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O bservationalstudies A uth or N Drugs (m ean Durationof Eligibility C riteria Y ear dose);durationof treatm ent C ountry treatm ent Sch lich purchase discount lotrel online symptoms after embryo transfer, 107 Z olpidem 6 month s O verage 40 order lotrel online from canada medications 10325,clearevidence of 1991 insomnia defined as sleep F rance onsetlatency ofmore th an30 minutes buy lotrel overnight medicine tour,numberofnocturnal awakenings each nigh tgreater th antwo safe 10mg lotrel medicine numbers,and /ortotalduration ofsleepeach nigh tless th an6 h ours. W ang,2001 1,222 cases, Z olpidem, 6 month s subjects aged >= 65 onJuly 1,1993, U S 4,888 controls benz odiaz epines, and h ave filled one ormore claims fora oth er nonprescriptionservice between January 1,1994 and December31, 1994 and h ave filled atleastone prescriptionforany medicationth rough th e M edicaid orPA A Dprograms of N ew Jersey ineach offourconsecutive 6-month periods beginningJanuary 1, 1993. Insomnia 297 of 309 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 9. O bservationalstudies A uth or O th erpopulation Design Datasources Tim e period A dverse events Y ear ch aracteristics of assessm ent C ountry assessm ent Sch lich , 74 females; Before-after clinicalexaminations 6 month s malaise 1991 meanage=63. C ase C ontrol N ew Jersey M edicaid 6 month s N R U S Program N ew Jersey Ph armaceuticalA ssistance to th e A ged and Disable (PA A D)Program N ew Jersey M edicare Insomnia 298 of 309 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 9. O bservationalstudies A uth or R esults F unding Y ear C ountry Sch lich , Tolerance:no evidence 1991 A dverse events:z olpidem vs. W ang,2001 H ipF racture: N ationalInstitute U S A djusted O R (95% C I)- adjusted forage and gender ondrugA buse z olpidem:1. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Esz opiclone A dult visualand auditory (Duggal, 1 45-yearold male difficultysleeping H allucinations subsided h allucinations 2007) nigh tsh iftworker,h ad to wake up erraticsleeppattern aftertakingmedication only a few h ours aftertaking visualand auditoryh allucinations and sleepingforth e medicationand fallingasleep afterwakingupa few h ours after recommended 8 h ours no h istory ofpsych iatricillness takingmedication(lastingseveral negative drugscreen minutes) takingseveraloth ermedications (doses unch anged) Z aleplon A dult C N S side effect (Stillwell, 1 drugabuse C N S depressionincludingslow notreported 2003) concurrentuse ofoth erdrugs movements and reactions,poor coordination,lack ofbalance,and poorattention Z aleplon A dult h allucination (Bh atia, 1 h ealth yfemale ligh th eaded notreported illusions A rora,& nonsmoker,occasionaldrinker illusion depersonaliz ation Bh atia, visualh allucinations 2001) Z aleplon Pediatrics somnambulism (L iskow & 1 majordepressive disorder, somnambulism with complex notreported Pikalov, moderate beh avior 2004) no h istory ofsleepdeprivation Z olpidem A dult anterograde (Tsai, 3 adultwomen compulsive repetitive beh aviors adverse events stopped amnesia 2007) (eating,sh opping,and cleaning) afterdiscontinuationof compulsive combined with anterograde amnesia z olpidem repetitive beh aviors (no recollectionofbeh aviors) Z olpidem A dult C N S side effect (C anaday, 2 notreported amnesia notreported 1996) Z olpidem A dult C N S side effect (M arkowitz 2 depression visualh allucination h allucinationceased & no h istory ofdrugabuse auditory h allucination Brewerton, concurrentuse ofantidepressants, confusion 1996) serotonin-reuptake inh ibitors difficulties atwork and marital Z olpidem A dult C N S side effect (Toner, 3 motorveh icle accidentor nigh tmare nigh tmares,h allucination 1999) psych iatrich istory h allucination and visualillusionceased visualillusion difficulty inconcentration Z olpidem A dult C N S side effect (Tripodina 1 no epilepticseiz ure nordrugabuse th e patients increased th e dose to notreported kis,2003) h istory 600mgperday epigastricpain,nausea,epileptic seiz ures and depression Z olpidem A dult delirium (F reudenre 1 depression agitated and confused notreported h allucination ich & disorganiz ed M enz a, visualh allucinations 2000) Insomnia 300 of 309 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 10. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z olpidem A dult dependence (A ragona, 1 h istory ofdrugabuse th e patientincreased th e dose upto epilepticseiz ure 2000) seiz ure h istory after 450-600mgperdayforanxiolytic benz odiaz epine discontinuation effect. Z olpidem A dult dependence (L iappas, 3 h istory ofdrugabuse patients increased th e dose upto confusion,amnesia or 2003) 300-600mgforsedation,reductionof epilepticseiz ure cocaine craving,stimulation,or euph oria. K aravatos, dependence and tolerance & K aprinis, M ild to severe with drawalsyndrome 2000) afterdiscontinuation. Insomnia 301 of 309 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 10. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z olpidem A dult dependence (Sh aran, 5 h istory ofdrug/alcoh oldependence dependence (includingsymptoms of 2 patients diagnosed with Elderly delirium 2007) and/ormentalillness (depression, with drawal,cravings, z olpidem dependence: bipolardisorder,late-onset appreh ension/anxiety,restlessness, both successfully psych osis) irritability,insomnia,palpitations) detoxified with elderly patients (3)alltaking10mg delirium (agitation,talking clonaz epam (8 mg/day), z olpidem (recommended dose for irrelevantly,unable to recogniz e with one ofth e two th e elderly is 5 mg) relatives,disorientation, relapsingafter3 month s auditory/visual/tactile h allucinations, 3 patients diagnosed with restlessness,violentbeh avior) delirium induced by z olpidem:symptoms subsided afterz olpidem was discontinued Z olpidem A dult dependence (K ao, 1 h istory ofsubstance abuse IV administrationforstimulanteffect yawning,rh inorrh ea and tolerance 2004) and euph oria and increased upto lacrimation 300-400 mg/day Z olpidem A dult dependence (Q uaglio et 2 no commonch aracteristics increasingtolerance no with drawal tolerance al. Z olpidem A dult h allucination (Van 2 one with outh istoryofpsych iatric h allucination notreported amnesia Puijenbroe disorders,th e oth erwith major amnesia k,Egberts, depressive disorderfor6 month & K rom, 1996) Insomnia 302 of 309 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 10. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z olpidem A dult h allucination (H oyler, 1 h istory ofpoth yroidism,mild agitated and disoriented to time and regained h erorientation, C N S side effect Tekell,& vasculardementia,and auditory place responded to redirection, Silva, h allucinations h allucinationand increased was able to communicate 1996) psych omotoractivity ath erusuallevelof efficiency,and h erbiz arre beh aviorwas resolved Z olpidem A dult H epaticproblem (C lark, 1 livertransplantation decline inmentality notreported 1999) h epaticenceph alopath y abdominalpain awoke ina stuporand was disoriented to place and time Z olpidem A dult h epaticproblem (K arsenti, 1 ch olecystectomy abdominalpain notreported Blanc, h epatotoxicity Bacq,& M elman, 1999) Z olpidem A dult oth ers-drug (O rtega 1 longterm benz odiaz epine user nervousness,irritability,fainting, allsymptoms disappeared interaction 1996) no psych iatrich istory asth enia,muscularcramps, excessive h earand sweating occasionalfebrile episodes,weigh t loss,and a surprisingsweettaste in th e mouth Z olpidem A dult seiz ure (G ericke & 1 depression consumed 150-280 mg/dayfor recurrence ofdepressive dependence L udolph , no seiz ure h istory stimulanteffect mood with apath y and tolerance 1994) drugcarving Z olpidem A dult sensory distortions (Pies, 1 no h istory ofpsych osis or sensory distortions notreported tolerance 1995) substance abuse Z olpidem A dult sleeprelated eating (N ajjar, 1 46-yearold female sleeprelated eatingdisorderstarting complete recoveryafter disorder 2007) h istory ofdepression, 3 weeks afterstartingz olpidem, z olpidem was h ypoth yroidism,h ypertensionand resultinginweigh tgain(50 pounds discontinued insomnia overa one-yearperiod)and th e developmentofobstructive sleep apnea Z olpidem A dult somnambulism (H araz in& 1 depression somnambulism somnambulism stopped Berigan, 1999) Z olpidem A dult somnambulism (Sattar, 1 bipolardisorder somnambulism insomnia R amaswa h istory ofdrugabuse difficulty inconcentration my, h istory ofalcoh oldependence Bh atia,& mania Petty, takingvalproicatth e same time 2003) Insomnia 303 of 309 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 10. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z olpidem A dult somnambulism (Y ang, 1 H eavy alcoh olconsumptionwith somnambulism no additionalepisodes of 2005) questionable delitium tremens but agitated and confused buth ad no sleepwalking h ad stopped drinkingalcoh ol20 psych oticexperiences years ago Traumatich ead injury Z olpidem A dult tolerance (C avallaro, 2 psych iatricdisorders increase dosage because of notreported 1993) tolerance with awakeningafter2-3 h. Z olpidem A dult abruption (A skew, 1 pregnantfemale cord blood testingresulted in with drawal-like symptoms vaginalspotting 2007) h istory ofz olpidem abuse (10–15 measurable z olpidem levels (possibly (nervousness,anxiety), periorbitalh eadach e tablets/nigh t) as h igh as peak plasma complained ofh eadach es abdominalpain concentrations aftera 5-mgdose of and inability to sleepafter respiratory problems th e drug),butno with drawal treatmentreduction trouble sleeping symptoms noted inth e neonate with drawal-like symptoms (nervousness, anxiety) Z olpidem A dult visualh allucinations (de H aas, 1 32-yearold male visualh allucinations starting20 adverse events subsided sleepiness 2007) negative psych iatricpersonalor minutes afterdrugintake and lasting aftera few h ours oftaking nausea family h istory 2 h ours th e medication diz z iness no concomitantmedicationorillicit sleepiness,nausea,diz z iness, diplopia drugs diplopia,and dysph asia (presentfor 3. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z olpidem Elderly C N S side effect (Brodeur& 1 Extensive medicalh istory delirium notreported Stirling, psych osis 2001) restless amnesia Z olpidem Elderly delirium (H ill, 1 no significantpsych iatrich istory no h allucination notreported mania O berstar, family h istory ofmild depression no suicidalorh omicidalideation & Dunn, mania 2004) Z olpidem Elderly dependence (M adrak & 1 h istory ofalcoh oland drugabuse use upto 100mg/day forth e last1. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z olpidem Pediatrics somnambulism (L ange, 1 depressive disorder somnambulism ch ange to citalopram 2005) h istory ofsomnambulism with outincident family h istory ofsomnambulism no epileptiform activity Z opiclone A dult dependence (A ranko, 1 depression th e patientincrease th e dose upto grand-mal-type convulsion H enriksso compulsive personality disorder 90mgperday foruninterrupted n,H ublin, h istory ofdrugabuse sleep. M emory difficulties & concurrentuse ofantidepressants cognitive impairments Seppalain dependence en,1991) Z opiclone A dult dependence (H aasen, 1 no h istory ofbenz odiaz epine or dependence R emainsymptom: M ueller- oth erpsych otropicsubstance use daily dosage of37. Z opiclone A dult dependence (Th akore & 1 depression dependence tach ycardia Dinan, h istory ofalcoh oldependency h and tremor 1992) h istory offluraz epam addiction weakness take z opiclone more due to anxiety panicattack and agoraph obia Insomnia 306 of 309 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 10. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z opiclone A dult extreme agitation (M oloney, 2 3-month h istory ofdepression one patientdeveloped insomnia, afterz opiclone was 2007) concomitantalpraz olam and restlessness,agitation,and a with drawn,adverse antidepressantmedication complete inability to relax3 weeks events resolved with in24- afterstartingz opiclone 48 h ours A noth erpatientbecame extremely agitated,developed forgetfulness, inabilityto sitstill,insomnia, nocturnalwandering,and racing th ough ts one week afterstarting z opiclone Z opiclone A dult globalamnesia (F ava, 1 no currentpsych iatric globalamnesia no furth erepisodes of 1996) symptomatology globalamnesia were no drinkingh istory observed duringa 6- no oth ermedication month period Z opiclone A dult incidence ofcancer (Stebbing 32 notreported 2 weeks ofz opiclone. C ase R eports Drug Sub-group A dverse Events Study # of C ase C h aracteristics Effects during treatm ent Effects during treatm ent cases reductionor discontinuation Z opiclone Elderly respiratory (Vogal, 1 C O PD drowsy notreported depression 1998) ex-smokerwith a h istory ofeth anol respiratory acidosis abuse Z opiclone Pediatrics oth ers (Sullivan, 3 h istory ofdrugabuse no evidence ofdependence notreported M cBride,& alcoh olabuse C lee, 1995) A lderman,C.

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Acute erythroid leukemia *Includes all AMLs with normal karyotype except for those included in the favorable Pure erythroid leukemia subgroup generic lotrel 10mg with mastercard medications starting with p. Erythroleukemia purchase 10 mg lotrel with visa medicine 834, erythroid/myeloid †For most abnormalities order lotrel online now medicine 3605 v, adequate numbers have not been studied to draw firm Acute megakaryoblastic leukemia conclusionsregardingtheirprognosticsignificance order lotrel 10 mg line treatment ketoacidosis. Acute basophilic leukemia ‡Three or more chromosome abnormalities in the absence of one of the WHO- Acute panmyelosis with myelofibrosis (also known as acute designated recurring translocations or inversions: t(15;17), t(8;21), inv(16) or myelofibrosis; acute myelosclerosis) t(16;16),t(9;11),t(v;11)(v;q23),t(6;9),inv(3),ort(3;3). Myeloid sarcoma (also known as extramedullary myeloid tumor, granulocytic sarcoma, chloroma) Diagnostic work-up/disease classification Myeloid proliferations related to Down syndrome Based on the revised World Health Organization (WHO) publica- Transient abnormal myelopoiesis (also known as transient tion WHO Classification of Tumors of Hematopoietic and Lymphoid myeloproliferative disorder) Tissues,7 a total of 7 entities are defined within the subgroup “AML Myeloid leukemia associated with Down syndrome with recurrent genetic abnormalities. All other entities in ABL1 Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged this category require the presence of at least 20% BM blasts at Mixed phenotype acute leukemia, B/myeloid, NOS diagnosis based on morphology. Two provisional entities defined by Mixed phenotype acute leukemia, T/myeloid, NOS the presence of gene mutations were added to this category: AML Provisional entity: Natural killer cell lymphoblastic leukemia/lymphoma with mutated NPM1 and AML with mutated CEBPA. The category “AML with mutated NPM1” is by far the largest subgroup defined ForadiagnosisofAML,aBMblastcountof 