European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Treatment of horizontal silage bunker runoff using biochar amended vegetative filter strips.

Horizontal silage bunkers produce leachate that contains contaminants that can be detrimental to the environment if released untreated. Vegetated filter strips are used to treat silage bunker runoff to prevent contamination of surface waters via infiltration, however increased infiltration poses risks to groundwater, particularly for nitrate (NO3-). Vegetated filter strip plots with a sandy loam soil, half of which are amended with biochar, were investigated to assess the treatment of silage bunker runoff over 20 application events. The subsurface effluent biological oxygen demand (BOD5), chemical oxygen demand (COD), and total phosphorus (TP) were reduced on average by 40%, 46%, and 75%, respectively, and there was no statistical difference between treatments. The total nitrogen (TN) was reduced by 49 and 64% for control and biochar plots, respectively, which was significantly different between treatments. Biochar significantly reduced nitrate nitrogen (NO3--N) leaching by 40% compared to the control, however, the NO3--N concentration in leachate was still high ranging from 0.19 to 191.04 mg NO3--N L-1 and 0.18-108.89 mg NO3--N L-1 for control and biochar plots, respectively. A mass balance suggests the primary mechanism for a decrease in TN and NO3--N leaching from biochar amended plots was greater retention of NO3--N and organic N (ORG-N) within the soil/biochar matrix. The development of oxygenated functional groups and/or formation of organomineral layer on the biochar surface likely enhanced N retention.

Nitrate sorption to biochar following chemical oxidation.

Biochar amendments can reduce nitrate (NO3) leaching in agricultural soil. It has been hypothesized that functional groups on the biochar surface from oxidation can increase NO3 sorption. This study evaluates the effect of chemical oxidation of biochar on NO3 sorption characteristics. Eight biochars, made from wood and corn cobs, underwent sodium hypochlorite (NaClO) and hydrogen peroxide (H2O2) oxidation and then assessed for NO3 sorption capacity using batch isotherm methods. The unoxidized and oxidized biochar produced at low temperatures (400 °C) had no significant NO3 sorption. Oxidized biochars produced at higher temperatures (600 °C and 700 °C) had calculated maximum NO3 sorption capacities (Smax) ranging from 0.50 to 3.97 mg NO3-N g-1. Biochar oxidations with 50 mmol NaClO g-1 (N50) in combination with an acid wash (AW) had the largest estimated sorption capacities of 3.68, 3.97, and 1.46 mg NO3-N g-1 for CTN50,AW, BW3N50,AW, and CC3N50,AW, respectively. Sorption capacity of wood-based biochars was higher than corn cob biochars due to increased oxidation as measured by total acid group content (TAGC). Wood biochar Smax values were correlated with ΔTAGC (R2 = 0.86), with a slope of 1.2 µmol NO3-N µmol TAGC-1 suggesting that cationic bridging of NO3 to oxidized sites is the primary mechanism for NO3 sorption.

Constraining the Spatial Extent of Marine Oil Snow Sedimentation and Flocculent Accumulation Following the Deepwater Horizon Event Using an Excess 210Pb Flux Approach.

Following the Deepwater Horizon (DWH) event in 2010, there were several lines of evidence indicating the presence of marine oil snow sedimentation and flocculent accumulation (MOSSFA). A significant amount of marine oil snow formed in the water column of the northern Gulf of Mexico (nGoM), settled rapidly, and ultimately accumulated in the sediments of the nGoM. This study utilized a commonly used radioisotope tracer (excess 210Pb, 210Pbxs) from 32 sediment cores collected from 2010 to 2013 to characterize the spatial extent of MOSSFA on the seafloor. Relative to pre-DWH conditions, an increase in 210Pbxs flux occurred in two distinct regions: (1) in the western portion of the study area on an east-northeast to west-southwest axis, stretching 230 km southwest and 140 km northeast of the DWH wellhead, and (2) in the eastern portion of the study area on a 70 km northeast to southwest axis near the DeSoto Canyon. The total sedimentary spatial extent of MOSSFA, as calculated by increased 210Pbxs flux after 2010, ranged from 12 805 to 35 425 km2. 210Pbxs flux provides a valuable tool for documenting the spatial extent of MOSSFA following DWH and will continue to aid in the determination of advective transport and ultimate depocenters of MOSSFA material.

The impact of biogas and fuelwood use on institutional kitchen air quality in Kampala, Uganda.

Experts have suggested that microscale biogas systems offer a source of renewable energy that improves indoor air quality, but such impacts have not been directly measured. This study documented cooking behaviors and measured 2.5-µm particulate matter (PM2.5 ), carbon monoxide (CO), and sulfur dioxide (SO2 ) concentrations within 14 institutional kitchens in Kampala, Uganda, that prepare meals using biogas (n=5), a mixture of biogas and fuelwood (n=3), and fuelwood (n=6). Small institutions (10-30 people) with biogas kitchens had 99% lower concentrations of PM2.5 (21 µg/m3 ) than fuelwood kitchens (3100 µg/m3 ). Larger institutions (>100 people) had biogas systems that produced insufficient gas and relied on fuelwood to meet over 90% of their energy needs. PM2.5 concentrations in these biogas-firewood kitchens were equivalent to concentrations in fuelwood kitchens. Although concentrations of hydrogen sulfide (H2 S) in biogas were as high as 2000 ppm, 75% of systems had undetectable H2 S levels (<100 ppm) in the biogas. Kitchens using biogas with high H2 S had correspondingly higher SO2 concentrations in the kitchen air. However, even the highest SO2 concentration in biogas kitchens (150 µg/m3 ) was lower than SO2 concentration in fuelwood kitchens (390 µg/m3 ). The results suggest that biogas systems can offer air quality improvements if sized properly for energy demands.

Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia.

Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.

Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503).

In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2 intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.

An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine-Induced Peripheral Neuropathy in Adults With Acute Lymphoblastic Leukemia.

Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying adult patients at high-risk. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by National Cancer Institute (NCI) criteria. CEP72 promoter genotype (rs924607) was determined using polymerase chain reaction (PCR)-based single nucleotide polymorphism (SNP) genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs. 10%, P = 0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (P = 0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy.

Canine cell line, IPC-366, as a good model for the study of inflammatory breast cancer.

Inflammatory breast cancer (IBC) is an aggressive type of cancer with poor survival in women. Inflammatory mammary cancer (IMC) in dogs is very similar to human IBC and it has been proposed as a good surrogate model for study the human disease. The aim was to determine if IPC-366 shared characteristics with the IBC cell line SUM149. The comparison was conducted in terms of ability to grow (adherent and nonadherent conditions), stem cell markers expression using flow cytometry, protein production using western blot and tumorigenic capacity. Our results revealed that both are capable of forming long-term mammospheres with a grape-like morphology. Adherent and nonadherent cultures exhibited fast growth in vivo. Stem cell markers expressions showed that IPC-366 and SUM149 in adherent and nonadherent conditions has mesenchymal-like characteristics, E-cadherin and N-cadherin, was higher in adherent than in nonadherent cultures. Therefore, this study determines that both cell lines are similar and IPC-366 is a good model for the human and canine disease.

Brincidofovir treatment of acyclovir-resistant disseminated varicella zoster virus infection in an immunocompromised host.

Brincidofovir (BCV) is a broad-spectrum antiviral agent active in vitro against double-stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and poxviruses. We report successful BCV use in management of disseminated acyclovir- and cidofovir-resistant varicella zoster virus in an immunocompromised hematopoietic stem cell transplant patient with chronic graft-versus-host disease who was intolerant to foscarnet.

Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

Effect of Wood Biochar in Manure-Applied Sand Columns on Leachate Quality.

Agricultural operations can pose a threat to the quality of nearby water sources particularly from nitrogen (N) and phosphorus (P) losses following land application of manure. Biochar application to soils has the potential to ameliorate degraded soils and reduce nutrient leaching to groundwater. The effects of amending sand soil columns with hybrid poplar biochar ( spp.) made by a slow-pyrolysis process at 450°C at varying rates (0, 1, 2, and 5% by weight) with repeated dairy manure applications over a 56-wk period was examined to evaluate the impact to leachate water quality. Increasing levels of biochar decreased cumulative levels of total N (TN) by 21 to 59%, nitrate (NO-N) by 17 to 46%, and ammonia (NH-N + NH-N) by 46 to 90% in leachate but increased cumulative leaching of total P (TP). Overall leachate pH was increased and peak levels of 5-d biological oxygen demand (BOD) in leachate after manure application were decreased with increasing levels of biochar amendment. The results from this study indicate that biochar amendments could be effective in reducing nitrogen leaching from soils, though further study is needed to determine practical application in a field setting.

Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia.

DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (⩾60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.

A novel clofarabine bridge strategy facilitates allogeneic transplantation in patients with relapsed/refractory leukemia and high-risk myelodysplastic syndromes.

Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m(2)/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity <20% and blasts <10%). Marrow cellularity (P<0.0001) and blast% (P=0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3-4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1-21), relapse was 29% (95% CI: 13-46) and OS was 71% (95% CI: 51-85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21-58) and 2 year OS was 31% (95% CI: 14-48). Disease at the nadir correlated with inferior OS after HCT (HR=1.22 for each 10% marrow blasts, 95% CI: 1.02-1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days, P=0.3) and OS (375 vs 195 days, P=0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009.

Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study.

Nilotinib (Tasigna) is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to imatinib. The 48-month follow-up data for patients with CML-CP treated with nilotinib after imatinib resistance or intolerance on an international phase II study were analyzed. Overall, 59% of patients achieved major cytogenetic response; 45% achieved complete cytogenetic response while on study. The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively. Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months. Of the 321 patients initially enrolled in the study, 98 (31%) were treated for at least 48 months. Discontinuations were primarily due to disease progression (30%) or adverse events (21%). Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to imatinib. Further significant improvements in therapy are required for patients who are resistant or intolerant to imatinib.

Prediction of outcomes in patients with Ph+ chronic myeloid leukemia in chronic phase treated with nilotinib after imatinib resistance/intolerance.

The purpose was to assess predictive factors for outcome in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) treated with nilotinib after imatinib failure. Imatinib-resistant and -intolerant patients with CML-CP (n=321) were treated with nilotinib 400 mg twice daily. Of 19 baseline patient and disease characteristics and two response end points analyzed, 10 independent prognostic factors were associated with progression-free survival (PFS). In the multivariate analysis, major cytogenetic response (MCyR) within 12 months, baseline hemoglobin ≥ 120 g/l, baseline basophils <4%, and absence of baseline mutations with low sensitivity to nilotinib were associated with PFS. A prognostic score was created to stratify patients into five groups (best group: 0 of 3 unfavorable risk factors and MCyR by 12 months; worst group: 3 of 3 unfavorable risk factors and no MCyR by 12 months). Estimated 24-month PFS rates were 90%, 79%, 67% and 37% for patients with prognostic scores of 0, 1, 2 and 3, respectively, (no patients with score of 4). Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients.