N. Sulfock. Quinnipiac College.

These outcomes are more important to patients order cheap tenormin line, family order tenormin 50mg otc, and care providers than surrogate or intermediate measures such as scores on psychometric scales buy tenormin 50mg amex. For example order tenormin once a day, a study might use very narrow inclusion criteria like an efficacy study, but like an effectiveness study might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. It was neither possible nor desirable to exclude evidence from these studies. Labeling each study as either an efficacy or an effectiveness study, while convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient. Studies across the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard to determine whether the characteristics of different drugs are related to their effects on disease. An evidence report reviews the efficacy data thoroughly to ensure that decision makers can assess the scope, quality, and relevance of available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how much of it there is, may have limited applicability to practice. Clinicians can judge the relevance of study results to their practice and should note where there are gaps in the available scientific information. Unfortunately, for many drugs there are few or no effectiveness studies and many efficacy studies. Consequently, clinicians must make decisions about treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of different drugs are uncertain. An evidence report indicates whether or not there is evidence that drugs differ in their effects in various subgroups of patients, but it does not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment. In the context of developing recommendations for practice, evidence reports are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep Topical calcineurin inhibitors Page 6 of 74 Final Report Drug Effectiveness Review Project in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is not true. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policies. Additional criteria include acceptability to physicians or patients, the potential for unrecognized harms, the applicability of the evidence to practice, and consideration of equity and justice. Topical calcineurin inhibitors Page 7 of 74 Final Report Drug Effectiveness Review Project INTRODUCTION Atopic dermatitis, also referred to as atopic eczema, is a highly pruritic, chronic, and relapsing inflammatory disease of the skin. The natural history of the disease is not fully understood, and popular notions about the etiology of atopic dermatitis such as “hygiene theory” and “atopic 1 march” are continuing to be reassessed. In general, atopic dermatitis primarily affects infants, children, and adolescents with a 15% to 30% prevalence, compared with 2% to 10% prevalence 2, 3 seen in adults. Approximately 45% of all cases occur during the first year of life and 85% of 4 cases occur before 5 years of age. Young children typically exhibit more severe and persistent disease than older patients, although new-onset atopic dermatitis in adults is possible. Furthermore, periods of remission usually occur more frequently as age increases. It is estimated that 40% to 70% of children older than 5 years may experience spontaneous resolution of their 2, 5 disease. Of these cases, however, more than 50% of patients can relapse back to active atopic 4 dermatitis, though the severity may not be as intense. Atopic dermatitis is associated with significant weakening of the skin barrier, allowing for increased susceptibility to water loss, to allergens, and to infectious pathogens. Several genes that encode proinflammatory cytokines (responsible for increased IgE and IgG activity via T- lymphocytes) have also been identified and linked to the complex pathogenesis of atopic 4, 6 dermatitis. Diagnosis of atopic dermatitis is based on a constellation of symptoms. The essential feature is pruritus, which provokes a vicious itch-scratch-rash cycle. Patient and family 6 history of atopy and recurrent eczematous lesions are additional features involved in diagnosis. Currently, however, there is no standard method for diagnosis and various criteria are used. The most commonly cited criteria is the Hanifin and Rajka criteria; however strong arguments in 7 favor of using the Sampson or the Williams criteria in children have also been made. There is no known cure for atopic dermatitis and no optimal regimen for long-term 8 maintenance of the disease. Treatment of atopic dermatitis usually involves a multipronged approach of reducing exposure to exacerbating factors, maintaining skin hydration with emollients, alleviating symptoms such as pruritus, and controlling active disease with topical 6 anti-inflammatory agents. Intensity of treatment with or without a topical anti-inflammatory agent depends on the severity of the disease. Of the topical agents, topical steroids are generally considered the mainstay of treatment. Until recently, the use of low- to mid-potency topical steroids has been recommended for maintenance therapy, whereas high-potency agents have 6 been reserved for significant flares. Currently, several different treatment regimens using mid- to high-potency topical steroids dosed less frequently are being implemented in clinical 1, 8, 9 practice. Despite the shift in topical steroid use, concerns about side effects associated with long-term topical steroid exposure continue to persist among patients and practitioners. Hence, treatments with alternate nonsteroid based agents are being sought. In December 2000 and 2001, two topical calcineurin inhibitors were approved for use in patients with atopic dermatitis in the United States and Canada. Since the approval of these agents, several case reports of malignancies (skin and lymphoma) have been reported to the United States Food and Drug Administration, causing a black box warning to be placed in each product’s labeling. Several pharmacokinetic analyses, commentaries, and editorials have been published refuting the addition of the black box warning. In light of these findings, this comparative effectiveness review of 2 topical calcineurin inhibitors was commissioned to identify whether additional good-quality studies on safety have been Topical calcineurin inhibitors Page 8 of 74 Final Report Drug Effectiveness Review Project published and to determine whether differences in efficacy and effectiveness exist between the 2 topical agents. Characteristics of tacrolimus and pimecrolimus Scientific name Tacrolimus Pimecrolimus Brand Protopic Elidel Chemical structure Macrolide Ascomycin derivative Manufacturer Astellas Pharma Novartis Approval date December 8, 2000 December 13, 2001 Country US, Canada US, Canada Dose 0. Not indicated for use in children less than 2 Not indicated for children younger years of age. Although a causal relationship has not been established, rare cases of malignancy (e. Therefore, continuous long-term use of topical calcineurin inhibitors in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis. Should be avoided on malignant or premalignant skin conditions. Malignant or premalignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), can present as dermatitis. Precautions Should not be used in patients with Netherton syndrome or other skin diseases where there is the potential for increased systemic absorption of pimecrolimus or tacrolimus. The safety of pimecrolimus or tacrolimus has not been established in patients with generalized erythroderma. Contraindicated in individuals with a history of hypersensitivity to tacrolimus or Contraindications pimecrolimus or any of the components of the cream or ointment. The mechanism of action of The mechanism of action of pimecrolimus tacrolimus in atopic dermatitis is not in atopic dermatitis is not known. Tacrolimus has been shown Pimecrolimus has been shown to bind with to inhibit T-lymphocyte activation by high affinity to macrophilin-12 ( also known Mechanism of action first binding to intracellular protein as FKBP-12) and inhibit calcineurin. As a macrophilin-12 (also known as FKBP- consequence, it inhibits T cell activation by 12).

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For adverse events outcomes order tenormin 50mg with mastercard, we also included observational studies of at least 6 months duration and a sample size of at least 100 (Table 4) discount tenormin online master card. Further details related to inclusion criteria are provided below in the Methods section under Study Selection order tenormin toronto. Boxed warnings associated with these products are provided in Appendix 1 C 100 mg tenormin sale. Dosing equivalency of the agents was based on the 2007 NAEPP Expert Panel publication. A comparison of labeled and delivered doses for inhalers is provided in Appendix D. Outcome measures and study eligibility criteria Outcome Outcome measures Study eligibility criteria • Asthma control - Asthma exacerbations • Randomized controlled clinical trials - Days/nights frequency of symptoms of at least 6 weeks duration and n ≥ - Frequency of rescue medication use 40 or quality systematic reviews - Courses of oral steroids • Quality of life • When sufficient evidence was not Efficacy / • Ability to participate in work, school, sports, or available for head-to-head trials within Effectiveness physical activity a specific diagnostic group we • Adherence evaluated placebo-controlled trials • Emergency department / urgent medical care visits • Hospitalization • Mortality • Overall adverse events reported • Randomized controlled clinical trials • Withdrawals due to adverse events of at least 6 weeks duration and n ≥ • Serious adverse events 40 • Specific adverse events including: - Growth • Observational studies of at least 6 Adverse - Bone mineral density months duration and n ≥ 100 Events/Safety - Osteoporosis/fractures - Ocular toxicity • When sufficient evidence was not - Suppression of HPA axis available for head-to-head trials within - Anaphylaxis a specific diagnostic group, we - Death evaluated placebo-controlled trials METHODS Literature Search ® To identify relevant citations, we searched MEDLINE , the Cochrane Database of Systematic ® ® Reviews , the Cochrane Central Register of Controlled Trials , and the International Pharmaceutical Abstracts (through September 2010), using terms for included drugs, indications, and study designs (see Appendix E for complete search strategies). We limited the electronic searches to “human” and “English language. In addition, we searched the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), the Canadian Agency for Drugs and Technology in Health, Controller medications for asthma 21 of 369 Final Update 1 Report Drug Effectiveness Review Project and the National Institute for Health and Clinical Excellence web sites for medical and statistical reviews, and technology assessments. Finally, we searched dossiers submitted by pharmaceutical companies for the current review. All citations were imported into an electronic database ® (Endnote v. Study Selection All citations were reviewed for inclusion using the criteria shown in Table 5. Two reviewers independently assessed titles and abstracts, where available, of citations identified from literature searches. If both reviewers agreed that the trial did not meet eligibility criteria, it was excluded. Full-text articles of potentially relevant citations were retrieved and again were assessed for inclusion by two reviewers. Results published only in abstract form and unpublished data were not included unless adequate details were available for quality assessment. Study inclusion criteria Populations • Adult or pediatric outpatients with persistent asthma 1 • Persistent asthma is defined using the NAEPP classification (see Table 1) Interventions/Treatments Inhaled corticosteroids: • Beclomethasone • Budesonide • Ciclesonide • Flunisolide • Fluticasone propionate • Triamcinolone • Mometasone Long-Acting Beta-2 Agonists (LABAs) • Formoterol • Arformoterol • Salmeterol Leukotriene modifiers • Montelukast • Zafirlukast • Zileuton Anti-IgE therapy • Omalizumab Combination products • Fluticasone propionate/Salmeterol xinafoate • Budesonide/formoterol Long-Acting Anticholinergics • Tiotropium Efficacy and effectiveness outcomes • Control of symptoms (e. Study inclusion criteria work/school/sports/physical activity, activity limitation, improved sleep/sleep disruption) • Urgent care services (Emergency department visits/urgent medical care visits) • Adherence • Hospitalization • Mortality Adverse events/safety outcomes • Overall adverse events • Withdrawals due to adverse events • Serious adverse events (e. Results from well-conducted, systematic reviews and head-to-head trials provide the strongest evidence to compare drugs with respect to effectiveness, efficacy, and adverse events; head-to-head trials were defined as those comparing one included treatment of interest (those listed in Table 5) with another treatment of interest. If sufficient evidence was available from head-to-head trials we did not examine placebo-controlled trials for general efficacy/effectiveness. If no head-to-head evidence was published, as was the case for omalizumab, we reviewed placebo-controlled trials. We did not include studies that compare step-down therapy for people with stable asthma, different doses of the same medication, or different delivery devices with the same medication unless there was another eligible comparator arm. We did not include studies evaluating adjustable dosing strategies. A review was considered to be systematic if it presented a systematic approach to reviewing the literature through a comprehensive search strategy, provided adequate data from included studies, and evaluated the methods of included studies (with quality review/critical appraisal). Data Abstraction We designed and used a structured data abstraction form to ensure consistency in appraisal for each study. A second reviewer read each abstracted article and evaluated the accuracy and completeness of the data abstraction. We abstracted the following data from included trials: study design, population characteristics (including age, sex, asthma severity, smoking status), inclusion and exclusion criteria, interventions (drugs, dose, delivery device, duration), comparisons, numbers enrolled, additional medications allowed, outcome assessments, attrition, withdrawals attributed to adverse events, results, and adverse events reported. We recorded intention-to-treat (ITT) results if available. Controller medications for asthma 23 of 369 Final Update 1 Report Drug Effectiveness Review Project Validity Assessment (Quality Assessment) Two independent reviewers assigned quality ratings; they resolved any disagreements by discussion or by consulting a third, senior reviewer. We assessed the internal validity (quality) of trials based on the predefined criteria (see www. Preventive Services Task Force and the National Health Service Centre for 14, 15 Reviews and Dissemination (U. Elements of internal validity assessment for trials included, among others, the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, crossover, adherence, and contamination; overall and differential loss to follow-up; and the use of intention- to-treat analysis. We assessed observational study designs based on the potential for selection bias (methods of selection of subjects and loss to follow-up), potential for measurement bias (equality, validity, and reliability of ascertainment of outcomes), and control for potential confounders. Systematic reviews which fulfilled inclusion criteria were rated for quality using predefined criteria (www. Studies that had a fatal flaw were rated “poor quality” and were not included in the evidence report. Trials that met all criteria were rated “good quality”. This includes studies that presumably fulfilled all quality criteria but did not report their methodologies to an extent that answered all our questions. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: the results of some fair-quality studies are likely to be valid, while others are only probably valid. A poor- quality trial is not valid—the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. A fatal flaw is reflected by failing to meet combinations of items of the quality assessment checklist. Attrition, or loss to follow-up, was defined as the number of persons randomized who did 16 not reach the endpoint of the study, independent of the reason and the use of intention-to-treat analysis. We adopted no formal cut-off point for loss to follow-up because many studies defined withdrawals due to acute worsening of the disease as an outcomes measure. Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. Trials that evaluated one included medication against another provided direct evidence of comparative effectiveness and adverse event rates. In theory, trials that make comparisons with other drug classes or placebos can also provide evidence about effectiveness. This is known as an indirect comparison and can be difficult to interpret for a number of reasons, primarily issues of heterogeneity between trial populations, interventions, and assessment of outcomes. Data from indirect comparisons are used to support direct comparisons, where they exist, and are also used as the primary comparison where no direct comparisons exist. Such indirect comparisons should be interpreted with caution. Controller medications for asthma 24 of 369 Final Update 1 Report Drug Effectiveness Review Project In addition to discussion of the findings of the studies overall, quantitative analyses were conducted using meta-analyses on outcomes for which a sufficient number of studies reported and for studies which they were homogeneous enough such that combining their results can be justified. Random effects models were used 17 for the estimation of pooled effects. Forest plots are presented to graphically summarize the 18 2 study results and the pooled results. The Q-statistic and the I statistic (the proportion of variation in study estimates due to heterogeneity) were calculated to assess heterogeneity 19, 20 between the effects from the studies. Potential sources of heterogeneity were examined with subgroup analysis by factors such as study design, study quality, variations in interventions, and patient population characteristics. Meta-analyses were conducted using Comprehensive Meta Analysis V2. Grading the Strength of Evidence We graded strength of evidence using a modified GRADE approach that included assessment of the following domains: design, quality, consistency, directness, and magnitude of effect of the set of studies relevant to the question. We also considered other domains that may be relevant for some scenarios, such as equipotency (for inhaled corticosteroids), a dose-response association, strength of association (magnitude of effect), and publication bias. Table 6 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer key questions on the comparative effectiveness, efficacy, and harms of the drugs included in this review. Grades do not refer to the general efficacy or effectiveness of pharmaceuticals. Two reviewers assessed each domain for each comparison and differences were resolved by consensus.

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This tenormin 50 mg on line, together with the possible impairment of semen quality results in a number of couples being advised to have IVF or ICSI 50 mg tenormin for sale. Following recent studies generic 50mg tenormin amex, this risk seems to be only theoretical buy tenormin 100 mg with visa. HIV infection of the woman in the early stages of pregnancy can increase the risk of transmission to the child. These depend on the technique applied and range from about € 500 to € 5,000 per cycle. In some countries, couples have cost-free access to treatment. Following successful reproductive treatment, couples are usually monitored for HIV status for 6-12 months after childbirth, depending on the center. The safety of sperm washing The technique of processing sperm from HIV+ men prior to the insemination of their negative partners was first published by Semprini in 1992. The first inseminations with sperm washed free of HIV were carried out in Italy and Germany as early as 1989 and 1991, respectively. Up to mid-2003, more than 1,800 couples had been treated in about 4,500 cycles, applying various techniques of assisted reproduction. More than 500 children have been born with no seroconversion reported in the centers closely following the protocol of washing and testing the sperm prior to assisted reproductive techniques (Bujan 2007). Native ejaculate mainly consists of three fractions: spermatozoa, seminal plasma and nuclear concomitant cells. The HIV progenome and virus have so far been detected in the seminal plasma, the concomitant cells, and occasionally in immobile sper- matozoa. Several studies have indicated that viable, motile spermatozoa are not likely to be a target for HIV infection (Pena 2003, Gilling-Smith 2003). Motile spermatozoa can be isolated by standardized preparation techniques. After separation of the spermatozoa from plasma fractions and NSC (non-spermatozoa cells), the spermatozoa are washed twice with culture medium and re-suspended in fresh culture medium. Incubation for 20–60 minutes allows motile sperm to “swim up” to the supernatant. To be more certain that it is not contaminated with viral particles, an aliquot of the sample should be tested for HIV nucleic acid using highly sensitive detection methods (Weigel 2001, Gilling-Smith 2003, Pasquier 2006). Depending on the method, the limit of detection is 10 copies/ml. After having studied the effectiveness of several methods of sperm processing, Anderson (2005) concluded that the combination of gradient density centrifugation and swim-up allows a 10,000-fold decrease of HIV-1 concentration in sperm. Since HIV could theoretically remain undetected, sperm washing is currently regarded as a very effective risk reduc- tion, although not risk-free. Most of the European centers that offer assisted reproduction to HIV-discordant couples are part of the CREATHE network, which aims to optimize treatment and safety of the methods as well as to compile an extensive database. Compiled data from several centers hint on the safety and reliability of sperm washing (Bujan 2007). Pre-Exposure Prophylaxis (PrEP) Even before the FDA approval of Truvada as the first antiretroviral agent for the prevention of HIV transmission through sexual intercourse, PrEP before periovula- tory unprotected intercourse was an option for serodiscordant couples in some coun- tries. Couples abstain from condom use only during the woman’s fertile days. HIV and Wanting to be a Parent 551 Preconditions are an effectively suppressed viral load, the exclusion of sexually trans- mitted diseases, and unimpaired fertility status of both partners. Data from Switzerland and Germany shows high acceptance in couples. No case of HIV trans- mission has been reported in 53 couples, the pregnancy rate was 75% (Vernazza 2011). A growing number of studies shows the feasibility of this approach, especially in resource-limited settings (Adenji 2013, Whetham 2013). The fertility of HIV-neg- ative men does not seem to be impaired by taking PrEP (Were 2014). Up to now, there is no evidence that PrEP further reduces the already negligible risk of infection when the viral load of the HIV+ partner is effectively suppressed. Nevertheless, some couples prefer this option because it increases their feeling of safety. Female HIV infection For many HIV+ women having a child now is an important part of planning for the future (Fiore 2008, Loutfy 2009). In France 32% of the HIV+ women of reproductive age want to become mothers (Heard 2007). Treatment and care during pregnancy should be carried out according to the pre- vailing national or international guidelines (Fakoya 2008, DAIG 2011, Loutfy 2012). In some European countries reproductive options for women with unimpaired fer- tility include natural conception on the basis of the EKAF Statement as well as self- insemination, while self-insemination is still seen as the safest procedure. Couples who decide for natural conception should undergo screening to exclude STDs. The transmission risk might be further reduced when the intercourse without condoms is limited to the time of ovulation. Women should be advised on the impor- tance of adherence and regular checks of the viral load (Fakoya 2008). If a woman is not taking ART, the viral load is not successfully suppressed, or concerns about the remaining risk are strong, self-insemination may be the method of choice. In some cases, ovarian stimulation may be advisable. This, however, requires highly qualified supervision to avoid multiple gestations. A simple inexpensive way of determining whether the cycles are ovulatory, helpful in women who have regular cycles, is a basal temperature chart beginning about three months before the first self-insemination. At the time of ovulation, couples can either have protected intercourse with a sper- micide-free condom and introduce the ejaculate into the vaginal cavity afterwards, or the ejaculate can be vaginally injected using a syringe or applied with a diaphragm or portio cap. Thus the conception remains within the private sphere of the couple. After 6–12 months of unsuccessful self-insemination, the couple should have further fertility investigations with a view to assisted conception. Should the couple experience problems with self-insemination, intrauterine insemination (IUI) can be considered. HIV-specific and infective diagnostics are recommended. If no pregnancy has occurred over a period of 6–12 months (or earlier, if the couple so wishes) fertility diagnostics should be carried out (Table 1). If there are indicators of reduced fertil- ity in one or both partners, fertility diagnostics might be carried out at an earlier stage in the counselling process. Fertility disorders In some cases, women will only be able to conceive by intercourse without condom or self insemination. Dependent on the fertility status of both partners, IVF and ICSI can be considered as methods of choice. Fertility disorders in HIV+ women seem to have a higher prevalence than in an age- matched negative population (Ohl 2005, Gingelmaier 2010) and might lead to a 552 Women and Children lower success rate of assisted reproduction (Coll 2006) although data show some conflicting results. Reasons might be infection of the upper genital tract (Sobel 2000), surgery due to cervical intraepithelial neoplasia (Gilles 2005) or a depletion of mito- chondrial DNA in the oocytes (Garrabou 2006, Lopez 2008). Data reported from a program in Strasbourg indicated infertility problems in most HIV+ women. IVF and ICSI were far more effective than IUI (Ohl 2005). In the Barcelona program, Coll (2006) observed a decreased pregnancy rate after IVF com- pared to age-matched HIV-negative controls and HIV+ women who received donated oocytes. Results indicated a decreased ovarian response to hyperstimulation. A slightly impaired ovarian response to stimulation during 66 ICSI cycles in 29 HIV+ women was also described by Terriou (2005).

