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Penegra

By T. Abe. Keuka College.

Hematology 2014 63 Indeed 100mg penegra, PK antisense oligonucleotides revealed thromboprotective constitutes a natural procoagulant cofactor in blood coagulation 100 mg penegra. Proc effects in mouse models of chemically and mechanically induced Natl Acad Sci U S A penegra 50 mg. Polyphosphate: an ancient molecule knockout mice 50 mg penegra, which indicates that PK inhibition could be a that links platelets 50mg penegra, coagulation penegra 100mg, and inflammation penegra 100 mg. Monocytes penegra 50mg, neutrophils , and contradictory results: inhibition of plasma kallikrein with different 42 platelets cooperate to initiate and propagate venous thrombosis in mice inhibitors produced a prothrombotic state , which is a relevant in vivo. Misfolded proteins activate factor XII in humans, leading to kallikrein formation without HK initiating coagulation. Knock-down of the murine kininogen gene 1 resulted in a mouse 10. Activation of the human contact without HK and low-molecular-weight kininogen. Furthermore, targeting HK reduced thrombus ization of prolylcarboxypeptidase as an endothelial cell prekallikrein formation in ischemic vessels and improved cerebral blood in mice, 44 activator. Physiologic activities of the contact activation system. Formation of bradykinin: a major contributor to The contact system provides a direct link between coagulation and the innate inflammatory response. Cleavage of HK by kallikrein produces the vasoac- 14. Plasma kallikrein: the bradykinin- tive protein BK, which has several inflammatory effects, but is also producing enzyme. Mice deficient for the BK B2 receptor are branch of innate immunity generating antibacterial peptides. These data provide evidence for an anticoagulation strategy target- 2009;7(Suppl 1):84-87. Increased activity of coagulation The contact pathway has seen a resurgence in interest because of the factor XII (Hageman factor) causes hereditary angioedema type III. Bork K, Wulff K, Meinke P, Wagner N, Hardt J, Witzke G. A novel of the contact proteins are protected against thrombosis. These mutation in the coagulation factor 12 gene in subjects with hereditary observations led to the development of several compounds targeting angioedema and normal C1-inhibitor. Missense mutations in the coagulation factor XII approach to target (one of the) contact proteins would constitute an (Hageman factor) gene in hereditary angioedema with normal C1 effective and safe strategy for antithrombotic treatment. In addition, it will be essential to identify the deficiency. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. Effects of factor XI deficiency on Conflict-of-interest disclosures: J. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the Correspondence mouse. Meijers, PhD, Department of Plasma Proteins, Sanquin factor XI prolongs APTT without increased bleeding risk in cynomolgus Research, Plesmanlaan 126, 1066 CX Amsterdam, the Netherlands; monkeys. Phone: 31-20-5123151; Fax: 31-20-5123310; e-mail: j. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel References antithrombotic strategy with lowered bleeding risk. A role for factor XIIa-mediated 2010:104(5):867-874. The procoagulant and proinflammatory plasma contact 3981-3989. The coagulation system and its function in anti-human factor XI antibodies prevent cessation of blood flow in a early immune defense. Thrombosis as an intravascular effector of antisense factor XI oligonucleotide treatment in primates. Prevention of vascular graft 64 American Society of Hematology occlusion and thrombus-associated thrombin generation by inhibition of 39. Factor XI Regulates generation through direct interaction with fibrin. Girolami A, Candeo N, De Marinis GB, Bonamigo E, Girolami B. Defective thrombus formation deficiency on haemostasis and thrombosis in mice: murine ortholog of in mice lacking coagulation factor XII. Factor XIIa inhibitor dase depletion induces vascular dysfunction with hypertension and recombinant human albumin Infestin-4 abolishes occlusive arterial faster arterial thrombosis. Factor XII regulates brain barrier damage, and inflammation. Factor XII inhibition knockout mice are protected from