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Regular treatment with salmeterol for chronic asthma: serious adverse events discount 60caps mentat with mastercard. Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults buy discount mentat 60caps on line. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma purchase cheapest mentat and mentat. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths discount mentat 60 caps on line. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Reports are not usage guidelines, nor should they be read as an endorsement of or recommendation for any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Update 3: October 2009 Update 2: November 2007 Update 1: May 2006 Original Report: September 2005 The literature on this topic is scanned periodically. McDonagh, PharmD Kim Peterson, MS Sujata Thakurta, MPA:HA Allison Low, BA Drug Effectiveness Review Project Marian McDonagh, PharmD, Principal Investigator Oregon Evidence-based Practice Center Mark Helfand, MD, MPH, Director Oregon Health & Science University Copyright © 2011 by Oregon Health & Science University Portland, Oregon 97239. Final Update 4 Report Drug Effectiveness Review Project The medical literature relating to this topic is scanned periodically. Prior versions of this report can be accessed at the DERP website. Attention deficit hyperactivity disorder 2 of 200 Final Update 4 Report Drug Effectiveness Review Project STRUCTURED ABSTRACT Purpose Attention deficit hyperactivity disorder (ADHD) affects children and adults and is treated with both pharmacologic and nonpharmacologic interventions. This review evaluates the evidence on how these drugs compare to each other in benefits and harms. Data Sources To identify published studies, we searched MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and reference lists of included studies. We also searched the US Food and Drug Administration Center for Drug Evaluation and Research website for additional unpublished data and requested information from pharmaceutical manufacturers. Review Methods Study selection, data abstraction, validity assessment, grading the strength of the evidence, and data synthesis were all carried out according to our standard review methods. Results and Conclusions Evidence on the comparative effectiveness of drugs to treat ADHD was insufficient. Evidence on the comparative efficacy in children and adolescents was moderate to low strength and indicated very few differences among the drugs in improving symptoms or in adverse event rates. Sustained-release formulations of stimulants showed benefit over comparators at specific times of day depending on the pharmacokinetics of the specific formulation, but overall differences were not found. Atomoxetine (a nonstimulant) was not found superior to some extended-release stimulant products. Atomoxetine resulted in higher rates of vomiting and somnolence, similar rates of nausea and anorexia, and lower rates of insomnia than stimulants. Extended-release formulations of other nonstimulant drugs (clonidine, guanfacine) have no comparative evidence to date. Immediate-release clonidine was similar to immediate-release methylphenidate. Comparative evidence in adults provided low-strength evidence of no significant differences in efficacy between switching to methylphenidate OROS compared with continuing with immediate-release methylphenidate or between immediate-release guanfacine or modafinil compared with immediate-release dextroamphetamine. Low-strength evidence found no significant differences between immediate-release guanfacine or modafinil compared with immediate-release dextroamphetamine. Evidence on the risk of serious harms was primarily indirect, and indicated atomoxetine has increased risk of suicidal behavior compared with placebo. Differences in risk for sudden death was unclear, cardiac adverse events were not different between stimulants, and cerebrovascular adverse events in adults did not differ between stimulants and atomoxetine. Dextroamphetamine immediate-release caused more inhibition of growth than other stimulants, but the difference was influenced by dose and resolved after 2 years of treatment. Atomoxetine Attention deficit hyperactivity disorder 3 of 200 Final Update 4 Report Drug Effectiveness Review Project caused similar inhibition of weight gain that lasted up to 5 years. Evidence on abuse, misuse, and diversion was limited, but indicated that stimulant use during childhood is not associated with increased risk of substance use later. Misuse and diversion rates varied by age and were highest among college students, and rates of diversion were highest with amphetamine-based products but similar among methylphenidate products. Evidence of effects in important subgroups of patients with ADHD (e. Attention deficit hyperactivity disorder 4 of 200 Final Update 4 Report Drug Effectiveness Review Project TABLE OF CONTENTS INTRODUCTION........................................................................................................................ What is the comparative efficacy or effectiveness of different pharmacologic treatments for attention deficit disorders? What is the comparative tolerability and safety of different pharmacologic treatments for attention deficit disorders?................................................................................................................. What is the evidence of serious adverse effects associated with use of pharmacologic treatments for attention deficit disorders?...................................................................... Evidence on the risk of abuse, misuse or diversion of drugs used to treat ADHD in patients with no previous history of misuse/diversion............................................................................ Are there subgroups of patients based on demographics (age, racial groups, gender, and ethnicity), other medications, or comorbidities for which one pharmacologic treatment is more effective or associated with fewer adverse events? What is the comparative or noncomparative evidence of misuse or illicit diversion of pharmacologic treatments for attention deficit disorders in patients with current or past substance use disorder comorbidities?......................................................................................................................... Attention deficit hyperactivity disorder drugs and indication.................................................... Definitions of the grades of overall strength of evidence......................................................... Numbers of head-to-head trials of drugs for attention deficit hyperactivity disorder............... Trials of immediate-release methylphenidate compared with methylphenidate OROS ® (Concerta )............................................................................................................................................ Immediate-release dextroamphetamine compared with immediate-release methylphenidate study characteristics.............................................................................................................................. Comparison of response rates to immediate-release methylphenidate.................................. Summary of differences in results of ADHD/Tourette’s disorder study................................... Long-term functional outcomes of methylphenidate from Hechtman, 1984........................ Response rates in placebo-controlled trials of methylphenidate OROS............................... Adverse events in placebo-controlled trials of atomoxetine.................................................. Adverse events in placebo-controlled trials of methylphenidate OROS................................ Direct comparisons of long-term height and weight outcomes.............................................. Relationship between stimulant treatment for ADHD and later substance abuse and dependence........................................................................................................................................... Authors of previous updates Update 3 authors Marian S. McDonagh, PharmD Vivian Christensen, PhD Kim Peterson, MS Sujata Thakurta, MPA:HA Update 2 authors Marian S. McDonagh, PharmD Kim Peterson, MS Tracy Dana, MLS Sujata Thakurta, MPA:HA Original Report and Update 1 authors Marian S. McDonagh, PharmD Kim Peterson, MS Suggested citation for this report McDonagh MS, Peterson K, Thakurta S, Low A. Drug class review: Pharmacologic treatments for attention deficit hyperactivity disorder. Prepared by the Oregon Evidence-based Practice Center for the Drug Effectiveness Review Project. These organizations selected the topic of the report and had input into its Key Questions.

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Indirect evidence Dexmethylphenidate ER Rates of overall adverse events were comparable for dexmethylphenidate ER and placebo in the short-term trials buy mentat master card, with rates of 16% to 28% with dexmethylphenidate ER compared with 16% to 68-70 22% with placebo in the 1-2 week trials mentat 60caps mastercard. The 7-week trial reported much higher purchase 60 caps mentat with mastercard, but similar cheap mentat 60caps, 67 rates in both groups; 75. The most frequently reported adverse events were typical of stimulant products and were generally comparable between dexmethylphenidate ER and placebo. These included decreased appetite, anorexia, upper abdominal