. To test the possibility that other variants in genes involved in vincristine pharmacodynamics were associated with vincristine neuropathy in early phases of the treatment, we evaluated the correlation with toxicity of 24 polymorphisms in 9 key genes in a large cohort of 152 Spanish children with B-ALL homogeneously treated. Results showed no association between any genetic variant in the TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4, MAPT, MIR146a, MIR202, and MIR411 genes and vincristine-related neurotoxicity. These results are in line with the hypothesis that there are different mechanisms causing pheripheral neurotoxicity after prolonged and short-term vincristine treatments.

Microbes Producing L-Asparaginase free of Glutaminase and Urease isolated from Extreme Locations of Antarctic Soil and Moss.

L-Asparaginase (L-asparagine aminohydrolase, E.C. 3.5.1.1) has been proven to be competent in treating Acute Lymphoblastic Leukaemia (ALL), which is widely observed in paediatric and adult groups. Currently, clinical L-Asparaginase formulations are derived from bacterial sources such as Escherichia coli and Erwinia chrysanthemi. These formulations when administered to ALL patients lead to several immunological and hypersensitive reactions. Hence, additional purification steps are required to remove toxicity induced by the amalgamation of other enzymes like glutaminase and urease. Production of L-Asparaginase that is free of glutaminase and urease is a major area of research. In this paper, we report the screening and isolation of fungal species collected from the soil and mosses in the Schirmacher Hills, Dronning Maud Land, Antarctica, that produce L-Asparaginase free of glutaminase and urease. A total of 55 isolates were obtained from 33 environmental samples that were tested by conventional plate techniques using Phenol red and Bromothymol blue as indicators. Among the isolated fungi, 30 isolates showed L-Asparaginase free of glutaminase and urease. The L-Asparaginase producing strain Trichosporon asahii IBBLA1, which showed the highest zone index, was then optimized with a Taguchi design. Optimum enzyme activity of 20.57 U mL

The role of biomarkers and echocardiography in the evaluation of cardiotoxicity risk in children treated for leukemia.

To describe the high-risk profile group, susceptible to develop anthracycline-induced cardiomyopathy in children with acute leukemia. The study involved 35 pediatric patients diagnosed with acute lymphoblastic (ALL) or acute myeloblastic leukemia (AML), from March 2014 to December 2016. Serologic markers used for the analysis of cardiac dysfunction were troponin T, NT-proBNP and PCRhs. Also, the patients have had echocardiographic evaluation at the beginning of treatment to determine LVEF, SF and A, E, E Doppler waves. Positive linear correlation was shown between NT-proBNP and leukocyte values, NT-proBNP and blast cells value, and NT-proBNP and LDH. Significant linear negative correlations between LVEF with leukocyte values, blast cells values, LDH, SF and leukocyte values, LVEF and NT-proBNP values and LVEF and troponin T values were also identified. A weak negative correlation between EE ratio and blast cells values has been observed. All of these correlations were statistically significant (p<0.05). Leukocyte value, as well as the other serological markers assessed (NT-proBNP, Troponin T), are useful tools to evaluate the risk of anthracycline-induced cardiotoxicity. The variation of the biological markers at the beginning of the cytotoxic treatment confirms the presence of an early myocardial dysfunction, emphasizing the importance of systematic evaluation of this particular group of patients.

Feasibility of Outpatient High-Dose Methotrexate Infusions in Pediatric Patients With B-Lineage Acute Lymphoblastic Leukemia.

High-dose methotrexate (MTX) given in four hospitalizations during interim maintenance for high-risk pediatric B-lineage acute lymphocytic leukemia significantly improves survival but increases resource utilization. Children remain hospitalized for intravenous hydration and blood or urine monitoring until MTX clearance parameters are reached. Improved supportive care, extended infusion center hours, and pediatric home health expertise afford alternatives to prolonged hospital admissions, potentially offering quality, cost-effective approaches that positively impact the delivery of care.

NK Cells as Possible Prognostic Factor in Childhood Acute Lymphoblastic Leukemia.

Deficiency or impaired function natural killer (NK) cells might result in the development of serious infections and promote the development of malignancies. The aim of our study was to assess the prognostic role of NK cell percentage in bone marrow on the day of acute lymphoblastic leukemia (ALL) diagnosis. 84 children (49 males 58% median age 5 yrs) with ALL were enrolled. The NK cell percentage was assessed using flow cytometry with antibodies against the cluster of differentiation (CD) CD3, CD56, and CD16. We evaluated two groups group I (NK), patients with NK cells in the bone marrow (

The frequency of NOTCH1 variants in T-acute lymphoblastic leukemialymphoma and chronic lymphocytic leukemiasmall lymphocytic lymphoma among Jordanian patients.

The transmembrane receptor NOTCH1 is thought to be associated with the development and progression of T-acute lymphoblastic leukemia (T-ALL)T-lymphoblastic lymphoma (T-LBL) and chronic lymphocytic leukemia (CLL)small lymphocytic lymphoma (SLL). The current study aimed to characterize NOTCH1 expression and elucidate the variants in the functional PEST domain of the receptor in T-ALLLBL and CLLSLL. The nuclear expression of NOTCH1 protein was detected in 25% and 5% of cases of T-ALLLBL and CLLSLL, respectively, whereas cytoplasmic expression was detected in 33.3% and 15% cases, respectively. The frequency of variants in T-ALLLBL was 33%, whereas 40% of CLLSLL cases possessed variants. Four novel variants were identified three of which were non-synonymous and one common variant c.72807280delG between T-ALLLBL and CLLSLL cases. The previously described variant, c.75417542delCT, was detected in 3 cases of CLLSLL. These results provide support for the contribution of NOTCH1 in the etiology of these types of cancers.

Understanding the evolutionary trend of intrinsically structural disorders in cancer relevant proteins as probed by Shannon entropy scoring and structure network analysis.

Malignant diseases have become a threat for health care system. A panoply of biological processes is involved as the cause of these diseases. In order to unveil the mechanistic details of these diseased states, we analyzed protein families relevant to these diseases. Our present study pivots around four apparently unrelated cancer types among which two are commonly occurring viz. Prostate Cancer, Breast Cancer and two relatively less frequent viz. Acute Lymphoblastic Leukemia and Lymphoma. Eight protein families were found to have implications for these cancer types. Our results strikingly reveal that some of the proteins with implications in the cancerous cellular states were showing the structural organization disparate from the signature of the family it constitutes. The sequences were further mapped onto respective structures and compared with the entropic profile. The structures reveal that entropic scores were able to reveal the inherent structural bias of these proteins with quantitative precision, otherwise unseen from other analysis. Subsequently, the betweenness centrality scoring of each residue from the structure network models was resorted to explore the changes in dependencies on residue owing to structural disorder. These observations help to obtain the mechanistic changes resulting from the structural orchestration of protein structures. Finally, the hydropathy indexes were obtained to validate the sequence space observations using Shannon entropy and in-turn establishing the compatibility.