20%isrequired,exceptforAMLwith by genomics, with a high incidence in both young and older AML the recurrent genetic abnormalities t(15;17), t(8;21), inv(16), or t(16;16) and some 8-10 casesoferythroleukemia. However, the association with cooperating genetic NOSindicatesnototherwisespecified. The favorable prognostic impact of mutant CEBPA eage dysplasia; AND absence of both prior cytotoxic therapy for unrelated disease that was demonstrated previously in several studies can be attrib- and aforementioned recurring genetic abnormalities; cytogenetic abnormalities uted to the subtype of AML with CEBPAdm. In patients with cytogenetically normal (CN) AML, agents,ionizingradiationtherapy,topoisomeraseIIinhibitors,andothers. Hematology 2013 325 Interestingly, RUNX1 mutations are almost mutually exclusive of Table 3. Categorization and frequency of gene mutations according other disease-defining genetic aberrations such as NPM1, CEB- to functional properties based on next-generation sequencing in PAdm, CBFB-MYH11, RUNX1-RUNX1T1, and PML-RARA. PML-RARA CBFB-MYH11 RUNX1-RUNX1T1 A recent landmark publication by the Cancer Genome Atlas PICALM-MLLT10 Research Network on the genomic and epigenomic landscapes of NPM1 mutations 27% adult de novo AML reported results from next-generation sequenc- Tumor suppressor genes 16% ing performed in 200 AML patients (n 50 whole-genome sequenc- TP53 ing, n 150 whole-exome sequencing). The median number of mutated DNA methylation 44% genes in coding sequences was 13 (range, 0-51). The investigators DNMT3A proposed a classification of gene mutations into 9 categories based DNMT3B on their biological function, with 199 of the 200 analyzed patients DNMT1 having at least one mutation in 1 of these categories (Table 3). These TET1 TET2 findings will probably influence the future disease classification IDH1 system. IDH2 Activated signaling 59% Prognostication of response to induction therapy FLT3 The achievement of CR after induction therapy is a commonly KIT accepted prerequisite for long-term survival and cure. CR rates vary Other tyrosine kinases widely in the different prognostic groups (Table 1), from 80% to Serin-threonine kinases 95% in the favorable risk group to only 32. If no Myeloid transcription factors 22% CR is achieved after induction therapy, the probability of dying RUNX1 22 CEBPA from AML is as high as 75% during 1 year. In this situation, Other myeloid transcription factors molecular and cytogenetic markers may help to guide patients and Chromatin modifiers 30% their families through the risks and benefits of induction MLL fusions chemotherapy. MLL-PTD NUP98-NSD1 Genetic mutations also aid in predicting response. NPM1 mutations, ASXL1 one of the most frequent gene mutations (occurring in 25%-35% of EZH2 all adults with AML)23 have consistently been reported as a KDM6A favorable prognostic factor for CR achievement, with CR rates of Other 90% and higher in younger patients either as a single marker or as Cohesin complex* 13% combined genotype, NPM1-mut/FLT3-ITDneg. The addition of all-trans retinoic acid to intensive induction therapy24 and the TP53 alterations including mutations and losses are found in intensification of daunorubicin within a standard “7 3” regimen25 approximately 70% of AML with complex karyotype. Whether FLT3-ITD adds value in prognostication been shown to be an independent poor prognostic factor among the of CR rate on the background of NPM1 is still a matter of debate. Whether more novel Schneider et al showed no impact of FLT3-ITD on CR rates in either agents, such as the demethylating agents, may improve the dismal NPM1-mutated or NPM1 wild-type AML. Such markers include mutations of the DNMT3A (incidence adult AML and the frequency decreases with increasing age.