pain, fatigue, insomnia, headache, and nausea. The only occasion for which rates of a specific adverse event were statistically significantly higher in patients taking dexmethylphenidate ER compared with placebo was for decreased appetite in the 7-week trial (30. Lisdexamfetamine dimesylate In the study of lisdexamfetamine and mixed amphetamine salts XR, the overall incidence of 117 adverse events were similar. With lisdexamfetamine, the most frequent were insomnia (8%) and decreased appetite (6%), while with mixed amphetamine salts XR the most frequent were upper abdominal pain (4%) and decreased appetite (4%). Significant differences were not found in our chi-square analysis. In a dose-ranging study, overall adverse event rates were significantly greater (P≤0. When compared with placebo, all dosages of lisdexamfetamine were associated with significantly greater rates (P≤0. Weight loss incidence was only greater for patients in the 70 mg group Attention deficit hyperactivity disorder 77 of 200 Final Update 4 Report Drug Effectiveness Review Project compared with placebo (19. Withdrawals due to any of these 240 adverse events only occurred in <1% of patients, however. Immediate-release methylphenidate In a small study (N=21) of children ages 6 to 12 with ADHD, sleep diaries were assessed over 7 days after receiving placebo, immediate-release methylphenidate 15 to 30 mg daily, or immediate-release methylphenidate 30 to 45 mg daily (divided into 3 daily doses) in a crossover 241 study. Based on an analysis of contrasts, there was no difference between the 2 dose levels, but medication periods caused statistically significant increased sleep onset latency (means of 41 and 44 minutes longer; P<0. Similarly, total sleep time was shorter with either immediate-release methylphenidate dose compared with placebo (means of 51 and 60 minutes less with low and high doses compared with placebo). Other sleep outcomes (wake after sleep onset, sleep efficiency, activity, and time of lights out) did not differ between groups. Clonidine ER Compared with placebo, overall rates of adverse events reported were similar between clonidine ER and placebo. Rate of discontinuation due to adverse event was greater in the fixed-dose study, with 19% in the 0. Across the 2 studies, somnolence and fatigue were the most common adverse events in the clonidine groups, and there was some evidence that the rate of adverse events peaked at 2 weeks in the clonidine groups. Guanfacine XR Adverse events were reported more frequently with guanfacine XR, in a dose-dependent manner, 160, 161, 163 in 2 of 3 studies compared with placebo. The rate of adverse events in drug groups ranged from 74% with fixed dosing (1 to 4 mg daily) to 88. Discontinuations due to adverse events were also more frequent in a dose-dependent manner with extended-release guanfacine. The rates for 2, 3, and 4 mg daily were: 3%, 9%, and 14% in 1 161 160 study and 10%, 15%, and 23% in the other compared with 8% and 1% with placebo respectively. Flexible dosing resulted in a 10% discontinuation rate due to adverse events. The most common individual adverse events reported in the guanfacine XR groups were somnolence, fatigue, and headache. Adolescents 170-179, 182, 242 Placebo-controlled trials of immediate-release methylphenidate provided limited evidence of short-term stimulant tolerability in adolescents. Immediate-release methylphenidate was associated with significant appetite and sleep disturbances across some, but not all placebo- 172, 173, 176, 179 controlled trials. Additionally, adolescents taking immediate-release methylphenidate frequently reported increases in dulled affect, social withdrawal, irritability, and 175, 179 stomachache in 2 placebo-controlled trials. Trials of other stimulants provide no long-term evidence on safety. One 17-day study comparing methylphenidate OROS and mixed amphetamine salts reported a single adverse event 180 – urinary difficulty – in a patient receiving methylphenidate OROS. Another multi-phase, Attention deficit hyperactivity disorder 78 of 200 Final Update 4 Report Drug Effectiveness Review Project placebo-controlled study of methylphenidate OROS reported no serious adverse events during the 2-week double-blind phase, although 1 serious adverse event (suicidal ideation) was reported during a run-in, open-label dose titration phase. Other adverse events commonly reported during the open-label dose titration phase were headache (25% of patients), decreased appetite (21%), insomnia (15%), and abdominal pain (9%). However, adverse event rates during the double- blind phase were similar for methylphenidate OROS and for placebo and the only withdrawal 181 due to adverse events was reported in a placebo patient. Results from