Immunotherapy in pediatric B-cell acute lymphoblastic leukemia.

Advances in multi-agent chemotherapy and supportive care have dramatically improved survival of children with B-cell acute lymphoblastic leukemia (B-ALL) however, patients with relapsed and refractory disease continue to represent a therapeutic challenge. Hematopoietic stem cell transplant was the first immunotherapeutic approach to be used in the treatment of patients with relapsed or refractory disease. However, novel therapies such as bispecific antibodies that engage T-cells and chimeric antigen receptor T-cells (CAR-T) therapy have emerged as novel FDA-approved options that have the potential to become the new standard of care for these difficult-to-treat leukemias. With multiple immunotherapeutic agents in the drug development pipeline, it is important for cancer researchers and oncologists to be familiar with these agents, including their mechanism of action, side effects and efficacy. In this paper, we review the role of the human immune system in the development and treatment of childhood ALL and provide an overview of current and upcoming immunotherapeutic treatment approaches.

FxCycle™ Based Ploidy Correlates with Cytogenetic Ploidy in B-Cell Acute Lymphoblastic Leukemia and Is Able to Detect the Aneuploid Minimal Residual Disease Clone.

Flow cytometry (FCM) is a simple, sensitive, and specific technique that can potentially determine DNA ploidy in B-cell precursor ALL (BCP-ALL) and is complementary to cytogenetics. A prospective FCM DNA ploidy analysis using FxCycle™ Violet (assay sensitivity 0.01%) was done in 125 consecutive new cases of BCP-ALL (90 cases <15 years of age) and compared with corresponding cytogenetic ploidy (karyotyping andor FISH) data wherever available. This assay was also subsequently evaluated for detection of residual aneuploid clone in few BCP-ALL cases. Of the total 125 BCP-ALL cases evaluated, flow ploidy analysis revealed diploidy (DI 0.96-1.05) in 44.8% (n 56), low-hyperdiploidy (DI 1.06 to 1.15) in 13.6% (n 17), high-hyperdiploidy (DI 1.16-1.39) in 32.8% (n 41) and near-tetraploidy (DI ≥ 1.80) in 2.4% (n 3) cases. The high risk sub-group of low-hypodiploidy (DI 0.70 to 0.88)near-triploidy (DI 1.40 to 1.79) constituted 5.6% (n 7) cases while there was only one case with haploidy (DI 0.58). Overall, high concordance of 90.4% (n 113) was noted between the combined cytogenetics ploidy and FCM ploidy. Of the total discordant cases (n 12), the maximum discordance was seen in the low-hyperdiploid DI subgroup (n 10), which included seven cases with low DNA index high hyperdiploidy (LDI-HHD). FCM DNA ploidy assay was able to detect the residual clone in all six MRD positive aneuploid cases evaluated. FxCycle™ based DNA ploidy ascertains strong correlation with cytogenetic profiles and yields complementary information that can be used by the cytogenetics laboratories or otherwise. © 2019 International Clinical Cytometry Society.

Blastic Plasmacytoid Dendritic Cell Neoplasm.

While there is a high initial response rate with standard chemotherapeutic regimens for blastic plasmacytoid dendritic cell neoplasm (BPDCN), the responses are typically not durable and this remains a very aggressive disease with generally poor outcomes. For this reason, the standard approach for eligible patients has been high-dose induction chemotherapy preferably with acute lymphoblastic leukemia (ALL)-based regimens followed by consolidation with allogeneic hematopoietic stem cell transplantation (alloHSCT). Unfortunately, many patients with this disease are elderly andor frail and cannot tolerate this therapy, and the low-dose regimens being used in this population are generally not as effective. However, this paradigm may be changing with the advent of newer targeted therapies, particularly the exploitation of CD123. SL-401 has shown very promising results with manageable toxicities and durable responses and appears to be a viable option for elderly or frail patients who are not eligible for transplant. The other CD123-directed therapies, especially chimeric antigen receptor-therapy (CAR-T), may also give promising results in trials that are currently underway. CAR-T has shown promise in a number of other hematologic malignancies, and toxicities have become more manageable as its use is becoming more widespread. While SL-401 has shown potential to provide durable responses even without transplant, we do not yet know whether it will be effective as a means to avoid transplant in patients who are otherwise eligible. All transplant-eligible patients should undergo alloHSCT consolidation given the current available data indicating this is the optimal approach to achieve a long-term remission. Once the CD123-directed therapies are established as standard regimens, future studies may be designed to investigate whether these therapies can be utilized without the use of transplant. Furthermore, combination therapy using anti-CD123 agents with high-dose induction chemotherapy or other low-dose regimens for elderlyfrail patients should be investigated. Given the promising results in early clinical trials, it appears CD123 is the most viable target for BPDCN, and future studies should continue to exploit its expression on BPDCN cells.

Bispecific Antibodies in Hematologic Malignancies When, to Whom, and How Should Be Best Used

The purpose of this review is to discuss the current recommendations for the use of bispecific antibodies (bsAb) in hematologic malignancies and explore the future in this field. Bispecific antibodies are molecules able to target two different antigen-binding sites one towards a tumor antigen and another to activate a cytotoxic cell. Phase IIIII trials on blinatumomab for acute lymphoblastic leukemia (ALL) have demonstrated its efficacy for treating minimal residual disease (MRD) and relapsed refractory (rr) Philadelphia positive (Ph) and negative (Ph-) ALL in adults and children. Currently, the only bispecific antibody (bsAb) approved for its use in hematologic malignancies is blinatumomab. However, multiple trials are under development not only to explore blinatumomabs clinical activity in other neoplasia, such as lymphoma or multiple myeloma, but also to develop new molecules against different antigens.

Risk of cancer in children and young adults conceived by assisted reproductive technology.