In NPM1-mutated AML order lotrel line medications 44334 white oblong, minimal with biallelic CEBPA gene mutations and normal karyotype represents a residual disease monitoring is clinically relevant because NPM1 distinct genetic entity associated with a favorable clinical outcome order lotrel overnight delivery medicines360. Prognostic significance of CEBPA patients at a high risk of relapse lotrel 5 mg low cost medicine 1950. Applicability of NPM1 minimal mutations in a large cohort of younger adult patients with acute myeloid residual disease monitoring for preemptive therapy is currently leukemia: impact of double CEBPA mutations and the interaction with under investigation purchase generic lotrel from india medicine 5277. Diagnostic testing for other molecular markers FLT3 and NPM1 mutations. However, it is likely that the accumulating concurrent genetic mutations, and gene expression features of AML data on the novel molecular markers will affect upcoming revisions with CEBPA mutations in a cohort of 1182 cytogenetically normal of risk classification systems. A better understanding of the role of AML patients: further evidence for CEBPA double mutant AML as a these molecular lesions in AML biology will hopefully result in the distinctive disease entity. Prognostic relevance of clinical outcome for our AML patients. Cytoplasmic nucleophosmin in acute myelogenous This work was supported in part by Grant BU 1339/5-1 from the leukemia with a normal karyotype. Deutsche Forschungsgemeinschaft and Grant 109675 by the Deut- 13. We thank Daniela Spa¨th for support with creating (NPM1) predicts favorable prognosis in younger adults with acute the figures in this manuscript and Hartmut Do¨hner for critically myeloid leukemia and normal cytogenetics: interaction with other gene reviewing the manuscript. Mutations and treatment Disclosures outcome in cytogenetically normal acute myeloid leukemia. Age-related risk profile and Off-label drug use: None disclosed. Favorable prognostic impact of Konstanze Do¨hner, MD, Department of Internal Medicine III, NPM1 mutations in older patients with cytogenetically normal de novo University Hospital of Ulm, Albert-Einstein-Allee 23, D-89081 acute myeloid leukemia and associated gene- and microRNA- Ulm, Germany; Phone: 49-731-500-45001; Fax: 49-731-500- expression signatures: a Cancer and Leukemia Group B study. Schlenk RF, Do¨hner K, Kneba M, et al; German-Austrian AML Study References Group (AMLSG). Diagnosis and management of all-trans retinoic acid in elderly patients with acute myeloid leukemia. The importance of diagnostic assessed by NPM1 mutation-specific RQ-PCR provide important prog- cytogenetics on outcome in AML: analysis of 1,612 patients entered nostic information in AML. Karyotypic analysis disease in NPM1-mutated acute myeloid leukemia: a study from the 40 American Society of Hematology German-Austrian acute myeloid leukemia study group. Analysis of FLT3-activating normal AML within the ELN Favorable genetic category. ASXL1 in acute myeloid leukemia: prevalence and prognostic value. Unfavorable impact of ASXL1 normal cytogenetics and the internal tandem duplication of FLT3: a mutations on achievement of complete remission and long term cancer and leukemia group B study. Insertion of FLT3 internal myeloid leukemia: a Cancer and Leukemia Group B study. J Clin tandem duplication in the tyrosine kinase domain-1 is associated with Oncol. The impact of FLT3 internal tandem risk cytogenetics. TET2 mutations in acute myeloid mutations in a large cohort of young adult patients with acute myeloid leukemia (AML): results from a comprehensive genetic and clinical leukemia. Mutations in epigenetic modifiers in the FLT3-ITD mutation and concomitant NPM1 mutation: relevance to pathogenesis and therapy of acute myeloid leukemia. Incidence and prognostic influence implication and interaction with other gene alterations. Clinical impact of DNMT3A de novo AML with noncomplex karyotype and confer an unfavorable mutations in younger adult patients with acute myeloid leukemia: a prognosis.