a 4-week trial found that when compared with placebo, mixed amphetamine salts XR was associated with higher rates of anorexia/decreased appetite (35. Five patients taking mixed amphetamine salts XR withdrew from the study due to adverse events. No placebo patients discontinued due to adverse events and no serious adverse events were reported in either group. In adolescents, lisdexamfetamine resulted in a higher rate of overall adverse events compared with placebo, with the highest rate associated with 70 mg daily (30 mg = 65%, 50 mg 184 = 69%, 70 mg = 72%, and placebo = 58%). Decreased appetite was the most frequent adverse event reported, at 34% for all lisdexamfetamine doses, compared with 2. Insomnia was reported by 11% with lisdexamfetamine and 4% with placebo, with the highest rate again being in the 70 mg daily group (14%). Weight decrease was reported in a clearly dose- dependent manner (30 mg = 4%, 50 mg = 9%, 70 mg = 15%, and placebo = 0). Adults Direct evidence Methylphenidate OROS compared with immediate-release methylphenidate Among 41 adults with good tolerability on immediate-release methylphenidate, the proportion with no adverse events dropped by 7% after switching to methylphenidate OROS. In contrast, the proportion with no adverse events increased by 25% among 12 adults who continued with immediate-release methylphenidate. The statistical significance of this difference is unclear, however, as analysis of the change was not presented and the study was limited by a small sample size and the presence of a between-groups imbalance at baseline in the proportion who 186 started out with no adverse effects. Immediate-release guanfacine compared with immediate-release dextroamphetamine The number of adverse events reported was similar in 17 adults after 2 weeks of once daily treatment with either immediate-release guanfacine 1. Muscle tension was the most common side effect with immediate-release dextroamphetamine (29%). Fatigue was the most common side effect with immediate-release guanfacine (23%). Withdrawals due to adverse events were not reported. Modafinil compared with immediate-release dextroamphetamine Modafinil and immediate-release dextroamphetamine were associated with similar rates of insomnia (38% compared with 19%, P=NS), muscle tension (24% compared with 19%; P=NS) 188 and appetite suppression (24% compared with 19%, P=NS). Attention deficit hyperactivity disorder 79 of 200 Final Update 4 Report Drug Effectiveness Review Project Indirect evidence Atomoxetine Adverse events were reported in all 8 placebo-controlled trials of atomoxetine of general samples 189-195 of adults with ADHD (Table 12). Withdrawals due to adverse events increased over time and were generally greater for atomoxetine than for placebo. Appetite disturbance was consistently significantly more common with atomoxetine than for placebo; whereas, the difference between atomoxetine and placebo was more variable with regard to insomnia. Adverse events in placebo-controlled trials of atomoxetine Author Year Treatment Withdrawals due to Appetite Sample size regimen adverse events disturbance Insomnia Spencer “Occurred “Did not occur 192 76 mg x 3 1998 4% vs. Immediate-release dextroamphetamine 198, 199 Some reporting of adverse events was available in both of 2 fair-quality trials. Between- group statistical comparisons were not reported in the 6-week trial of 51 adults, but rates were generally higher for immediate-release dextroamphetamine 23. In the second trial of 98 adults, after 20 weeks there was no significant difference between immediate-release dextroamphetamine 20 mg twice daily or placebo in withdrawals due to adverse events (13% compared with 8%), but rates of individual adverse events were not 198 reported. Attention deficit hyperactivity disorder 80 of 200 Final Update 4 Report Drug Effectiveness Review Project Extended-release dexmethylphenidate We included 1 fair-quality, placebo-controlled trial of 5 weeks of treatment with extended- 200 release dexmethylphenidate (N=221). There was no significant difference between extended- release dexmethylphenidate and placebo in withdrawals due to adverse events (11% compared with 8%), decreased appetite (18% compared with 11%), or insomnia (16% compared with 11%). Lisdexamfetamine 201 202 We included 1 fair-quality trial and 1 poor-quality trial of lisdexamfetamine. In the fair- quality trial, rates of various common adverse events were reported for lisdexamfetamine and placebo, but statistical analysis of between-groups differences was not reported. For lisdexamfetamine 30 mg, 50 mg, 70 mg, and placebo, respectively, rates of withdrawals due to adverse events were 3%, 7%, 7%, and 2% and rates of decreased appetite were 29%, 28%, 23%, and 2%.