Do children conceived by ART have an increased risk of cancer Overall, ART-conceived children do not appear to have an increased risk of cancer. Despite the increasing use of ART, i.e. IVF or ICSI worldwide, information about possible long-term health risks for children conceived by these techniques is scarce. A nationwide historical cohort study with prospective follow-up (median 21 years), including all live-born offspring from women treated with subfertility treatments between 1980 and 2001. All offspring of a nationwide cohort of subfertile women (OMEGA study) treated in one of the 12 Dutch IVF clinics or two fertility clinics. Of 47 690 live-born children, 24 269 were ART-conceived, 13 761 naturally conceived and 9660 were conceived naturally or through fertility drugs, but not by ART. Information on the conception method of each child and potential confounders were collected through the mothers questionnaires and medical records. Cancer incidence was ascertained through linkage with The Netherlands Cancer Registry from 1 January 1989 until 1 November 2016. Cancer risk in ART-conceived children was compared with risks in naturally conceived children from subfertile women (hazard ratios HRs) and with the general population (standardized incidence ratios SIRs). The median follow-up was 21 years (interquartile range (IQR) 17-25) and was shorter in ART-conceived children (20 years, IQR 17-23) compared with naturally conceived children (24 years, IQR 20-30). In total, 231 cancers were observed. Overall cancer risk was not increased in ART-conceived children, neither compared with naturally conceived children from subfertile women (HR 1.00, 95% CI 0.72-1.38) nor compared with the general population (SIR 1.11, 95% CI 0.90-1.36). From 18 years of age onwards, the HR of cancer in ART-conceived versus naturally conceived individuals was 1.25 (95% CI 0.73-2.13). Slightly but non-significantly increased risks were observed in children conceived by ICSI or cryopreservation (HR 1.52, 95% CI 0.81-2.85 1.80, 95% CI 0.65-4.95, respectively). Risks of lymphoblastic leukemia (HR 2.44, 95% CI 0.81-7.37) and melanoma (HR 1.86, 95% CI 0.66-5.27) were non-significantly increased for ART-conceived compared with naturally conceived children. Despite the large size and long follow-up of the cohort, the number of cancers was rather small for subgroup analyses as cancer in children and young adults is rare. Overall, ART-conceived children do not appear to have an increased cancer risk after a median follow-up of 21 years. This large study provides important results, enabling physicians to better inform couples considering ART about the long-term safety of ART for their children. However, larger studies with prolonged follow-up are needed to investigate cancer risk in adults and in children conceived by ICSI andor from cryopreserved embryos. This work was supported by The Dutch Cancer Society (NKI 2006-3631) which funded the OMEGA-womens cohort and Children Cancer Free (KIKA147) which funded the OMEGA-offspring cohort. We declare no competing interests.

Anti-CD19 chimeric antigen receptors T cells for the treatment of relapsed or refractory E2A-PBX1 positive acute lymphoblastic leukemia report of three cases.

Patients with relapsed or refractory E2A-PBX1 positive acute B lymphoblastic leukemia (B-ALL) receiving anti-CD19 chimeric antigen receptor T cells (CAR-T) were retrospectively assessed to evaluate the efficacy and safety of disease burden on outcomes and to identify predictive variables. Of the three case patients, case 1 relapsed after hematopoietic stem cell transplantation. After being treated with anti-CD19 CAR-T, the patient showed minimal residual disease (MRD), and his fusion genes turned negative. Case 2, who suffered refractory leukemia, received anti-CD19 CAR-T treatment in an attempt to remove the MRD before transplantation. She showed MRD, and her fusion genes turned negative. Case 3 received anti-CD19 CAR-T treatment because of relapse after allo-SCT at the molecular level. After infusion, she developed severe pneumonia accompanied with the indication that the leukemia had progressed. Our findings suggest that anti-CD19 CAR-T cells therapy with a remarkable MRD eradicating ability might be an effective option for patients with relapsed and refractory E2A-PBX1 positive B-ALL.

Aneuploidy in children with relapsed B-cell precursor acute lymphoblastic leukaemia clinical importance of detecting a hypodiploid origin of relapse.

Aneuploidy is common in paediatric B-cell precursor acute lymphoblastic leukaemia (ALL). Specific subgroups, such as high hyperdiploidy (>50 chromosomes or DNA Index ≥1·16) and hypodiploidy (<45 chromosomes), predict outcome of patients after primary treatment. Whether aneuploidy has a prognostic value for relapsed disease is yet to be determined. Using DNA index and centromere screening by multiplex ligation-dependent probe amplification, we investigated aneuploidy in 413 children treated for first relapse of B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. Ten-year event-free survival of patients with high hyperdiploid relapses approached 70%, whereas it was only 40% in low hyperdiploid relapses. Three patients with apparent hyperdiploid relapse had TP53 mutations. In these cases, array-based allelotyping revealed a hypodiploid origin with absence of the hypodiploid founder clone (masked hypodiploidy). Collectively, patients with evident or masked hypodiploid relapses showed an extremely low event-free survival rate of 9%. Importantly, the current relapse risk stratification did not identify cases with masked hypodiploidy as high-risk patients, due to their favourable clinical presentation. In multivariate analysis, hypodiploidy proved to be an independent prognostic factor. This finding supports stratification of relapses with hypodiploid origin into high-risk arms in future trials or allocation of patients to alternative treatment approaches.

Lymphocytes in Cellular Therapy Functional Regulation of CAR T Cells.

Lymphocytes especially autologous T cells have been used for the treatment of numerous indications including cancers, autoimmune disorders and infectious diseases. Very recently, FDA approved Chimeric Antigen Receptor T cells (CAR T cells) therapy for relapse and refractory CD19 B cell acute lymphoblastic leukemia (rr B-ALL) and rr diffuse large B cell lymphoma (rr DLBCL) upon their remarkable success in multiple Phase I-II clinical trials. While CAR T cells are considered as major breakthrough in the field of cancer immunotherapy, the regulation of CAR T cells remains poorly understood. In this review we will discuss the strategies that regulate the CAR T cells efficacy and persistence with focus on roles of different structural component of CAR construct. Different domains of CAR construct, for example, antigen binding domain, hinge, transmembrane, and signaling domain as well as immune-regulatory cytokines have significant impact on CAR T cell efficacy. Finally, this review will highlight the strategies that will promote CAR T cells efficacy and will reduce the toxicity.

Genome-wide identification of microRNA signatures associated with stemprogenitor cells in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignant transformation with uncontrolled proliferation of lymphoid precursor cells within bone marrow including a dismal prognosis after relapse. Survival of a population of quiescent leukemia stem cells (LSCs, also termed leukemia-initiating cells (LICs)) after treatment is one of the relapse reasons in Ph

Hematologic malignancies and Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene

Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission final results of quality of life and long-term outcome analysis of a phase 3 randomised study.

We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (11) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mgkg with either total body irradiation (12 Gy) or busulfan (12·8 mgkg intravenously or 16 mgkg orally), with or without etoposide (30-60 mgkg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov. In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n83) or to the non-ATLG group (n72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p0·02 treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 95% CI -26·4 to -3·1 p0·014) and social function (-19·1 -38·0 to -0·2 p0·047), gastrointestinal side-effects (8·8 2·5-15·1 p0·008) and effect on family (13·5 1·2-25·8 p0·032). Extended follow-up (median 5·9 years IQR 1·7-7·9) confirmed a lower 5-year cGVHD incidence (30·0% 95% CI 21·4-41·9 vs 69·1% 59·1-80·1 analysis for entire follow-up, p<0·001), no increase in relapses (35·4% 26·4-47·5 vs 22·5% 14·6-34·7 p0·09), improved cGRFS (34·3% 24·2-44·5 vs 13·9% 7·1-22·9 p0·005), and fewer patients still in immunosuppression (9·6% vs 28·3% p0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups. The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. Neovii Biotech.

