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.

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.

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.

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.

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.

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.

Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders.

By in situ chromosomal hybridization, the GM-CSF and FMS genes were localized to human chromosome 5 at bands q23 to q31, and at band 5q33, respectively. These genes encode proteins involved in the regulation of hematopoiesis, and are located within a chromosome region frequently deleted in patients with neoplastic myeloid disorders. Both genes were deleted in the 5q-chromosome from bone marrow cells of two patients with refractory anemia and a del(5)(q15q33.3). The GM-CSF gene alone was deleted in a third patient with acute nonlymphocytic leukemia (ANLL) who has a smaller deletion, del(5)(q22q33.1). Leukemia cells from a fourth patient who has ANLL and does not have a del(5q), but who has a rearranged chromosome 5 that is missing bands q31.3 to q33.1 [ins(21;5)(q22;q31.3q33.1)] were used to sublocalize these genes; both genes were present on the rearranged chromosome 5. Thus, the deletion of one or both of these genes may be important in the pathogenesis of myelodysplastic syndromes or of ANLL.

Studies of the human c-myb gene and its product in human acute leukemias.

The myb gene is the transforming oncogene of the avian myeloblastosis virus (AMV); its normal cellular homolog, c-myb, is conserved across a broad span of evolution. In humans, c-myb is expressed in malignant hematopoietic cell lines and in primary hematopoietic tumors. Partial complementary DNA clones were generated from blast cells of patients with acute myelogenous leukemia. The sequences of the clones were compared to the c-myb of other species, as well as the v-myb of AMV. In addition, the carboxyl terminal region of human c-myb was placed in an expression vector to obtain protein for the generation of antiserum, which was used to identify the human c-myb gene product. Like v-myb, this protein was found within the nucleus of leukemic cells where it was associated with the nuclear matrix. These studies provide further evidence that c-myb might be involved in human leukemia.

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.

Cytochalasin B is a potent mitogen for chronic lymphocytic leukemia cells in vitro.

It is widely accepted that the neoplastic B cells from patients with chronic lymphocytic leukemia (CLL) respond poorly to common mitogens. The fungal metabolite cytochalasin B (0.5 micrograms/ml) is a weak mitogen for normal lymphocytes. However, when peripheral blood lymphocytes from 19 patients with CLL of B cell origin (B-CLL) were cultured with 0.5 micrograms cytochalasin B/ml, significant new DNA synthesis ( [14C]thymidine incorporation) occurred in 18. Stimulation indices with cytochalasin B varied widely (range = 1.9-28.2, mean +/- SD = 10.6 +/- 7.5; delta cpm range = 1,157-153,818; n = 26) but in 11 cases exceeded those seen with concanavalin A (Con A), phytohemagglutinin, or pokeweed mitogen. In all 11, the mitogenic response to cytochalasin B exceeded that to pokeweed mitogen, which is believed to be a T cell-dependent B cell mitogen. In three cases, the responses to cytochalasin B were 8.6, 3.5, and 2.3 times greater than those to Con A. As with other mitogens, the DNA synthetic response to cytochalasin B was time and dose dependent. Peak thymidine incorporation occurred at 72-88 h and declined thereafter. Significant mitogenic effects were observed with 0.1-5 micrograms cytochalasin B/ml with a peak at 0.5-2 micrograms/ml. Stimulated DNA synthesis was abolished by 1 mM hydroxyurea. Cells from two patients with B-CLL were separated by rosetting with sheep erythrocytes (E). Depletion of E-rosette-positive cells from the CLL cell population abolished the response to Con A but did not affect the response to cytochalasin B. Cytochalasin B is a potent mitogen for B-CLL cells and may be useful in cytogenetic studies of this often indolent neoplasm.

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.

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.

Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome.

PURPOSE: This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. RESULTS: After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. CONCLUSION: Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

Pre-transplant ganciclovir and post transplant high-dose valacyclovir reduce CMV infections after alemtuzumab-based conditioning.

Alemtuzumab (Campath-1H)-based conditioning regimens are effective in preventing GVHD, but are associated with very high rates of cytomegalovirus (CMV) infection, a major limitation to their use. We evaluated 85 patients receiving conditioning with fludarabine 30 mg/m2/day (day -7 to day -3), alemtuzumab 20 mg/day (day -7 to day -3), and melphalan 140 mg/m2 on day -2. The initial patients received post transplant CMV prophylaxis with high-dose acyclovir. A very high incidence of CMV viremia was observed as has been commonly reported after alemtuzumab-based conditioning. Sixty-seven subsequent patients received pre-transplant ganciclovir and high-dose valacyclovir after engraftment. The cumulative incidence of CMV infection in the valacyclovir cohort was 29%. This compared favorably to the cumulative incidence of 53% in patients receiving only acyclovir (P = 0.004) and to literature data. CMV prophylaxis with pre-transplant ganciclovir and high-dose valacyclovir after engraftment appears effective in preventing the excessive incidence of CMV infection after alemtuzumab-based conditioning regimens.