Suicide rates did not differ significantly among study groups buy discount mentat online. Adverse events were reported by physicians rather than patients; the nonresponse rate was 40 percent buy mentat with mastercard. Therefore buy 60caps mentat fast delivery, measurement bias effective 60caps mentat, selection bias, and potential confounding may compromise these results. Three RCTs were powered primarily to detect differences in adverse events between 229 80 fluvoxamine and citalopram and fluvoxamine and paroxetine, and fluvoxamine and 67 fluoxetine. A Dutch multicenter trial was designed to assess between-group comparisons of Second-generation antidepressants 74 of 190 Final Update 5 Report Drug Effectiveness Review Project gastrointestinal side effects between citalopram (20-40 mg/d) and fluvoxamine (100-200 229 mg/d). Overall, 57 percent of patients reported adverse events. Significantly more patients in the fluvoxamine group had an excess incidence of diarrhea (+13%; P=0. However, the authors did not provide a baseline comparison of gastrointestinal illnesses between groups. The second study enrolled 60 patients to fluvoxamine (50-150 mg/d) or paroxetine (20-50 80 mg/d) for 7 weeks. Sweating was the only significantly higher adverse event: 30 percent in paroxetine patients compared with10 percent in fluvoxamine patents (P=0. The third trial assessed differences in adverse events between fluvoxamine (100-150 67 mg/d) and fluoxetine (20-80 mg/d) in 100 patients over 7 weeks. Fluoxetine-treated patients suffered under nausea significantly more often than fluvoxamine patients (42. Psychiatrists recorded adverse events at each patient visit. The WHO adverse reaction terminology was used for outcome assessment. Significantly more sertraline patients had the diagnosis of depressive disorder at baseline (P<0. Diarrhea occurred more frequently in the sertraline group than in the other SSRI groups (P<0. However, abdominal pain was reported more frequently by other SSRI users than sertraline users (P<0. No other adverse event differed significantly across groups. We pooled data from efficacy trials to assess differences in overall loss discontinuation rates, discontinuation rates because of adverse events, and discontinuation rates because of lack of efficacy of SSRIs as a class compared to other second-generation antidepressants in adult outpatients with MDD (Exhibit 6). Available data were insufficient to determine some results for desvenlafaxine and nefazodone. The only statistically significant difference in pooled estimates was a higher discontinuation rate because of adverse events for venlafaxine-treated patients than for patients on SSRIs (RR, 1. Overall, this finding was balanced by lower discontinuation rates because of lack of efficacy for venlafaxine (RR, 0. No significant differences could be detected between SSRIs and mirtazapine or between SSRIs and bupropion. Numerical differences in discontinuation rates attributed to adverse events generally favored SSRIs over mirtazapine and bupropion but did not reach statistical significance. A meta-analysis of 15 RCTs did not find any statistically significant differences in 231 discontinuation rates because of adverse events between fluoxetine and other SSRIs as a class. Second-generation antidepressants 75 of 190 Final Update 5 Report Drug Effectiveness Review Project Table 20. Mean incidence of specific adverse events across comparative trials Drug Diarrhea Dizziness Headache Insomnia Nausea Somnolence a Mean Percentage (95% confidence interval) Bupropion 8. Statistics are descriptive only and comparisons across different drugs should be made with caution given differences in assessment and reporting of adverse events across trials B. Specific Adverse Events A nested case control study examined the risk of sudden cardiac death or near death in patients 232 treated with citalopram, fluoxetine, or venlafaxine. The study was based on the United Kingdom General Practice Research Database which included data on more than 207,000 patients who initiated treatment with citalopram, fluoxetine, or venlafaxine for MDD or anxiety. Within the cohort, 568 cases of sudden cardiac arrest or near death occurred. These cases were matched with more than 14,000 controls. Results showed that no significant differences in risks for sudden cardiac death or near death were obvious between the examined medications. The adjusted odds ratio associated with venlafaxine relative to fluoxetine was 0. We identified three case control studies examining anassociation between antidepressant 233 234 235 use and the risk of stroke , ,. A well conducted Dutch study by Trifirò et al investigated the association between ischemic stroke and SSRIs in 996 Dutch patients, 65 years and older, included in a longitudinal Second-generation antidepressants 76 of 190 Final Update 5 Report Drug Effectiveness Review Project general practice research database (Integrated Primary Care Information Database). Results of this population-based, nested case-control study showed a significantly increased risk of stroke with respect to the current use of SSRIs compared with non-use (OR 1. No excess risk could be found for the use of tricyclic and other antidepressant drugs. Another good, nested case-control study conducted in patients on antidepressant medication included in an American multi-state managed care