Acute leukemias harboring KMT2AMLLT10 fusion a 10-year experience from a single genomics laboratory.

The MLLT10 (formerly AF10) gene is the fourth most common KMT2A fusion partner across all acute leukemias and requires at least 3 breaks to form an in-frame KMT2AMLLT10 fusion due to the opposite orientation of each gene. A 10-year retrospective review was performed to identify individuals from all age groups that harbor KMT2AMLLT10 fusion obtained by our KMT2AMLLT10 dual-color dual-fusion fluorescence in situ hybridization (D-FISH) assay. Of the 60 unique individuals identified, 31 were male and 29 were female (MF ratio, 1.11) with ages ranging from 3 days to 86 years (mean 21.5 years, median 5.5 years). The diagnoses included acute myeloid leukemia (AML) (49 patients, 82%), B- or T-lymphoblastic leukemialymphoma (7 patients, 12%), myeloid sarcoma (3 patients, 5%), and a single case (2%) of undifferentiated leukemia. Twenty-seven of 49 patients (55%) with AML were in the infant or pediatric age group. Fifty-three of 60 patients (88%) had KMT2AMLLT10 D-FISH signal patterns mostly consisting of single fusions. In addition, 10 (26%) of 38 patients with conventional chromosome studies had normal (5 patients) or abnormal (5 patients) chromosome studies that lacked structural or numeric abnormalities involving chromosomes 10 or 11, implying cryptic cytogenetic mechanisms for KMT2AMLLT10 fusion. Lastly, mate-pair sequencing was performed on 4 AML cases, 2 of which had normal chromosome studies and cryptic KMT2AMLLT10 fusion as detected by KMT2AMLLT10 D-FISH studies, and verified the multiple breaks required to generate KMT2AMLLT10 fusion.

Blinatumomab as a bridge to trasplantation in refractory Philadelphia chromosome negative b-cell acute lymphoblastic leukemia a case report.

Blinatumomab is a first class bispecific T-cell engager that has been shown to achieve negative minimal residual disease in patients with relapsed or refractory pre-B acute lymphoblastic leukemia after conventional chemotherapy. Nevertheless, there is little evidence about its role as an off label enhancer of cytological remission prior to stem cell transplantation (SCT). We describe the case of a patient with an excellent performance status who was allowed to undergo alogenic SCT after a single blinatumomab cycle, as well as the management of adverse events and the observed results.

Clinical Implications of Methotrexate Pharmacogenetics in Childhood Acute Lymphoblastic Leukaemia.

In the past two decades, a great body of research has been published regarding the effects of genetic polymorphisms on methotrexate (MTX)-induced toxicity and efficacy. Of particular interest is the role of this compound in childhood acute lymphoblastic leukaemia (ALL), where it is a pivotal drug in the different treatment protocols, both at low and high doses. MTX acts on a variety of target enzymes in the folates cycle, as well as being transported out and into of the cell by several transmembrane proteins. We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. This review has intended to summarize the current knowledge concerning the clinical impact of polymorphisms in enzymes and transporters involved in MTX disposition and mechanism of action on paediatric patients with ALL. In this work, we describe why, in spite of the significant research efforts, pharmacogenetics findings in this setting have not yet found their way into routine clinical practice.

Second primary cancers in patients with acute lymphoblastic, chronic lymphocytic and hairy cell leukaemia.

Improvement of survival in lymphocytic leukaemia has been accompanied by the occurrence of second primary cancer (SPCs). Based on Swedish Family Cancer Database, we applied bi-directional analyses in which relative risks (RRs) were calculated for any SPCs in patients with chronic lymphocytic leukaemia (CLL), acute lymphoblastic leukaemia (ALL) and hairy cell leukaemia (HCL) and the risks of these leukaemias as SPCs. After CLL, RRs were significant for 20 SPCs, and high for skin squamous cell cancer (24·58 for in situ and 7·63 for invasive), Merkel cell carcinoma (14·36), Hodgkin lymphoma (7·16) and Kaposi sarcoma (6·76). Conversely, 15 CLL cancer pairs were reciprocally increased. The increased risks were reciprocal for ALL and four cancers. RR for ALL was 15·35 after myeloid neoplasia. HCL showed reciprocally increased RRs with non-Hodgkin lymphoma and melanoma. The concordance between RRs for bi-directional associations between CLL and different cancers, and HCL and different cancers was highly significant. For CLL (also for HCL), the bi-directional risks with skin cancers and other immune-related cancers suggest the probable involvement of immune dysfunction. For ALL, treatment may contribute to risks of multiple SPCs. Increased risk of ALL after haematological neoplasms may indicate bone marrow dysfunction. These findings may help guide treatment decisions and prognostic assessment.

Ponatinib a novel multi-tyrosine kinase inhibitor against human malignancies.

Human malignancies are often the result of overexpressed and constitutively active receptor and non-receptor tyrosine kinases, which ultimately lead to the mediation of key tumor-driven pathways. Several tyrosine kinases (ie, EGFR, FGFR, PDGFR, VEGFR), are aberrantly activated in most common tumors, including leukemia, glioblastoma, gastrointestinal stromal tumors, non-small-cell lung cancer, and head and neck cancers. Iclusig™ (ponatinib, previously known as AP24534) is an orally active multi-tyrosine kinase inhibitor and is currently approved by the US Food and Drug Administration for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, specifically targeting the BCR-ABL gene mutation, T315I. Due to ponatinibs unique multi-targeted characteristics, further studies have demonstrated its ability to target other important tyrosine kinases (FGFR, PDGFR, SRC, RET, KIT, and FLT1) in other human malignancies. This review focuses on the available data of ponatinib and its molecular targets for treatment in various cancers, with a discussion on the broader potential of this agent in other cancer indications.

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IUm

Treatment abandonment in childhood acute lymphoblastic leukaemia in China a retrospective cohort study of the Chinese Childrens Cancer Group.

Before 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Childrens Cancer Group ALL protocol between 2015 and 2016. Demographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government. At a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standardhigh-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications. The rate of ALL treatment abandonment has been greatly reduced in China. Standardhigh-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment. ChiCTR-IPR-14005706, pre-results.

AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.

It has been shown that 5-amino-4-imidazolecarboxamide riboside (AICAr) can inhibit cell proliferation and induce apoptosis in childhood acute lymphoblastic leukemia (ALL) cells. Although AICAr could regulate cellular energy metabolism by activating AMPK, the cytotoxic mechanisms of AICAr are still unclear. Here, we knocked out TP53 or PRKAA1 gene (encoding AMPKα1) in NALM-6 and Reh cells by using the clustered regularly interspaced short palindromic repeatsCas9 system and found that AICAr-induced proliferation inhibition was independent of AMPK activation but dependent on p53. Liquid chromatography-mass spectrometry analysis of nucleotide metabolites indicated that AICAr caused an increase in adenosine triphosphate, deoxyadenosine triphosphate, and deoxyguanosine triphosphate levels by up-regulating purine biosynthesis, while AICAr led to a decrease in cytidine triphosphate, uridine triphosphate, deoxycytidine triphosphate, and deoxythymidine triphosphate levels because of reduced phosphoribosyl pyrophosphate production, which consequently impaired the pyrimidine biosynthesis. Ribonucleoside triphosphate (NTP) pool imbalances suppressed the rRNA transcription efficiency. Furthermore, deoxy-ribonucleoside triphosphate (dNTP) pool imbalances induced DNA replication stress and DNA double-strand breaks, followed by cell cycle arrest and apoptosis in ALL cells. Exogenous uridine could rebalance the NTP and dNTP pools by supplementing pyrimidine and then attenuate AICAr-induced cytotoxicity. Our data indicate that RNA transcription inhibition and DNA replication stress induced by NTP and dNTP pool imbalances might play a key role in AICAr-mediated cytotoxic effects on ALL cells, suggesting a potential clinical application of AICAr in future ALL therapy.-Du, L., Yang, F., Fang, H., Sun, H., Chen, Y., Xu, Y., Li, H., Zheng, L., Zhou, B.-B. S. AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.

Leukemia-derived exosomes and cytokines pave the way for entry into the brain.

Infiltration of acute lymphoblastic leukemia (ALL) blasts into the CNS remains as a major clinical problem, with high risk for chemotherapy-resistant relapse and treatment-related morbidity. Despite the common inclusion of CNS prophylaxis treatments in therapy regimens, there are significant gaps in understanding the mechanisms that mediate leukemia cell entry into the CNS as well as roles for resident cells in the brain. In this study, we employ a xenograft model of human B cell precursor (BCP)-ALL in immunocompromised mice. This model system recapitulates key pathological characteristics of leptomeningeal involvement seen in patients and provides insights into rare cases that involve parenchymal invasion. We examine the infiltration of engrafted leukemia blasts into brains of recipient mice and provide evidence that the interaction between blasts and brain resident cells causes aberrant activation of host cells in the brain microenvironment. BCP-ALL blasts also release multiple cytokines and exosomes containing IL-15 that bind and are internalized by astrocytes and brain vessel endothelial cells. Leukemic invasion is linked to production of VEGF-AA by astrocytes and disruption of the blood-brain-barrier (BBB) integrity. Knockdown of either IL-15 or IL-15Rα in the NALM6 cell line decreases CNS infiltration in engrafted mice. These results provide important insights into the multiple mechanisms by which lymphoblasts modulate the brain microenvironment to breach the BBB for metastatic invasion.

Cyclophosphamide for the treatment of acute lymphoblastic leukemia A protocol for systematic review.

Previous clinical trials have reported that cyclophosphamide can be used for the treatment of acute lymphoblastic leukemia (ALL). However, its efficacy is still unclear. In this systematic review study, we aim to evaluate its efficacy and safety for ALL. The following 9 databases will be searched from their inception to the present Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), and four Chinese databases. The randomized controlled trials or case control studies of cyclophosphamide that assess the clinical efficacy and safety in patients with ALL are included. The methodological quality of all eligible included studies will be assessed by the Cochrane risk of bias tool.The primary outcome measurement will be all-cause mortality at the period of treatment and follow-up. The secondary outcome measurements will include the health-related quality of life (HRQL), postinduction complete remission (CR) rate, event-free survival (EFS), relapse rate, and adverse events. Two authors will independently select eligible studies, exact data, and assess the methodological quality of included studies. RevMan 5.3 software will be used to synthesize the data. Reporting bias will be evaluated by the funnel plots, Begg, and Egger tests. This systematic review will evaluate the clinical efficacy and safety of cyclophosphamide for ALL. The findings of this review will summarize the present evidence of cyclophosphamide for ALL, and may provide guidance for clinical practice of cyclophosphamide for ALL. Its results will be published through peer-reviewed journals. This study does not need ethic approval, because it will not involve the individual data. PROSPERO CRD42018119333.

Aerobic physical exercise for adult patients with haematological malignancies.

Although people with haematological malignancies have to endure long phases of therapy and immobility, which is known to diminish their physical performance level, the advice to rest and avoid intensive exercises is still common practice. This recommendation is partly due to the severe anaemia and thrombocytopenia from which many patients suffer. The inability to perform activities of daily living restricts them, diminishes their quality of life and can influence medical therapy. In this update of the original review (published in 2014) our main objective was to re-evaluate the efficacy, safety and feasibility of aerobic physical exercise for adults suffering from haematological malignancies considering the current state of knowledge. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2018, Issue 7) and MEDLINE (1950 to July 2018) trials registries (ISRCTN, EU clinical trials register and clinicaltrials.gov) and conference proceedings. We did not apply any language restrictions. Two review authors independently screened search results, disagreements were solved by discussion. We included randomised controlled trials (RCTs) comparing an aerobic physical exercise intervention, intending to improve the oxygen system, in addition to standard care with standard care only for adults suffering from haematological malignancies. We also included studies that evaluated aerobic exercise in addition to strength training. We excluded studies that investigated the effect of training programmes that were composed of yoga, tai chi chuan, qigong or similar types of exercise. We also excluded studies exploring the influence of strength training without additive aerobic exercise as well as studies assessing outcomes without any clinical impact. Two review authors independently screened search results, extracted data and assessed the quality of trials. We used risk ratios (RRs) for adverse events, mortality and 100-day survival, standardised mean differences (SMD) for quality of life (QoL), fatigue, and physical performance, and mean differences (MD) for anthropometric measurements. In this update, nine trials could be added to the nine trials of the first version of the review, thus we included eighteen RCTs involving 1892 participants. Two of these studies (65 participants) did not provide data for our key outcomes (they analysed laboratory values only) and one study (40 patients) could not be included in the meta-analyses, as results were presented as changes scores only and not as endpoint scores. One trial (17 patients) did not report standard errors and could also not be included in meta-analyses. The overall potential risk of bias in the included trials is unclear, due to poor reporting.The majority of participants suffered from acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), malignant lymphoma and multiple myeloma, and eight trials randomised people receiving stem cell transplantation. Mostly, the exercise intervention consisted of various walking intervention programmes with different duration and intensity levels.Our primary endpoint overall survival (OS) was only reported in one of these studies. The study authors found no evidence for a difference between both arms (RR 0.67 P 0.112). Six trials (one trial with four arms, analysed as two sub-studies) reported numbers of deceased participants during the course of the study or during the first 100 to 180 days. For the outcome mortality, there is no evidence for a difference between participants exercising and those in the control group (RR 1.10 95% CI 0.79 to 1.52 P 0.59 1172 participants, low-certainty evidence).For the following outcomes, higher numbers indicate better outcomes, with 1 being the best result for the standardised mean differences. Eight studies analysed the influence of exercise intervention on QoL. It remains unclear, whether physical exercise improves QoL (SMD 0.11 95% CI -0.03 to 0.24 1259 participants, low-certainty evidence). There is also no evidence for a difference for the subscales physical functioning (SMD 0.15 95% CI -0.01 to 0.32 8 trials, 1329 participants, low-certainty evidence) and anxiety (SMD 0.03 95% CI -0.30 to 0.36 6 trials, 445 participants, very low-certainty evidence). Depression might slightly be improved by exercising (SMD 0.19 95% CI 0.0 to 0.38 6 trials, 445 participants, low-certainty evidence). There is moderate-certainty evidence that exercise probably improves fatigue (SMD 0.31 95% CI 0.13 to 0.48 9 trials, 826 patients).Six trials (435 participants) investigated serious adverse events. We are very uncertain, whether additional exercise leads to more serious adverse events (RR 1.39 95% CI 0.94 to 2.06), based on very low-certainty evidence.In addition, we are aware of four ongoing trials. However, none of these trials stated, how many patients they will recruit and when the studies will be completed, thus, potential influence of these trials for the current analyses remains unclear. Eighteen, mostly small RCTs did not identify evidence for a difference in terms of mortality. Physical exercise added to standard care might improve fatigue and depression. Currently, there is inconclusive evidence regarding QoL, physical functioning, anxiety and SAEs .We need further trials with more participants and longer follow-up periods to evaluate the effects of exercise intervention for people suffering from haematological malignancies. To enhance comparability of study data, development and implementation of core sets of measuring devices would be helpful.

