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 chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has advanced to a stage where many patients achieve very low or undetectable levels of disease. Remarkably, some of these ...patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at least operationally cured of their disease. Accurate definition of deep molecular responses (MRs) is therefore increasingly important for optimal patient management and comparison of independent data sets. We previously published proposals for broad standardized definitions of MR at different levels of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants.
This article examines the effectiveness of a technology-based algebra curriculum in a wide variety of middle schools and high schools in seven states. Participating schools were matched into similar ...pairs and randomly assigned to either continue with the current algebra curriculum for 2 years or to adopt Cognitive Tutor Algebra I (CTAI), which uses a personalized, mastery-learning, blendedlearning approach. Schools assigned to implement CTAI did so under conditions similar to schools that independently adopt it. Analysis of posttest outcomes on an algebra proficiency exam finds no effects in the first year of implementation, but finds evidence in support of positive effects in the second year. The estimated effect is statistically significant for high schools but not for middle schools; in both cases, the magnitude is sufficient to improve the median student's performance by approximately eight percentile points.
Rising levels of atmospheric carbon dioxide could be curbed by large-scale sequestration of CO₂ in the deep sea. Such a solution requires prior assessment of the impact of hypercapnic, acidic ...seawater on deep-sea fauna. Laboratory studies were conducted to assess the short-term hypercapnic tolerance of the deep-sea Tanner crabChionoecetes tanneri, collected from 1000 m depth in Monterey Canyon off the coast of central California, USA. Hemolymph acid–base parameters were monitored over 24 h of exposure to seawater equilibrated with ~1% CO₂ (seawater$\mathrm{P}_{\mathrm{CO}_{2}}$~6 torr or 0.8 kPa, pH 7.1), and compared with those of the shallow-living Dungeness crabCancer magister. Short-term hypercapnia-induced acidosis in the hemolymph ofChionoecetes tanneriwas almost uncompensated, with a net 24 h pH reduction of 0.32 units and a net bicarbonate accumulation of only 3 mM. Under simultaneous hypercapnia and hypoxia, short-term extracellular acidosis inChionoecetes tanneriwas completely uncompensated. In contrast,Cancer magisterfully recovered its hemolymph pH over 24 h of hypercapnic exposure by net accumulation of 12 mM bicarbonate from the surrounding medium. The data support the hypothesis that deep-sea animals, which are adapted to a stable environment and exhibit reduced metabolic rates, lack the short-term acid–base regulatory capacity to cope with the acute hypercapnic stress that would accompany large-scale CO₂ sequestration. Additionally, the data indicate that sequestration in oxygen-poor areas of the ocean would be even more detrimental to deep-sea fauna.
RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant ...patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 87.5% crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.
For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The ...debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.
Hepatitis B virus (HBV) infection reactivation is associated with high morbidity and mortality in patients with haematologic malignancy and/or haematopoietic stem cell transplantation (HSCT). ...However, information on this issue is limited. The scope of this position paper is to provide recommendations on HBV screening, monitoring, prophylaxis, treatment and vaccination in the patients described above.
These recommendations were developed from one meeting of experts attended by different Italian scientific societies as well as from a systematic literature review (of articles published through December 31, 2016) on HBV infection in haematologic patients and in patients who underwent haematopoietic stem cell transplantation published in the same issue of the journal. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess each recommendation's quality.
These recommendations provide the answers to the following questions: (a) HBV screening and monitoring: Who should be screened before chemotherapy? Which screening tests should be used? Should HBV-DNA detection be used to monitor HBV reactivation before starting antivirals? What is the best timeline to monitor HBV reactivation? (b) Prophylaxis in HBsAg-positive patients: Which antiviral drugs should be used to treat HBsAg-positive patients? How long should antiviral prophylaxis be provided to HBsAg-positive patients? (c) Prophylaxis in patients with resolved HBV infection: Which patients with resolved HBV infection should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (d) HBV infection management strategy in autologous (auto-HSCT) and allogeneic HSCT (allo-HSCT): Which HSCT recipients should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (e) Choice of antiviral drugs in the treatment of HBV reactivation: Should third-generation anti-HBV drugs be preferred to first- or second-generation antiviral drugs in the treatment of HBV reactivation with or without hepatitis flare in haematologic patients? (f) Immunization against HBV in patients with haematologic malignancies and/or patients who underwent HSCT: Should these patients be vaccinated? Which HBV vaccination schedule should be adopted?
Haematologic patients should be screened for hepatitis B surface antigen (HBsAg) plus anti-hepatitis B core protein (HBc), and HBV DNA before chemotherapy. HBV DNA levels should be monitored monthly in all HBV-positive patients who do not receive prophylaxis. HBsAg-positive haematologic patients and those undergoing HSCT should receive third-generation antiviral therapy as prophylaxis. Anti-HBc-positive lymphoma patients and those receiving HSCT should receive antiviral prophylaxis. All HBV-negative haematologic patients should be vaccinated for HBV. The acquisition of data from well-designed studies is desirable in the near future.
In reducing the pollutant load contained in laundry wastewater such as COD and phosphate levels can be processed through anaerobic process and will be followed by phytoremediation methods. The ...purpose of this study is to reduce levels of COD and phosphate in laundry wastewater. This research was conducted in a laboratory scale with variations in plant mass. One type of aquatic plants that has the potential in phytoremediation waste management is algae (Hydrillaverticillata). The initial step in this research was carried out the seeding stage in anaerobic reactors with the aim of breeding bacteria with a suspended culture method which was marked by a decrease in COD with +10% fluctuations. Followed by the running stage in the anaerobic reactor until the reduction in COD ≥60% then, the stage of neutralization and acclimatization of plants with the aim of removing impurities in plants and adaptation of plants with microorganisms in wastewater. The last stage is the running stage of the phytoremediation process which is carried out by observing the value of COD and Phosphate in wastewater with variations in plant mass of 50, 100, 150, 200 and 250 grams in each reactor with contact time treatment for 7 days. Based on the analysis of COD parameters for each plant after anaerobic and phytoremediation processes on the last day the average efficiency of COD removal at 50 grams of plant mass is 86.34%, 100 gram plant mass of 81.81%, plant mass of 150 grams of 85.21%, 200 gram plant mass of 90.87% and 250 gram plant mass of 87.47% while the results of the analysis of Phosphate COD parameters for each plant the average removal efficiency of Phosphate in 50 gram plant mass is -25 %, 100 gram plant mass of -298.81%, 150 gram plant mass of -417.86%, 200 gram plant mass of -501.19% and 250 gram plant mass of -462.5%.
Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic ...leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytic leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35-45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer (EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n=278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.
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