Harrison buy tenormin 50 mg, Northern Institute for Cancer Research generic 100 mg tenormin, Newcastle University purchase tenormin online now, Sir James Spence Institute 100mg tenormin sale, Queen Victo- ria Road, Newcastle upon Tyne NE1 4LP, United Kingdom; Phone: 44-191-2821320; Fax: 44-191-2821326; e-mail: christine. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Progress in the treatment of adults with acute lymphoblastic leukemia. Prognostic effect Hematology 2013 123 of chromosomal abnormalities in childhood B-cell precursor outcome in first relapse of childhood acute lymphoblastic acute lymphoblastic leukaemia: results from the UK Medical leukemia. CREBBP HAT and adults with acute lymphoblastic leukemia (ALL). J Clin domain mutations prevail in relapse cases of high hyperdiploid Oncol. The clinical relevance of chromosomal and 1797-1803. Genes commonly childhood B-cell precursor acute lymphoblastic leukemia. Driessen EM, van Roon EH, Spijkers-Hagelstein JA, et al. Immunoglobulin heavy affecting the RAS pathway is common in childhood acute chain locus chromosomal translocations in B-cell precursor lymphoblastic leukemia. FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly 9. Demographic, clinical, mutually exclusive in high hyperdiploid childhood acute and outcome features of children with acute lymphoblastic lymphoblastic leukemia. Deregulated expression of landscape of hypodiploid acute lymphoblastic leukemia. Nat cytokine receptor gene, CRLF2, is involved in lymphoid Genet. CRLF2 is associated with mutation of JAK kinases, alteration 11. Mullighan CG, Collins-Underwood JR, Phillips LA, et al. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. Activating mutation in the subtype of childhood acute lymphoblastic leukaemia with poor TSLPR gene in B-cell precursor lymphoblastic leukemia. Identification of P2RY8-CRLF2 rearrangement is associated with a poor progno- novel cluster groups in pediatric high-risk B-precursor acute sis in non-high-risk precursor B-cell acute lymphoblastic lymphoblastic leukemia with gene expression profiling: leukemia in children treated according to the ALL-BFM 2000 correlation with genome-wide DNA copy number altera- protocol. Translation of the Philadelphia chromosome into mia. Kuiper RP, Schoenmakers EF, van Reijmersdal SV, et al. Improved early High-resolution genomic profiling of childhood ALL reveals event-free survival with imatinib in Philadelphia chromosome- novel recurrent genetic lesions affecting pathways involved in positive acute lymphoblastic leukemia: a children’s oncology lymphocyte differentiation and cell cycle progression. Key pathways are positive acute lymphoblastic leukemia (Ph ALL). Hematology frequently mutated in high risk childhood acute lymphoblastic Am Soc Hematol Educ Program. NUP214-ABL1 fusion gene in B-cell acute lymphoblastic 18. Tyrosine kinase 124 American Society of Hematology inhibitor therapy induces remission in a patient with refractory predictive of outcome and age in infant acute lymphoblastic EBF1-PDGFRB positive acute lymphoblastic leukemia. Breakpoint-specific and PI3K/mTOR pathway signaling occurs in human CRLF2- multiplex polymerase chain reaction allows the detection of rearranged B-precursor acute lymphoblastic leukemia. IKZF1 intragenic deletions and minimal residual disease moni- 2012;120(4):833-842. An embarrassment of riches for chronic myeloid leukemia patients Timothy Hughes1 and Deborah White1 1South Australian Health and Medical Research Institute, SA Pathology, and University of Adelaide, Adelaide, Australia With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia, clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid leukemia patients. All of these considerations need to be made in the context of the patient’s comorbidities, which may lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of achieving optimal response. The current scene in chronic myeloid leukemia levels is due mainly to reduced activity of the OCT-1 influx pump. What is the best therapeutic evidence of low activity, as measured by the OCT-1 activity approach for this particular patient given