organization medical claims 233 database found similar results. The risk of ischemic stroke in current SSRI users compared with remote or nonusers was significantly increased. The study, which included SSRIs, tricyclic antidepressants and other antidepressants, found no increased risk of idiopathic venous thromboembolism among users of SSRIs. The unadjusted OR for current use of SSRIs compared with nonusers of any antidepressant (past use and nonusers combined) was 0. Changes in weight A 32-week acute and continuation trial assessed differences in weight changes among patients 124 treated with fluoxetine, paroxetine, and sertraline. Paroxetine patients showed a significantly greater mean weight change (+3. Significantly more patients in the paroxetine group (25. A 1-year, placebo-controlled continuation trial of fluoxetine reported similar 73 findings. Initially, fluoxetine treatment led to a modest weight loss; from week 12 to week 50, however, a significant weight gain compared to placebo was reported (+3. Other SSRIs lead to greater weight gains (sertraline +1. A pooled analysis of two RCTs comparing 238 escitalopram and paroxetine reported a similar gain in body weight for both patient groups. After 27 weeks of followup, patients on escitalopram gained 1. A double-blinded placebo-controlled 52-week acute and continuation trial assessed 239 weight changes during bupropion treatment. Bupropion-treated patients showed a modest but nevertheless significant decrease of body weight from baseline (-1. The magnitude of weight change was closely related to the body mass index (BMI). Patients with a higher BMI experienced greater weight loss. Consistently, studies comparing mirtazapine with other second-generation antidepressants reported higher weight gains for mirtazapine than for the comparator groups. In 88-90 three RCTs, these differences reached statistical significance. Second-generation antidepressants 77 of 190 Final Update 5 Report Drug Effectiveness Review Project Gastrointestinal bleeding 240 241, 242 Evidence from one good and two fair case-control studies indicate an increased risk of upper gastrointestinal tract bleeding during SSRI treatment. The good quality case control study matched 11,025 case patients suffering from bleeding abnormalities with 21,846 control patients. In addition, the study compared 1,008 patients with gastrointestinal bleeding with 1,990 control patients based on the ARNO database, a population-based database for drug use in Italy. This study excluded patients with a prescription for non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antihemorrhagics and antithrombotic agents. Seven percent of case patients with any bleeding disorder and 6.

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The variation in response rates from 20% to 80% resistance to therapy is the major cause of treatment failure and is can be attributed to the significant biological and clinical heteroge- also more common among patients over age 70 60 caps mentat, suggesting that neity of patients enrolled mentat 60 caps low cost, but this makes comparative analysis of even in the absence of known biologic risk factors order mentat online from canada, advanced age salvage regimens difficult mentat 60caps discount. Few randomized studies stratified for confers resistance to leukemia treatment. Of course, regardless of significant variables that are available to guide therapy and, in the risk, relapsed leukemia, leukemia refractory to induction chemo- absence of effective postremission strategies for the majority of therapy, and leukemia characterized by the persistence of minimal patients, it is difficult to demonstrate a superior survival of residual disease after induction chemotherapy define high-risk combination regimens over single-agent high-dose cytarabine. Of these, residual disease defined by multiparameter flow cytometry or positive PCR for disease-specific genes describes a Against this background of high-dose cytarabine salvage, a variety group of patients with significant risk of early recurrence after of agents have been added, including anthracyclines, etoposide, and consolidation therapy, including consolidation in the form of purine analogs. The addition of anthracyclines has some basis in allogeneic transplantation. Whether this translates to management later in the disease course is subject to question. Prior infusion with fludarabine or Treatment of high-risk AML cladribine has been shown to increase the araCTP accumulation in The major question for physicians managing acute leukemia is to leukemia blasts induced by high-dose cytarabine, prompting a define effective alternative therapy based on a risk-adapted model. Another question is whether currently available risk-adapted therapy Clofarabine is a second-generation purine analog that combines the offers an advantage over standard treatment or if disease models cytotoxic characteristics of both fludarabine and cladribine and merely identify prognostic variables that cannot be addressed studies demonstrate that, like the parent compounds, synergistic clinically. Supportive of this somewhat pessimistic perspective is a cytotoxicity can be achieved with cytarabine. The largest trial of recent report from the German AML Intergroup that prospectively salvage therapy in older patients with high-risk AML was the Hematology 2013 203 CLASSIC I