Use of chimeric antigen receptor T cells in allogeneic hematopoietic stem cell transplantation.

The chimeric antigen receptor T (CAR-T) cells play an antileukemia role, and can be used to treat or prevent relapse by targeting minimal residual disease for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the infusion of allogeneic CAR-T cells may also cause graft-versus-host disease, which limited their applications during and after allo-HSCT. In this review, we discuss the clinical trials that applying CAR-T cells before allo-HSCT and the use of donor-derived CAR-T cells as conditioning regimen during allo-HSCT. At last, we analyzed the effect of donor-derived CAR-T cells on preventive infusion after allo-HSCT.

Diagnostics and treatment challenges of Ph-like acute lymphoblastic leukemia a description of 3 clinical cases.

B-cell acute lymphoblastic leukemia (B-ALL) is a diverse group of malignant blood disorders both with regard to the biological properties of the tumor and to therapeutic approaches. Immunophenotyping, molecular genetic techniques, whole-genome sequencing characterize B-ALL as a very diverse group for sensitivity to chemotherapy and prognosis. We present three clinical cases of patients with B-ALL and expected good response to standard therapy, in whom standard protocol treatment failured refractoriness, persistence of minimal residual disease (MRD), and progression (MRD increase). The remission in these patients was achieved after chemotherapy change to immunological targeted therapy. Nowadays a unified therapeutic approach to all primary patients of the B-ALL is considered generally outdated. Great efforts are carrying out to develop molecular genetic classifications. The molecular dissection of subtypes of B-ALL goes on, and new protocols for selective treatment with targeting are clearly outlined for each subtype of B-ALL.

The role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia literature review and own experience.

The analysis of experience of nelarabine use in refractoryrelapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was ad- ministered as intravenous infusion at a dose of 650 mgm2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. From 2009 to 2017, 54 patients with refractoryrelapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34±8% vs 8±8%, p0,05). In patients after allo-HSCT EFS, OS and CIR were 51±10%, 50±10% and 39,1±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established dur- ing controlled clinical trials.

Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia.

To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol. The study included 115 adult patients with firstly diagnosed Ph-negative ALL 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n101) and in hematology departments of regional hospitals (n14). All patients received therapy of ALL-2009 protocol (ClinicalTrials.gov, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLLt(11q23), с-MYCt(8q24), TP53 deletion 17p13, CDKN2A deletion 9p21, translocation t(119)E2A-PBX1 и t(1221)ETV6-RUNX1 iAMP21 identification. Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients 9p21CDKN2A deletion in 24.3%, MLLt(11q23) gene abnormalities in 7.8%, 17p13TP53 deletion in 5.2%, abnormalities of c-MYCt(8q24) in 1.7%, t(119)E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signalsabsence of signals from gene locuses) in 26.4%, t(1221)ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21CDKN2A deletion with high serum lactate dehydrogenase activity (p0.02) MLLt(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p0.0016), hyperploidy - with normal leukocyte count (p0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLLt(11q23) and c MYCt(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9 plt0.0001) and chance of recurrence (HR - 6.4 p0.02). Adverse prognostic factors in terms of therapeutic management provided in ALL-2009 protocol were MLLt(11q23) and с-MYCt(8q24) genes abnormalities. CDKN2A9p21 and TP5317p13 genes deletions, quantative and complex karyotype abnormalities were not prognostic factors in adult patients with Ph-negative ALL in ALL-2009 protocol use.

Molecular profiling of adult acute myeloid and lymphoid leukemia in a major referral center in Lebanon a 10-year experience report and review of the literature.

Recurrent genetic abnormalities confer distinct morphologic features and play a role in determining the clinical behavior, prognosis and adequate treatment of acute leukemia. In the MENA region, only one study targets the frequency of genetic modifications in AML, reporting a higher occurrence of acute promyelocytic leukemia in Lebanon. Determining the frequency of translocations and gene mutations in acute myeloid and lymphoid leukemia cases in an adult patients population in Lebanon and comparing the resultant genetic profile with the published international molecular profile of adult acute leukemia. Laboratory results of adult patients diagnosed with AML or ALL presenting to AUBMC for genetic profiling between years 2006 until June 2016 were reviewed. Genetic profiling of AML cases in our CAP accredited molecular diagnostics laboratory consists of a validated lab developed RT-PCR for the detection of RUNX1RUNX1T1, CBFBMYH11, KMT2AMLLT3, PML-RARA, and BCR-ABL and mutations in the FLT3 receptor, NPM1, c-kit and CEPBA genes. The ALL panel tests for the presence of BCR-ABL1, ETV6RUNX1 KMT2AAFF1, and TCF3-PBX1. We reviewed 580 AML and 175 ALL cases. In the AML cohort, the MF ratio was 1.31 with a mean age of 50 years. t(1517) was present in 7.6%, t(821) in 4.2%, inv(16) in 3.7%, t(922) in 2.2% and t(911) in 1.7% of cases. FLT3 mutation (ITD or TKD) was present in 25.2% of all cases and 30.1% of Cytogenetics-normal (CN) patients. Mutations of the NPM1 gene was present in 31.4% of AML cases and in 43.8% of CN patients. Double positive (NPM1FLT3) cases accounted for 20% of NK patients. CEBPA and c-kit mutations were detected in 7.3% and 2.4% respectively. In the ALL cohort, the mean age was 37 years. B- and T-lymphoblastic leukemia constituted 84.6% and 15.4% of ALL cases and the MF ratio was 1.21 and 2.861 respectively. B-ALL patients were positive for t(922) in 14.2%, t(411) in 5.4%, t(119) in 2.7% and t(1221) in 1.4%. T-ALL patients were negative for translocations found in our ALL panel. A lower mean age was found in our adult leukemic Lebanese population as compared to the Western cases. Other interesting findings were the lower percentage of inv(16), lower incidence of TCF3-PBX1, and the mild increase in Philadelphia positivity in our AML cohort. In our ALL cohort, t(922) positivity was less than expected for adult lymphoblastic leukemia. Full molecular profiling by next generation sequencing is required for further classification of cases into prognostic categories. This study will be a baseline reference for future research and epidemiological data useful for transplant centers and oncologists both in Lebanon and the region.