the excellent therapies assay. Assuming that the tyrosine kinase inhibitors (TKIs) CP-CML is the frequency of kinase domain mutations that emerge imatinib, nilotinib, and dasatinib are locally approved, which they on imatinib therapy. Although twice as high as those on the nilotinib arm (7% vs 3. Detailed knowledge of the safety profile and efficacy of each TKI, the patient’s comorbidities, and clarity about the therapeu- On the positive side, there are virtually no worrying organ toxicity tic goals will assist drug selection. Before examining the decision signals emerging after prolonged exposure to imatinib. The early process, it is worthwhile reviewing the strengths and weaknesses of concerns about an increase in cancer susceptibility and cardiac the 3 most commonly used frontline TKIs. The other potential advantage is the imminent availability of generic imatinib in many countries, Imatinib which could potentially greatly ease the cost burden of long-term There are several hundred thousand patients on imatinib therapy therapy for CML. What is clear is that it is a highly The IRIS trial showed an 8-year survival for imatinib recipients of effective TKI for 60% of CML patients, poorly tolerated in 85%, 93% if only CML-related deaths were considered. For the 20%, and inadequate to achieve or maintain an optimal response 60% of patients who remained on imatinib in the IRIS trial at last in a further 20%. Evidence for response (CCyR) and the progression rate in the years beyond the first 3 was close to zero. Randomized studies comparing 400 and 800 mg/d to inadequate cellular uptake even in the presence of adequate drug did not demonstrate a clear advantage with the higher dose, except 168 American Society of Hematology in the case of the German CML IV study, in which higher rates of Table 1. Comparison of the efficacy profiles (% achievement) of molecular response (MR) were achieved with 800 mg/d. However, nilotinib,13 dasatinib,19 and bosutinib45 in the 3 registration phase no evidence of an improvement in progression-free or overall 3 studies compared with imatinib survival has been observed in any of the randomized trials End point Nil(300) IM DAS IM BOS IM comparing different dosing schedules. CCyR by 12 mo 80 65 85 73 70 68 CCyR by 24 mo 87 77 86 82 87 81 Nilotinib MMR by 24 mo 53 27 46 28 41 27 Worldwide experience with nilotinib has increased greatly over the MMR by 24 mo 69 44 64 46 61 50 past 5 years. Although structurally similar to imatinib, its affinity for MR4. Only 5 mutations are of major concern (T315I, F359V, E255K/V, and Y253H). They Nil(300) indicates nilotinib 300 mg; IM, imatinib; DAS, dasatinib; and BOS, bosu- are the mutations that most frequently emerge on frontline or tinib. The day-to-day toxicity of nilotinib is generally quite favorable; edema is rare and gastrointestinal toxicity is uncommon. Elevated Nilotinib is also associated with hyperglycemia, possibly by induc- lipase and abnormal liver function tests are each observed in 5% to ing insulin resistance. In the ENESTnd trial, 20% of patients on the 10% of patients, but do not often lead to discontinuation of nilotinib 300 mg arm who were not diabetic at baseline were therapy. Diabetic in superior rates of cytogenetic and MR and a lower rate of patients who are starting nilotinib therapy should be closely progression compared with imatinib at a dose of 400 mg/d. Estimated 4-year rates of freedom Many CML patients have been treated with dasatinib in recent from progression to the accelerated phase (AP) or blast crisis (BC) years. In vitro, dasatinib is the most potent of the 3 available TKIs, on study (including events during follow-up after discontinuation) but in the clinical setting, it would appear to have similar potency to were 97% (P. A unique aspect of the pharmacokinetics of dasatinib is imatinib arm. However, after 4 years, the lower risk of transforma- its relatively short half-life, suggesting that it would be optimally tion had not translated into a survival advantage when all patients delivered in 2 or 3 divided daily doses.

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