study. The cytarabine dose administered was 1 g/m2 as a 2-hour infusion daily for 5 days given 3 hours after completion of Several agents directed at kinase mutations have been incorporated clofarabine or placebo. The choice of the cytarabine dose was based into therapy for AML characterized by flt3 ITD. Originally devel- on the saturable kinetics of araCTP incorporation and the advanced oped as antagonists for use in the relapsed and refractory settings, it age of the population under study. Given the advanced age of the is conceivable that one of these agents may make it to initial subjects, the postremission strategies consisted, in general, of a management. Midostaurin, lestaurtinib, quizartinib, and sorafenib single, optional consolidation cycle of unproven efficacy; few have all shown single-agent activity in the relapsed setting. The combination most promising among these for the treatment of relapsed disease, therapy worked, at least in terms of inducing remission. Response quizartinib, may induce or select for unique mutations that confer was significantly higher for the combination arm (46. However, the combination arm produced such as ponatinib. Midostaurin has been studied in combination significantly more treatment-related adverse events in this high-risk, with induction chemotherapy for newly diagnosed AML character- older population, including deaths as a result of these adverse events ized by flt3 mutation, but results have not yet been published. The causes of deaths in the phase 1/2 study of sorafenib combined with high-dose cytarabine combination arm included cerebral hemorrhage, pneumonia, pulmo- (1. Disease yielded complete remission in 14 of 15 patients with flt3-mutated progression contributed to deaths in both groups. Because the study AML, suggesting that the additional agent may have made an was designed with survival as the primary end point, the effect on impact on response rate. Results of sorafenib combined with low-dose statistical significance either for the patients with refractory AML or cytarabine in elderly patients with AML, irrespective of flt3 for those with relapsed disease, although event-free survival at 4 mutational status, were not encouraging based on both toxicity and a months favored the combination arm. As demonstrated in the clofarabine/cytarabine trial, tion of cytarabine and daunorubicin in a fixed molar ratio of 5:1. It uncertainty about the best postremission strategy can render an has shown activity in the relapsed setting, particularly in the setting advantage in rate of remission meaningless. Without specifying of secondary leukemia, a target for a current phase 3 clinical trial in postremission therapy, the impact of a better induction regimen is patients with untreated high-risk AML. Furthermore, anything that may enhance the cytotoxic effect important if demonstrating a survival advantage remains the out- of cytarabine could, in theory, prolong myelosuppression or contrib- come demanded for regulatory approval. Combinations of cytotoxic agents may affect response rates, but are unlikely to make Several novel agents, built on a cytotoxic model, have been an impact on survival unless there is a plan for postremission evaluated in advanced acute leukemia. Elacytarabine is a novel consolidation with allogeneic transplantation, the only proven form nucleoside analog that is cytotoxic and independent of the trans- of postremission therapy for patients with relapsed/refractory AML porter hENT1 for cellular uptake and activity. These include alone and in combination with agents such as lenalidomide, are also gemtuzumab; farnesyl transferase inhibitors; inhibitors of flt3 or under study, although responses in the relapsed setting seem histone deacetylase, and CXCR4. Originally studied with G-CSF given as a tion presented its results of a phase 3 open-label study of gemtu- priming agent, cytarabine alone or with other cytotoxic agents has zumab given for 3 doses of 3 mg/m2 on days 1, 4, and 7 during been studied for increased efficacy and toxicity after mobilization of conventional 7&3 induction and included the drug in consolidation blasts from the BM niche. Complete response was primed with the agent, and then treated with a combination of similar in both groups; however, the 2-year event-free survival was mitoxantrone, etoposide, and cytarabine after an initial phase 1/2 40. Relapse-free survival and overall agents could provide a chemotherapy bridge to the more-definitive survival were both significantly better for the combination group allogeneic transplantation (Table 3). The UK National Cancer setting or, for that matter, moving these agents to initial therapy Research Institute AML Working Group reported a favorable based on approval for distinct biologic or clinical subtypes depends 204 American Society of Hematology Table 3. Novel investigational agents for newly diagnosed and transplantation seems much lower that what has been reported after relapsed/refractory AML multiple cycles of consolidation chemotherapy. Elacytarabine CPX-351 Allogeneic transplantation is also recommended as postremission Immunoconjugate management for patients whose disease is characterized by adverse Gemtuzumab ozogamicin cytogenetics, leukemia arising from antecedent myelodysplasia, or Alternative targeted agents for leukemia in second or greater remission. Although these