thrombosis by increased nitric oxide reduces thrombus formation in a primate thrombosis model. A factor XIIa inhibitory decrease thrombosis in Bdkrb2 / mice by increasing NO and antibody provides thromboprotection in extracorporeal circulation with- prostacyclin to reduce platelet spreading and glycoprotein VI activation. Meijers1,2 1Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and 2Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecular- weight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. The contact system has a remarkable resemblance to the innate Learning Objectives 3 immune system based on the recognition molecules. Indeed, the ● To understand that the contact system consists of 4 proteins: contact system recognizes an increasing number of bacterial patho- factor XI, factor XII, PK, and HK gens and other types of microorganisms. Therefore, the contact system is part of the new method to prevent thrombosis in mice research field referred to as “immunothrombosis. In the accompanying chapters by Gailani and Key, the preclinical work in other rodents Introduction and primates and the epidemiological and clinical studies on the The contact system consists of 4 plasma proteins: factor XI, factor contact system and thrombosis are summarized. XII, prekallikrein (PK), and high-molecular-weight kininogen (HK). The proteins were recognized in the 1950s and 1960s after identification of individuals with (severely) prolonged activated Biochemistry of the contact system partial thromboplastin times (aPTTs). Originally, the proteins were The contact system consists of 3 proenzymes (factor XII, PK, and given names such as Hageman factor (factor XII), Fletcher factor factor XI) and a cofactor (HK). The domain structure of the contact (PK), Williams-Fitzgerald-Flaujeac factor (HK), and plasma throm- proteins is shown in Figure 1. The contact system assembles on boplastin antecedent (factor XI). Artificial charged surfaces and will then initiate procoagulant and proinflam- surfaces that are used in catheters or cardiopulmonary bypass will matory reactions via the intrinsic pathway of coagulation and the also lead to activation of the contact system and, over recent years, kallikrein-kinin system, respectively. HK also deficiency of one of the other contact factors is not associated with bleeding. Recently, some exciting data have become available that binds directly and, because it is in the circulation in complex with point to a role for the contact system in thrombosis. Even though the PK and factor XI, the complete contact system becomes assembled majority of the data were obtained from animal experiments, the on the surface. According to current insights, the contact system is not 60 American Society of Hematology Figure 1. Cleavage sites for activation are indicated with an arrow. The most important system on (negatively) charged surfaces results in a series of argument for this statement is the lack of a bleeding diathesis in procoagulant and proinflammatory reactions. Binding of factor XII patients deficient in factor XII, PK, or HK. Coagulation occurs to a negatively charged surface causes a conformational change of when the plasma protease activated factor VII comes into contact the protein and results in (limited) activation to factor XIIa. The Activated factor XII cleaves PK into kallikrein (Kal), which TF/factor VIIa complex can activate factor X, which can convert reciprocally activates additional factor XIIa (Figure 2). Thrombin, in turn, is involved in can activate factor XI to factor XIa, which further initiates thrombin multiple pathways, one of which is the conversion of fibrinogen into and fibrin formation. HK serves as a nonenzymatic cofactor for the fibrin, which constitutes the clot. Therefore, for this sequence of activation of both PK and factor XI. Apart from factor XIIa, PK can events, TF must come into contact with blood, for example, upon also be activated by prolylcarboxypeptidase on endothelial cells. In addition, a TF-independent pathway has Plasma kallikrein cleaves BK from HK. BK has many physiological evolved in vertebrates: the contact system. Assembly of the contact and pathophysiological effects (Figure 3)12; it is involved in blood Figure 