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Subsequent MFC-MRD monitoring tracks previously order genuine lotrel symptoms jaundice, together with the problems in using morphology to these diagnostic LAIPs (sometimes using tailored antibody combi- reliably assess remission status order 10mg lotrel free shipping medicine 75, there is clearly a very strong nations) order 5 mg lotrel free shipping counterfeit medications 60 minutes, with a cluster of 20 cell events in the LAIP gate being rationale for use of MRD detection methods to provide a more potentially sufficient to identify MRD—resulting in a maximum objective assessment of treatment response to develop a more sensitivity of between 10 4 and 10 5 when 500 000 nucleated cells individualized approach to management order 10mg lotrel visa treatment for strep throat. Identifying specific LAIPs at diagnosis may be the various platforms available at present or in the near future, take improved by incorporation of more colors, thereby allowing the account of their relative advantages and limitations, and discuss the addition of further simultaneous markers required to define an most informative approach depending on the subtype of AML and abnormal cell. However, this is a double-edged sword because clinical scenario, recognizing the challenges for the laboratory instability of even 1 of the LAIP markers after treatment increases involved in the successful delivery of MRD-directed therapy. Experience of which phenotypic Hematology 2014 223 Figure 1. Outline of antibody groups used in panels for identification of AML-aberrant immunophenotypes (both for LAIP and “different- from-normal” approaches) and subsequent residual disease monitoring. Core markers are those selected for the backbone of the panel to identify myeloid blast populations. These are combined with markers from lymphoid/myelomonocytic maturation groups (megakaryocytic markers and NG2 [for MLL-rearranged AML] are not included but are more useful in pediatric AML). A stem cell combination may be included (as in the United Kingdom [UK] National Cancer Research Institute [NCRI] AML trial panel) to detect potential immunophenotypic LSC. Most sensitive, robust, aberrant phenotypes include cross-lineage expression and CD34 human leukocyte antigen (HLA) DR weak/negative. Some aberrant phenotypes may be sensitive (by testing detection by serial dilution in normal marrow) but less stable/useful in follow-up samples. Blue, antibody marker; bold blue, marker in NCRI AML trial panel; red, type of aberrant phenotype potentially detected by marker group. These may result from the phenotypic changes discussed The second analysis approach, initially validated by the Children’s previously or emergence of initially minor subpopulations (less than Oncology Group,9,20 circumvents the problems of false negatives 5% to 10% of blasts at presentation) excluded by the LAIP assay or from phenotypic shifts and emerging subclones by using a fixed may reflect chemoresistant leukemic cells that lack sufficiently antibody panel (also based on combinations in Figure 1) and an specific immunophenotypic aberrancies, even if these are identified analysis that screens for established immunophenotypic profiles to in other leukemic subpopulations. Although extensive antibody distinguish abnormal leukemic cells (including more mature sub- panel screens increase the chances of detecting rarer aberrancies, populations) from normal cells irrespective of diagnostic leukemic cost-effectiveness and sample size are practical considerations immunophenotype. This is termed “different-from-normal” MFC- limiting their use. Alternatively the chemoresistant reservoir of MRD, perhaps confusingly, because diagnostic LAIPs in the first MRD may predominate in extramedullary sites or consist of rare approach are also different from normal. This type of MFC-MRD leukemic cells/leukemic stem cells (LSC) below the detection assay has been successfully applied to allogeneic transplant pa- threshold of 10 4. Assays detecting LSC rather than bulk AML blast tients,21 in which there frequently are insufficient data from subpopulations may increase sensitivity and predictive value of referring hospitals to monitor diagnostic LAIPs and there may be MRD monitoring. Because functional xenograft assays for LSC are no known leukemia-specific genetic marker (Figure 2). One not clinically applicable, the alternative strategy is to monitor the potential consideration of this approach is that different-from- frequency of candidate immunophenotypic populations enriched for normal phenotypes, particularly in more mature myeloid cells, LSC. Published assays have mainly focused on the CD34 CD38 may result from preleukemic clones22-24 and these, although compartment, which in normal BM contains hematopoietic stem chemoresistant, will have a lower early relapse risk compared cells, either using aberrant differential expression of non- with leukemic clones. The implications of this for relapse hematopoietic stem cell markers27 similar to the LAIP/different-from- prediction is likely to be particularly relevant to older patients normal approach or measuring abnormal expansion of a with their higher prevalence of background myelodysplasia CD34 CD38 stem/progenitor compartment previously function- (MDS)/preleukemic clones and also apply to the LAIP assay 28 ally characterized to contain AML LSC. However, LSC are not since aberrant blast immunophenotypes have been observed in 25 restricted to this immunophenotypic subset in all patients, because low risk MDS. AML blasts with LSC activity defined functionally by xenotrans- plant models have heterogenous surface marker profiles including MFC-MRD assay sensitivity those of CD34 CD38 and sometimes CD34 populations. An experienced laboratory and an adequate sampling26 that xenograft LSC frequency of different AML genetic subclones 224 American Society of Hematology Figure 2. Examples of detecting MRD with “different-from-normal approach” applied to myeloblast population.

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