Heterogeneity of O6-alkylguanine-DNA alkyltransferase activity in peripheral blood lymphocytes: relationship between this activity in lymphocytes and in lymphoblastoid lines from normal controls and from patients with Hodgkin's disease or non-Hodgkin's lymphoma.

We determined O6-alkylguanine-DNA alkyltransferase (AGT) activity in the peripheral blood lymphocytes (PBLs) of normal controls and patients with Hodgkin's disease or non-Hodgkin's lymphoma and compared these values with those of Epstein-Barr virus (EBV)-transformed cell lines prepared from the same PBL samples. PBLs have an AGT level characteristic of the individual from whom the cells were obtained. The AGT activity of lymphoblastoid cell lines obtained from a control group of PBLs was significantly correlated with the activity of the PBLs from which they were derived (r = 0.742). There was no significant correlation between PBLs and EBV-transformed lines derived from these PBLs in Hodgkin's disease/non-Hodgkin's lymphoma patients (r = 0.407, -0.225, and 0.270 for patients prior to, during, or after therapy, respectively). The lack of significant correlation between lines and PBLs was not due to random fluctuations in AGT activity, because multiple lines prepared from the same PBL sample were found to be highly correlated in AGT activity. In order to account for these results, we suppose that PBLs from a given individual are a heterogeneous population with respect to AGT activity. In normal individuals, the AGT activity of early passages of the multi-clonal EBV-transformed cell lines reflect the AGT activity of the PBLs from which they were derived. Malignancy and/or treatment with chemotherapeutic agents may selectively affect those lymphocytes which are targets for EBV-transformation so that the resultant cell line is no longer representative (with respect to AGT activity) of the total PBL population. Long-term culture of lymphoblastoid cell lines results in changes in AGT activity in some but not all cell lines suggesting that with time in culture, subsets with different AGT activities may be selected. There appears to be no growth advantage of low AGT activity and only rarely have we obtained lines with no measurable AGT activity, even after long periods in culture.

Establishment of a leukemia cell line with i(12p) from a patient with a mediastinal germ cell tumor and acute lymphoblastic leukemia.

We report the establishment of a leukemia cell line (UoC-B10) from a patient who developed leukemia several months after the diagnosis of a mediastinal yolk sac tumor. The patient's yolk sac tumor responded to combination chemotherapy, and a mature teratoma with focal areas of hematopoiesis was subsequently resected. However, 5 months after the initial diagnosis, the patient developed an acute lymphoblastic leukemia with a precursor B-cell phenotype. Cytogenetic analysis showed an i(12p) abnormality in the patient's leukemia cells and in the UoC-B10 cell line. The i(12p) was also identified retrospectively in the mediastinal tumor cells by fluorescent in situ hybridization analysis. The UoC-B10 cell line, which has been growing continuously for > 24 months in culture, was Epstein-Barr virus negative and was generally concordant with the patient's leukemia cells by analysis of immunophenotype, karyotype, and genotype. The UoC-B10 cell line possesses receptors for granulocyte-colony-stimulating factor, a cytokine which the patient received as part of his treatment protocol. This cell line may be useful in studying the relationship between i(12p) and hematological differentiation of human mediastinal germ cell tumors.

Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study.

The FLT3 gene is mutated by an internal tandem duplication (ITD) in 20-25% of adults with acute myeloid leukemia (AML). We studied 82 adults <60 years of age with primary AML and normal cytogenetics, who received uniform high-dose therapy and found FLT3 ITD in 23 (28%) patients. When the 23 FLT3 ITD+ cases were compared with the 59 cases with wild-type (WT) FLT3, disease-free survival (DFS) was inferior (P = 0.03), yet overall survival (OS) was not different (P = 0.14). However, 8 (35%) of 23 FLT3 ITD/+ cases also lacked a FLT3 WT allele (FLT3(ITD-R)) as determined by PCR and loss of heterozygosity. Thus, three genotypic groups were identified: normal FLT3(WT/WT), heterozygous FLT3(ITD/WT), and hemizygous FLT3(ITD/-). DFS and OS were significantly inferior for patients with FLT3(ITD/-) (P = 0.0017 and P = 0.0014, respectively). Although DFS and OS for FLT3(WT/WT) and FLT3(ITD/WT) groups did not differ (P = 0.32 and P = 0.98, respectively), OS of the FLT3(ITD/-) group was worse than the FLT3(WT/WT) (P = 0.0005) and FLT3(ITD/WT) (P = 0.008) groups. We propose a model in which FLT3(ITD/-) represents a dominant positive, gain-of-function mutation providing AML cells with a greater growth advantage compared with cells having the FLT3(WT/WT) or FLT3(ITD/WT) genotypes. In conclusion, we have identified the FLT3(ITD/-) genotype as an adverse prognostic factor in de novo AML with normal cytogenetics. A poor prognosis of the relatively young FLT3(ITD/-) adults (median age, 37 years), despite treatment with current dose-intensive regimens, suggests that new treatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients.

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.