Current development of chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy has achieved great success in recent years, with encouraging complete remission rate and long-term durability of response, especially in advanced B-cell malignancies. With the approval of tisagenlecleucel and axi-cel by FDA to treat refractoryrelapsed acute lymphoblastic leukemia and non-Hodgkin lymphoma, our understanding of CAR T cells has been progressing rapidly. In this review, we discussed the designs of CAR T cells, factors affecting response, adverse effects, as well as application beyond B-cell malignancies.

Targeting protein kinase CK2 and CDK46 pathways with a multi-kinase inhibitor ON108110 suppresses pro-survival signaling and growth in mantle cell lymphoma and T-acute lymphoblastic leukemia.

Overexpression and constitutive activation of CYCLIN D1 and Casein Kinase 2 are common features of many hematologic malignancies, including mantle cell lymphoma (MCL) and leukemias such as T-cell acute lymphoblastic leukemia (T-ALL). Although both CK2 and CDK4 inhibitors have shown promising results against these tumor types, none of these agents have achieved objective responses in the clinic as monotherapies. Because both proteins play key roles in these and other hematological malignancies, we have analyzed the therapeutic potential of ON108110, a novel dual specificity ATP-competitive inhibitor of protein kinase CK2 as well as CDK46 in MCL and T-ALL. We show that in cell growth inhibition assays, MCL and T-ALL cell lines exhibited increased sensitivity to ON108110 when compared to other tumor types. Treatment with ON108110 reduced the level of phosphorylated RB-family proteins. In addition, ON108110 treatment resulted in concentration dependent inhibition of PTEN phosphorylation and a concomitant decrease in PI3K-AKT signaling mediated by CK2. Accordingly, cells treated with ON108110 rapidly accumulated in the G

The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2Lyl1.

T cell acute lymphoblastic leukaemia (T-ALL) cases include subfamilies that overexpress the TAL1LMO, TLX13 and HOXA transcription factor oncogenes. While it has been shown that TAL1LMO transcription factors induce self-renewal of thymocytes, whether this is true for other transcription factor oncogenes is unknown. To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL. We find that thymocytes from preleukaemic NHD13-Tg mice can serially transplant, demonstrating that they have self-renewal capacity. Transcriptome analysis shows that NHD13-Tg thymocytes exhibit a stem cell-like transcriptional programme closely resembling that induced by Lmo2, including Lmo2 itself and its critical cofactor Lyl1. To determine whether Lmo2Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice. This showed that Lyl1 is essential for expression of the stem cell-like gene expression programme in thymocytes and self-renewal. Surprisingly however, NHD13 transgenic mice lacking Lyl1 showed accelerated T-ALL and absence of transformation to AML, associated with a loss of multipotent progenitors in the bone marrow. Thus multiple T cell oncogenes induce thymocyte self-renewal via Lmo2Lyl1 however, NHD13 can also promote T-ALL via an alternative pathway.

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of hematologic malignancies, arising from diverse genetic alterations in the early lymphocyte development. T-cell subtype of ALL (T-ALL) accounts for about 15% and 25% of ALL in children and adults, respectively. Being less frequent among ALL subtypes, T-ALL represents a high-risk factor for poor prognosis due to its aggressiveness and resistance to common antileukemic drugs. Mitochondria were widely explored recently as a target for anticancer treatment because they are involved in a metabolic reprogramming of a cancer cell and play key roles in reactive oxygen species generation, Ca

Detection of Minimal Residual Disease in B Cell Acute Lymphoblastic Leukemia Using an Eight-Color Tube with Dried Antibody Reagents.

Flow cytometry is a powerful tool for the detection of minimal residual disease (MRD) of B cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. However, the staining process and the choice of antibodies rely on laboratory expertise and may be source of variability or technical errors. Recently, Beckman Coulter commercialized a ready to use tube with dried format reagents for BCP-ALL MRD detection. The aim of this study is to evaluate the applicability of this tube and to compare it to a conventional (liquid format reagents) method. Thirty-one samples from B ALL patients were analyzed 19 bone marrow (BM) aspirations, 10 peripheral blood (PB) samples and 2 cerebrospinal fluids at different stages of the follow-up. In addition, we tested 5 bone marrow samples mixed into non-pathological (control) bone marrow. The dried format tube included seven antibodies CD45Kro, CD58FITC, CD34ECD, CD10PC5.5, CD19PC7, CD38AA700, CD20AA750, with possibility of additional antibodies for blast markers identified at diagnosis. For comparison, a liquid format tube was prepared, and considered as the reference. This tube was validated for daily routine laboratory, with satisfying qualitative (MRD or MRD-) and quantitative (MRD percentages) correlation with the reference tube. With this single dried format tube, we showed interesting results for BCP-ALL MRD detection in the aim of standardization and reliable interlaboratory results. It allows accurate MRD detection including low levels (10-4), and offers possibility to increase performance (supplementary antibody) within a preestablished effective antibody panel for BCP-ALL MRD. © 2018 International Clinical Cytometry Society.

A novel fusion gene involving PDGFRB and GCC2 in a chronic eosinophilic leukemia patient harboring t(25)(q37q31).

Platelet-derived growth factor receptor beta (PDGFRB) rearrangement has been reported in a number of patients with chronic eosinophilic leukemia (CEL), B-acute lymphoblastic leukemia, myeloproliferative neoplasms, and juvenile myelomonocytic leukemia. Here, we report a case of CEL carrying a novel fusion gene involving PDGFRB and GRIP and coiled-coil domain containing 2 (GCC2). A 54-year-old man presenting with a cough and dyspnea was diagnosed with acute eosinophilic pneumonia. Cytogenetic analysis of the bone marrow revealed the presence of t(25)(q37q31). Fluorescence in situ hybridization analysis in the peripheral blood leukocytes revealed the presence of a split signal at PDGFRB gene. Imatinib treatment was effective, and disappearance of t(25)(q37q31) in the bone marrow was confirmed after three months of imatinib therapy. Whole-genome sequencing was performed in peripheral blood leukocytes collected before imatinib therapy. A novel fusion gene between exon 22 of GCC2 and exon 12 of PDGFRB was detected and the presence of GCC2-PDGFRB was confirmed by PCR. This is the first case report demonstrating the GCC2 gene as a partner of PDGFRB in the pathogenesis of CEL.