Farnesyltransferase inhibitors variables also predict for a high risk of relapse after allogeneic Histone deacetylase inhibitors transplantation,65-67 transplantation is simply the best or only option flt3 antagonists Others offering potential long-term survival in patients with AML charac- Chemosensitizing agent terized by adverse disease biology and even among those with CXCR4 antagonist adverse clinical features such as older age. Newer strategies to deliver the adoptive immunotherapy potential of the allograft with dose-reduced preparative conditioning may be associated with a on showing an improvement in survival. Right now, the only higher risk of leukemia relapse than what has been seen with approach that seems to work is allogeneic transplantation. Allotrans- conventional myeloablative conditioning, but offers transplantation plantation as initial management for disease refractory to induction or chemotherapy-resistant relapse does not seem to be an encourag- to a more representative population of older patients: those who ing option. Survival in fewer than 10% to 20% of selected patients have been heavily treated in the past and those with comorbid does not provide convincing evidence that allogeneic transplanta- medical conditions but whose disease warrants transplantation. No center There are presently no alternatives available to improve the results has convincingly demonstrated that an alternative conditioning of consolidation therapy for those patients with high-risk AML and regimen exists that would simultaneously address chemotherapy- there are no drugs in development that target postremission resistant leukemia and induce long-term survival. The Center for management as a pathway to regulatory approval. International Blood and Marrow Transplant Research reviewed the results of allogeneic transplantation in 2255 patients with acute Concluding points leukemia in relapse or with primary induction failure between 1995 62 Identifying high-risk features of AML at diagnosis, outside of a and 2004. The 3-year survival was 19% among patients with AML clinical trial, is mandatory both for prognosis and for recommenda- and 16% for patients with ALL. The morality at 100 days after transplantation was 39%. As expected, first complete remission tions regarding postremission therapy for the majority of adults duration less than 6 months, the presence of circulating blasts, an under age 70. Although identifying adverse disease biology at unrelated/alternative donor, and poor performance status predicted diagnosis has not yet led to a change in remission-induction for a dismal outcome. More importantly, the presence of poor-risk strategies using approved agents, features such as monosomal cytogenetics also predicted for poor outcome. The poor outcome karyotype, flt3 mutational status, and leukemia characterized by was most frequently progression of leukemia. A combination of all short first remission will very likely influence the choice of of the risk factors made it virtually impossible to achieve long-term treatment in the near future. For now, it is advisable to initiate, at the survival. The statistics have led some to suggest that delaying minimum, a complete karyotypic profile by FISH and conventional allogeneic transplantation by administering salvage chemotherapy cytogenetics, as well as molecular assessment for mutations in flt3, may not be warranted,63 but the poor survival rate for those with NPM1, kit, and CEBP- , with careful attention to additional multiple risk factors suggests that planting new sod when the markers such as IDH2 and DNMT3 that may become important in existing lawn is full of weeds is not likely to yield a weed-free turf. Patients should also be evaluated at their first visit with histocompatibility testing and evaluation for potential family Allogeneic transplantation for patients whose AML was character- or alternative donors should be initiated as soon as authorized. For ized by a first remission of greater than 6 months, intermediate-risk patients with AML characterized by adverse disease features and for cytogenetics, and no circulating blasts produces a favorable long- those whose disease has recurred after short first remission or has term outcome in approximately 40%, suggesting that survival rates been refractory to conventional induction, I strongly recommend for patients with lower disease-risk would be comparable to those referral to a center capable of entering the patient into a clinical trial whose disease was in complete remission before transplantation. To continue to earlier in leukemia management is the better strategy. Still, adverse administer 7&3 or single-agent high-dose cytarabine to patients disease biology confers increased risk. Although there are no with AML characterized by adverse disease biology or chemo- prospective trials of donor versus no donor for the management of high-risk AML in first remission, retrospective studies suggest that therapy resistance, respectively, is to continue to settle for a wholly the adoptive immune therapy achieved with allogeneic transplanta- inadequate standard. For those of us committed to changing the tion offers a survival advantage for patients with AML characterized outcome of therapy for the sizeable percentage of leukemia patients by flt3 ITD or adverse cytogenetics.

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