2. Factor XII (FXII) can be activated by negatively charged surfaces such as polyphosphates (polyP) derived from activated platelets or neutrophil extracellular traps (NETs). PK can be activated to kallikrein (Kal) by prolylcarboxylase (PRCP) on endothelial cells. Factor XIIa will also activate PK and thereby allows reciprocal activation, resulting in the generation of additional factor XIIa. Factor XIIa can initiate coagulation via the activation of factor XI. Both PK and factor XI are in complex with their cofactor, HK. Activation of the contact system leads to the liberation of BK from HK by kallikrein. BK and its derivatives have important functions in blood pressure regulation, vasodilation, and inflammation. The major inhibitor of the classical complement pathway (C1 esterase inhibitor, C1INH) is also in important regulator of kallikrein and factor XIIa activity. Furthermore, as a vasoactive factor XI plasma levels. However, the molecular basis for BK can be further cleaved after which the various kinins are factor XII autoactivation in vivo is not known. Nonetheless, patients involved in both acute and chronic inflammatory responses. BK can also Hereditary angioedema activate the B1 receptor in response to tissue injury and inflamma- The major inhibitor of plasma kallikrein is C1-esterase inhibitor tion in an IL- and TNF-dependent manner, thereby modulating the 14 (C1INH), a protease belonging to the serine protease inhibitor immune response. Furthermore, contact activation can lead to the (serpin) family. Patients with either a deficiency of C1INH (type 1) release of kininogen-derived antimicrobial peptides, providing a 15 or a dysfunctional C1INH protein (type 2) have a disease called principal first-line defense against invading pathogens. This rare, autosomal-dominant disor- der is characterized by life-threatening swelling episodes that can Hemorrhagic phenotypes associated with contact develop suddenly and unexpectedly. Some episodes are accompa- factor deficiencies nied by urticaria. Patients can be treated with IV infusion of The only contact factor deficiency that is associated with a bleeding recombinant or plasma-derived C1INH concentrates, which shorten phenotype is factor XI. These substances can also be used XI-deficient patients is usually mild and injury induced. Bleeding proteases C1r and C1s, which belong to the classical complement typically occurs after trauma or surgery, especially when surgery pathway (Figure 3). Therefore, a deficiency of C1INH or a involves tissues with high fibrinolytic activity, such as oral and dysfunctional C1INH protein will lead to uncontrolled activation of nasal cavities, tonsils, and the urinary tract. The management of the complement and contact system, as well as massive BK release. There is a third type of HAE, called type III, which is linked to factor XII,18 resulting in enhanced factor XII enzymatic activity in Factor XII these patients. However, this activity is not detected in routine Since the factor XII-deficient index patient John Hageman died of coagulation tests, and specialized (genetic) testing is necessary for pulmonary embolism, there has not been much interest in factor XII identification of patients. Several mutations in the factor XII gene 32 as an antithrombotic target. Therefore, the available data on factor have been identified in patients with HAE type III and all of these 18-20 XII is much more limited compared with factor XI. In recent years, mutations are in the same factor XII gene region. This suggests however, there is renewed interest in factor XII and its role in an association between altered processing of the factor XII protein thrombosis. In part, this is due to unexpected observations in factor and the disorder. However, how a defective factor XII protein XII-knockout mice. Like humans, these mice have significantly affects BK levels is not understood yet.

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K reder M ulticenter O penlabel12m onth Patientscom pleting 12wk N onespecified 2002 (m ultinational) study R CT enrolled Abram s penegra 100mg,2001 M ulticenter 100mg penegra,E urope O penlabel penegra 50 mg, m aleandfem alepatients 50 mg penegra,age clinicallysignificantstressincontinence penegra 50mg,hepatic or uncontrolled penegra 100 mg,12 >18(≥65yinone4-week renaldisease 100 mg penegra,recurrentorsym ptom atic U TI 50mg penegra, m onths study) ,urodynam icallyproven conditionscontraindicating antim uscarinic therapy , overactivebladderand clinicallysignificantvoiding difficultywith riskof sym ptom sof urinary urinaryretention,treatm entwith orinitiationduring the frequency(average(≥8 studyof,anyantim uscarinic drug oranydrug for m icturitions/24h),urgency, bladdercontrolproblem sorbladdertraining,within an/orurgeincontinence 14dpriortothebaselinevisit. M ichel, M ulticenter, O penlabel, none none 2005 G erm any uncontrolled,9 m onths Tol= Tolterodine,O xy= O xybutynin,IR = Immediaterelease,ER = Extendedrelease,R C T = R andom C ontrolledTrial,U TI= U rinarytractinfection Overactive bladder 182 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 8. O veractive bladdersyndrom e observationalstudies:A dverse events N um berscreened/ A ge A uth or, eligible/ G ender Y ear Interventions enrolled Eth nicity Abram s Tol2m g twicedaily 895eligible/714enrolled Agerange18-92 2001 M eanage60yrs 69% fem ale K reder TolE R 4m g oncedaily(nodoseadjustm ents 1337eligible/1077enrolled Agerange20-93 2002 allowed) M eanage60yrs 82% fem ale Abram s,2001 Tol2m g twicedailywith optionalreductionto screenedN R /895eligible m eanage59. O veractive bladdersyndrom e observationalstudies:A dverse events W ith drawals due A uth or, to adverse Y ear H ow adverse effects assessed A dverse events reported events Abram s Spontaneouslyreportedadverseevents,withdrawals,and 77% reportedanadverseevent. Adverseevents D rym outh 289(41%)(27% m ild,3% severe) classifiedasm ild,m oderate,severe. SevereAdverse U TI 10% eventswereassessedforrelationship toTol. K reder Spontaneouslyreportedadverseevents,withdrawals,and D rym outh 139(12. Severeadverse U R I 43(4%) reason: eventswereassessedforrelationship toTol. Blood 4seriousadverseeventsconsideredpossiblyrelatedtoTolE R : drym outh 19 chem istry/hem atology. Abram s,2001 spontaneouslyreportedAE ,withdrawalsanddosage 41% drym outh (27% m ild,10% m oderateand35severe)O ther105patients reductionsandat6m onth assessm entvisit. AE were AE :autonom ic nervoussystem disorders,generalbody (15%) classifiedasm ild(easilytolerated),m oderate(sufficient disorders,gastrointestinaldisordersandurinarydisorders. O veractive bladdersyndrom e observationalstudies:A dverse events A uth or, Y ear Setting Study Design Eligibility criteria Exclusioncriteria Takei, ex tensionof openlabel, 2005 Hom m a,2003,a uncontrolled,12 com parative m onths controlledR CT O xybutynin (O xy) G leason M ulticenter O penlabel12week M enandwom enwith U ncontrolledm edicalcondition,postvoidresidual 1999 U SA study idiopathic urgeincontinenceorvolum e>100m lorsignificantberuriaorpyuria. Salvatore, K ingsCollege openlabel,random wom enwith videourodynam ic N R 2004 HospitalL ondon, allocationtostarting diagnosisof D O orlow U K dose(notdescribed), bladdercom pliance openended continuation,follow-up after2y O xybutynin (O xy)vs. Tolterodine (Tol) L awrence Pharm acyBenefit Pharm acyClaim s N ew prescriptionforTolor Term inatedcoveragewith plan,receivedm orethan 2000 M anagem ent D ataforApril- O x y 30daysupply,incom pletedata D atabase D ecem ber1998 U SA Tol= Tolterodine,O xy= O xybutynin,IR = Immediaterelease,ER = Extendedrelease,R C T = R andom C ontrolledTrial,U TI= U rinarytractinfection Overactive bladder 186 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 8. O veractive bladdersyndrom e observationalstudies:A dverse events N um berscreened/ A ge A uth or, eligible/ G ender Y ear Interventions enrolled Eth nicity Takei, Tol4m g oncedaily 188outof 293continued m eanage63. Thesedosesweretobeself adjusted 96enrolled allfem ale,noethnicityreported bythepatientstoalevelwheresideeffects wereconsideredacceptable. Tolterodine (Tol) L awrence TolorO x y(IR ) 1531eligible/1020 M edianageTol73(range18-93), 2000 analyz ed O x y70(range18-95) % fem ale:Tol68%,O x y97% Tol= Tolterodine,O xy= O xybutynin,IR = Immediaterelease,ER = Extendedrelease,R C T = R andom C ontrolledTrial,U TI= U rinarytractinfection Overactive bladder 187 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 8. O veractive