Advances in biology of acute lymphoblastic leukemia (ALL) and therapeutic implications.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and also occurs in adults. Although the outcomes of multi-agent chemotherapy regimens have greatly improved, high toxicity and relapses in many patients necessitate the development of novel therapeutic approaches. Advances in molecular profiling and cytogenetics have identified a broad range of genetic abnormalities, including gene mutations, chromosome translocations and aneuploidy, which has provided a more comprehensive understanding of the biology and pathogenesis of ALL. This understanding has also led to new targeted therapeutic approaches, including the use of selective small molecule inhibitors, nucleic acid-based therapies and immune-based therapies mediated by specific monoclonal antibodies and cellular immunotherapy, which are poised to revolutionize the treatment of various ALL subtypes. The main focus of this review is to highlight the latest advances in ALL biology, including the identification of prognostic factors and putative therapeutic targets. We also review the current status of, and ongoing progress in, the development of targeted therapies for ALL.

Regulatory Network and Prognostic Effect Investigation of PIP4K2A in Leukemia and Solid Cancers.

Germline variants of

Chronic fatigue and associated factors among long-term survivors of cancers in young adulthood.

The role of adiponectin, LEPTIN, and ghrelin in the progress and prognosis of childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Dysregulation of adipokine pathways is implicated in the carcinogenesis and ALL. The aim of this study is to present the most recent data available regarding the role of leptin, adiponectin and ghrelin in the pathogenesis and prognosis of ALL. The PubMed database was searched using Leptin, Adiponectin, Ghrelin, Cancer, Children and Acute Lymphoblastic Leukemia as keywords. The majority of the studies indicated that leptin levels are increased and adiponectin levels are decreased in ALL children at diagnosis, as well as in ALL survivors. Ghrelin levels were found to be lower at diagnosis and progressively increased during treatment. Further research is warranted, as the heterogeneity of the current studies, various treatment protocols and differences in sample sizes make it difficult to deduce solid conclusions regarding the role of adipokines in ALL.

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib.

Adults with relapsed or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of RR B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.

Erythroleukemias. Recategorization according to the World Health Organizations criteria.

Acute leukemia is the most frequent malignant disease in childhood. Acute lymphoblastic leukemia represents 75% and acute myeloblastic leukemia 25% of them. Erythroleukemia is a rare entity, corresponding to less than 5% of acute myeloblastic leukemia. Its definition has changed over the time. WHO in 2017 defines erythroleukemia when the percentage of erythroblasts represent 80% of the total cellularity of the bone marrow aspirate. This analytical and retrospective study was performed with the aim of reviewing morphology, flow cytometry and cytogenetic features, response to treatment and outcome of cases previously defined as erythroleukemia in our center during the last 25 years and, in addition to reclassify those cases which do not meet the new WHO 2017 criteria. From January 1990 to December 2015, 576 patients were diagnosed as acute myeloblastic leukemia and 11 (1.9%) of them were classified as erythroleukemia. Ten cases were evaluable. Sex distribution was 11 and the median age at diagnosis was 5 (range 0.9-14) years. Six of them had presented with previous myelodysplastic syndrome. None of the analyzed cases can be currently defined as erythroleukemia, according to the new criteria. When reclassified, the cases were defined as leukemias of subsets with poor prognosis such as acute undifferentiated leukemia, without differentiation and megakaryoblastic leukemia. Only 2 patients remain leukemia-free and this could be explained both by the unfavorable prognosis of these leukemia subtypes, and the antecedent of myelodysplastic syndrome in most of the cases.

Gastrointestinal mucormycosis in a child with acute lymphoblastic leukemia An uncommon but ominous complication.

Invasive fungal infections constitute a major cause of morbidity and mortality in children undergoing therapy for hematological malignancies. We report a 1-year-old boy who was receiving chemotherapy for acute lymphoblastic leukemia. His clinical course was complicated by a clinical syndrome consistent with neutropenic enterocolitis to which he succumbed. Histopathology of the surgically resected bowel revealed evidence of mucormycosis. Gastrointestinal mucormycosis is an unusual presentation which requires high degree of clinical suspicion and aggressive management.

Distraction Osteogenesis After Stem Cell Transplantation A Pioneer Approach.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy and is without alternative for certain groups of patients. Successful HSCT induces both long-lasting remission and tolerance without the need for further immunosuppression. In this case, cellular repair and regenerative processes work in a physiologic manner allowing elective surgical procedures, such as the interdisciplinary correction of dentofacial anomalies. Here, we report the successful management of transverse maxillary deficiency by transpalatal distraction and subsequent orthodontic treatment in a 12-year-old boy who underwent HSCT for high-risk acute lymphoblastic leukemia at 5 years of age.

Growth hormone deficiency and neurocognitive function in adult survivors of childhood acute lymphoblastic leukemia.

The impact of growth hormone deficiency (GHD) on neurocognitive function is poorly understood in survivors of childhood acute lymphoblastic leukemia (ALL). This study examined the contribution of GHD to functional outcomes while adjusting for cranial radiation therapy (CRT). Adult survivors of ALL (N 571 49% female mean age, 37.4 years age range, 19.4-62.2 years) completed neurocognitive tests and self-reported neurocognitive symptoms, emotional distress, and quality of life. GHD was defined as a previous diagnosis of GHD or a plasma insulin-like growth factor1 level less than -2.0 standard deviations for sex and age at the time of neurocognitive testing. Hypothyroidism, hypogonadism, sex, age at diagnosis, CRT dose, and intrathecal and high-dose intravenous methotrexate were included as covariates in multivariable linear regression models. Of the 571 survivors, 298 (52%) had GHD, and those with GHD received higher doses of CRT (P .002). Survivors who had GHD, irrespective of prior growth hormone treatment, demonstrated poorer vocabulary (z-score, -0.84 vs -0.61 P .02), processing speed (z-score, -0.49 vs -0.30 P .04), cognitive flexibility (z-score, -1.37 vs -0.94 P .01), and verbal fluency (z-score, -0.74 vs -0.44 P .001), and they self-reported more neurocognitive problems and poorer quality of life compared with survivors who did not have GHD. Multivariable and mediation models revealed that GHD was associated with small effects on quality of life (general health, P .01 vitality, P .01 mental health, P .01) and CRT dose accounted for the lower neurocognitive outcomes. Adult survivors of childhood ALL who receive CRT are at risk for GHD, although poor neurocognitive outcomes are determined by CRT dose and not by the presence of GHD.