bladdersyndrom e observationalstudies:A dverse events W ith drawals due A uth or, to adverse Y ear H ow adverse effects assessed A dverse events reported events Takei, safetywasassessedat4,12,24,36and52weeksof the totalincidenceof drym outh 33. Clinicallab assessm ent AE (serum chem ,hem atologyandurinalysis)at12,24,and 52weeks. E CG atbaseline,and12and52weeksorupon withdrawal O xybutynin (O xy) G leason R eportsof adverseeventsweresolicitedatvisitsatweeks D rym outh 59% (36% m ild,23% m oderatetosevere) 20(8%)M ost 1999 1,4,8and12. N otclearif treatm entcitedAE questionnairewasadm inisteredpriortotreatm ent. Tolterodine (Tol) L awrence D eterm ineddiscontinuationof m edicationbygap inrefill Continuing therapyfor6m onths: 2000 data,assessedtim etodiscontinuation. PatientsdiscontinuedO x ysignificantlyearlier(m ean45days) thanTol(m ean59days)(p<0. N everrefilling prescription: O x y68% Tol55% Tol= Tolterodine,O xy= O xybutynin,IR = Immediaterelease,ER = Extendedrelease,R C T = R andom C ontrolledTrial,U TI= U rinarytractinfection Overactive bladder 188 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 8. O veractive bladdersyndrom e observationalstudies:A dverse events A uth or, Y ear C om m ents Takei, 2005 O xybutynin (O xy) G leason 1999 Salvatore, 68. Tolterodine (Tol) L awrence 2000 Tol= Tolterodine,O xy= O xybutynin,IR = Immediaterelease,ER = Extendedrelease,R C T = R andom C ontrolledTrial,U TI= U rinarytractinfection Overactive bladder 189 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 8. O veractive bladdersyndrom e observationalstudies:A dverse events A uth or, Y ear Setting Study Design Eligibility criteria Exclusioncriteria Solifenacin (Sol) Haab, ex tensionof openlabel, inadditiontocriteriafor clinicallysignificantoutflow obstruction,postvoid 2005 Cardoz o,2004a uncontrolled,40 originalstudy:inform ed residualurine≥ 200m L ,persistentorrecurrenturinary placebocontrolled weeks consentandcom pletionof tractinfection,bladderstones,chronic interstitial trial treatm entintheprevious cystitis,previouspelvic radiationorpreviousor double-blindstudieswithin hem atologyandurinalysis,3-daydiary,andQ oL 50%)of theepisodesof drym outh,constipationandblurred questionnaire. Darifenacin (Dar) Haab, safetywasassessedat0and2weeksandthen treatm entrelatedAE s:total= 343(47. O veractive bladdersyndrom e observationalstudies:A dverse events A uth or, Y ear C om m ents Solifenacin (Sol) Haab, 81% of enrolled 2005 patients com pleted40 weeksof open labeltreatm ent Darifenacin (Dar) Haab, 2006 Tol= Tolterodine,O xy= O xybutynin,IR = Immediaterelease,ER = Extendedrelease,R C T = R andom C ontrolledTrial,U TI= U rinarytractinfection Overactive bladder 193 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 9. Q uality assessm entofobservationalstudy A scertainm ent N on-biased and O utcom es pre- tech niques adequate Statisticalanalysis of N on-biased L ow overallloss to specified and adequately ascertainm ent potential A uth or,year selection? H aab, 2006 yes yes yes yes yes yes Overactive bladder 194 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 9. Q uality assessm entofobservationalstudy A dequate duration A dequate sam ple O verallquality offollow-up? Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy)vs. Tolterodine (Tol) L eung Tol2m g twicedaily 106enrolled 2002 O x y 5m g twicedaily Hong K ong L ee Tol2m g twicedaily 228enrolled(Tol112,O x y 116) 2002 O x y 5m g twicedaily South K orea M alone-L ee Tol2m g twicedaily 482screened 2000 O x y 5m g twicedaily x 8weeks 379random iz ed U K andIreland D osereductionallowedinO x y group 378analy z ed(1receivednodrugs) Tol190,O x y 188 *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 196 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy)vs. Tolterodine (Tol) L eung X erostom iaQ uestionnaireat4and10weeks,independentreporting of othersideeffects. Statesthat F air 2002 Significantdeteriorationonallm easuresof dry nessex ceptdenturefit,forboth drugs. L ee Spontaneously reportedadverseeventswerereportedandratedasseriousornonseriousand O verall29(13%) F air 2002 according tointensity ,andrelationship tostudy drug. Tol11(6dry m outh, South K orea 227patientsassessed 55%) Tol:62patientsreported101adverseevents O x y 18(16dry m outh, O x y :94patientsreported154adverseevents(p = 0. N odescriptionof scalefor 22(12%)Tol,28(15%)D osereductions U K andIreland assessm entof intensity orseriousness. O x y requestedby 6% Tol, Atleastoneadverseevent:69% Tol,81% O x y D uetodry m outh:3% 25% O x y (p<0. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 197 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Abram s Tol2m g twicedaily 293enrolled 1998 O x y 5m g threetim esdaily (118Tol,118O x y ,57Pl) U K ,Irelandand Placebothreetim esdaily Sweden Subjects> /= 65y rsinU K andIrelandcouldstart thedoseof O x y at2. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 198 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Abram s Alladverseeventswererecordedandcategoriz edby intensity (m ild,m oderate,severe). The O verall:10% F air 1998 likelihoodof relationship tostudy drug wasevaluatedforseriousadverseeventsandpatient Tol8%,O x y 17%,Pl D osereductions U K ,Irelandand withdrawnif deem edm edically necessary orpatientwishedwithdrawal. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 199 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy)vs F lavoxate (F la) M ilani F la400m g orO x y 5m g threetim esdaily ,then 50enrolled 1993 crossover Italy Zeegers R andom iz edtoeither: Statedtobeconsecutivepatients 1987 F la200m g orE m p 200m g orPlthreetim esdaily x 60enrolled(30inF la/E m p/Pl,30in N etherlands,Austria 3weekseach O x y /E m p/Pl) or O x y 5m g orE m p 200m g orPlthreetim esdaily x 3 weekseach O rderof drugsalsorandom iz ed. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 200 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy)vs F lavoxate (F la) M ilani Adverseeventswereelicitedat4wks,andratedasseriousornonseriousandaccording to 5(10%)notclearwhen Poor 1993 intensity. Italy By ITT:F la11/50(22%),O x y 42/50(84%),plus5patientswithdrawnduetoadverseevents. D ry m outh:F la2%,O x y 78% Abdom inalorstom ach pain:F la24%%,O x y 36% Zeegers Com binedinscore O verall20% Poor 1987 15% Pl,26% E m p,8% F la,17% O x y 2Pl,8E m p,0F la,2 N etherlands,Austria O x y *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 201 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Im m ediate R elease vs Im m ediate R elease (IR vs IR ) Trospium ch loride IR vs O xybutyninIR Halaska 2003 Average54weeksof treatm entwith eitherO x y 5 ScreenedN R m g twicedaily orTrospium 20m g twicedaily. E ligible358 M ultipleappointm entsforevaluationthrough the E nrolled 357 courseof thetrial M aderspacher 1995 Initialoneweekwashoutfollowedby 2weeksof ScreenedN R treatm entwith eitherO x y 5m g threetim esdaily or E ligibleN R Trospium 20m g twicedaily. Tom aintaindouble E nrolled95 blindconditionstheTrospium group receiveda 52Trospium ,43O x y. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 202 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Im m ediate R elease vs Im m ediate R elease (IR vs IR ) Trospium ch loride IR vs O xybutyninIR Halaska 2003 Alladverseevents:Trospium 68%,O x y 77% 91withdrew:Trospium F air. Alladverseeventspossibly /probably connectedwith treatm ent:Trospium 48%,O x y 59%, 67(25%),O x y 24 L ong F U. Twenty "wellbeing"item saskeddirectly by investigatorbeforeandatendof trial. Trospium 3 (6%) Allpatientsspinalcord Severity grading assessedusing 4pointscale. O verallrateof sideeffectsreportedas"alm ostcom parable"inboth groups. Ty peandlevelof injury D ry m outh:Trospium 54%,O x y 56% notspecified. Severedry m outh:Trospium 4%,O x y 23% Concurrentm edications notnoted. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 203 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Extended R elease vs. Im m ediate R elease (ER vs IR ) O xybutyninER v O xybutyninIR Versi O x y E R 5-20m g oncedaily orO x y IR 5-20m g/d- screened417 2000 schedulenotreported eligible/enrolled226 U SA Birns O x y E R 10m g oncedaily orO x y 5m g twicedaily 162screened 2000 130random iz ed U K Anderson E R O x y 5-30m g oncedaily orIR O x y 5m g onceto 158screened 1999 fourtim esdaily.. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 204 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Extended R elease vs. Im m ediate R elease (ER vs IR ) O xybutyninER v O xybutyninIR Versi R eportsof adverseeffectsrecordedateach ptvisit O verall:10(8%) F air 2000 D ry m outh:E R 48%,IR 59% E R :3(3%) M eandurationof U SA K aplanM eieranaly sism oderateorseveredry m outh reportsindicatesasignificantdifference(p IR :7(6%) treatm ent/follow-up not = 0. Birns Assessedduring visitsevery twoweeks 1(consideredunlikely F air 2000 78ptsreportedadverseevents(60%) duetostudy drug) M ix edty pesof U K (E R 55%,IR 67%) incontinence D ry m outh:E R 23%,IR 17% Study includedarun-in D iz z inessE R 2%,IR 9% phasetoestablish Visionabnorm ality E R 7%,IR 5% tolerability ,patientswith Cough E R 3%,IR 5% adverseeventsex cluded HeadacheE R 0,IR 5% during run-in Anderson Spontaneously reportedandanti-cholinergic effectsassessedateach study visit 2(4%)ineach group F air 1999 D ry m outh: duetoanticholinergic Previously allptshad U SA E R 68%,IR 87% (p = 0. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 205 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) N illsson O x y E R 10m g oncedaily 17enrolled 1997 O x y 5m g twicedaily F inland crossover R adom ski 2004 O x y IR twicedaily atdoseatdiscretionof #screenednotreported. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 206 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents N illsson Patientsreportedonaquestionnairethroughoutstudy ,classifiedasm ild,m oderate,severe N onereported Poor 1997 14/16onE R ,5/17onIR reportedatleastoneadverseevent Very high num bersof F inland D ry m outh:E R 69%,IR 82% subjectsreporting HeadacheE R 44%,41% adverseevents D y spepsiaE R 31%,IR 12% fatigueE R 13%,24% Blurredvision25%,IR 12% % Severe:E R 17%,IR 14% reportedthatthesewereN S,butunclearwhatdatabeing com pared. R adom ski 2004 Adverseeventscollectedduring scheduledvisitsandenteredindiary. O x y IR first,ex posedto BackPain:E R 8%,IR 8% E ventsreported: longerdurationof E R. Pain-unspecified:E R 42%,IR 17% severestom ach pain, Study openlabel Increasedsalivation:E R 17%,IR 8% m ildperipheraledem a, Asthenia:E R 8%,IR 17% severevisiondistortion Peripheraledem a:E R 8%,IR 8% Barkin O x y E R vsO x y IR (%) O x y IR :12(20%) 2004 D ry m outh:overall:68% vs72%;m oderateorsevere:38% vs45% O x y E R :11(17%) Phary ngitis(dry throat):35% vs40% D ry skin:17% vs12% D iarrhea:14% vs5% Headache:12% vs22% U riniary tractinfection:12% vs18% D iz z iness:11% vs18% D y spepsia:11% vs17% R hinitis:11% vs15% Abdom inalpain:9% vs10% Asthenia:18% vs15% Constipation:8% vs10% Tasteperversion:8% vs12% Cough increased:6% vs13% D y sphagia:6% vs13% D ry ey es:3% vs15% N ausea:5% vs17% *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 207 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Extended R elease vs. Im m ediate R elease (ER vs IR ) Tolterodine ER vs Tolterodine IR VanK errebroeck TolE R 4m g oncedaily orTolIR 2m g orPlacebo 1529enrolled 2001 twicedaily TolE R :507 M ultinational TolIR :514 placebo:508 Swift TolE R 4m g (n= 417)oncedaily vs. TolE R :417 R e-analy sisof datafor TolIR :408 wom enonly inVan placebo:410 K errebroeck2001study (above) Extended R elease vs. Im m ediate R elease (ER vs IR ) O xybutyninER v Tolterodine IR Appell E R O x y 10m g oncedaily 378enrolled(O x y E R 185,Tol193) 2001 Tol2m g twicedaily 332com pleted(O x y E R 160,Tol U SA 172) *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 208 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Extended R elease vs. Im m ediate R elease (ER vs IR ) Tolterodine ER vs Tolterodine IR VanK errebroeck Spontaneously reported eventswerecategoriz edandcausationassigned O verall88(5. D ry m outh classifiedas R e-analy sisof datafor D ry m outh:105/415(25. Im m ediate R elease (ER vs IR ) O xybutyninER v Tolterodine IR Appell Patientreported O verall7. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 209 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Extended R elease vs. E nrolled= 608 2003 O x y IR 3m g threetim esdaily x 12wks TolE R = 240 O x y IR = 246 Pla= 122 Extended R elease vs. Tolterodine ER Chapple F lex ibledosing,W eeks0-4: F ullanaly sisset(F AS):1177 2005 Sol5m g qd STAR trial TolE R 4m g qd Stable-dosephase,W eeks5-12: Sol5m g qd(Sol5) Sol10m g qd (Sol10) TolE R 4m g qd(Tol4) *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 210 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10.

Coexistence of BCL1/CCND1 and CMYC aberrations in blastoid mantle cell lymphoma: a rare finding although some report that simple identification of MYC rearrange- associated with very poor outcome 100 mg penegra. B-cell lymphomas with MYC/8q24 these cases remains of great interest (Table 4) penegra 50 mg. At the present time 50mg penegra, rearrangements and [email protected]/t(14;18)(q32;q21): an aggressive dis- the most definite and objective finding that many believe should ease with heterogeneous histology penegra 100 mg, germinal center B-cell immunophe- affect therapeutic strategies remains the identification of the very notype and poor outcome penegra 50mg. Double-hit lymphoma with a netic studies penegra 100mg, but otherwise requires cytogenetic FISH studies 100mg penegra, feature of follicular lymphoma concurrent with clonally related B which should at a minimum be performed in the subset of large lymphoblastic leukemia: a preference of transformation for the bone B-cell lymphomas with an enhanced chance of having MYC and marrow 50 mg penegra. B-cell lymphomas with cases is also of interest largely for prognostic purposes , but it is not a concurrent IGH-BCL2 and MYC rearrangements are aggressive neo- surrogate for finding DHL/THL . Future studies should help to plasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Clinicopathological sive behavior, further our understanding of their biologic correlates, features of lymphoma/leukemia patients carrying both BCL2 and MYC and better define the role of the BCLU category in the 2008 WHO translocations. Lymphomas with tantly, whether their recognition can lead to improved patient concurrent BCL2 and MYC translocations: the critical factors associ- outcomes remains our most critical goal. High-grade B cell lymphoma, unclassifiable, with blastoid features: an unusual morphologi- Disclosures cal subgroup associated frequently with BCL2 and/or MYC gene Conflict-of-interest disclosure: The author declares no competing rearrangements and a poor prognosis. Valera A, Lopez-Guillermo A, Cardesa-Salzmann T, et al. MYC protein Correspondence expression and genetic alterations have prognostic impact in patients Steven H. Swerdlow, MD, Professor of Pathology, Director, with diffuse large B-cell lymphoma treated with immunochemotherapy. Division of Hematopathology, University of Pittsburgh School of Haematologica. Medicine, UPMC Presbyterian, 200 Lothrop St, G-335, Pittsburgh, 17. MYC/BCL2 protein coexpres- sion contributes to the inferior survival of activated B-cell subtype of PA 15213; Phone: (412)647-5191; Fax: (412)647-4008; e-mail: diffuse large B-cell lymphoma and demonstrates high-risk gene expres- [email protected] B-cell lymphoma, unclassifiable, MYC and BCL2 in diffuse large B-cell lymphoma treated with with features intermediate between diffuse large B-cell lymphoma and rituximab plus cyclophosphamide, doxorubicin, vincristine, and predni- Burkitt lymphoma. Immunohistochemical double-hit 98 American Society of Hematology score is a strong predictor of outcome in patients with diffuse large MYC- or double-hit MYC/BCL2 translocations. B-cell lymphoma treated with rituximab plus cyclophosphamide, doxo- 2014;92(1):42-48. Burgesser MV, Gualco G, Diller A, Natkunam Y, Bacchi CE. MYC gene rearrange- lymphoma, unclassifiable, with features intermediate between diffuse ments are associated with a poor prognosis in diffuse large B-cell large B-cell and Burkitt lymphomas: a study of 44 patients from lymphoma patients treated with R-CHOP chemotherapy. Copie-Bergman C, Cuillere-Dartigues P, Baia M, et al. MYC transloca- spectrum of diffuse large B-cell lymphoma in the world health tion partner gene is a predictive factor of survival in diffuse large B-cell organization classification. Expression and/or “High-grade” Morphology in Non-Burkitt, Diffuse 22. Rearrangement of MYC is Aggressive B-cell Lymphomas: A SWOG S9704 Correlative Study. B-cell lymphoma of germinal center origin with BCL2 translocations 42. Chromosomal alterations detected by have poor outcome, irrespective of MYC status: a report from an comparative genomic hybridization in subgroups of gene expression- International DLBCL rituximab-CHOP Consortium Program Study. Recurrent mutation of the tures intermediate between diffuse large B-cell lymphoma and Burkitt ID3 gene in Burkitt lymphoma identified by integrated genome, exome lymphoma. Does the proliferation fraction MYC, BCL2, and BCL6 rearrangements in patients with diffuse large help identify mature B cell lymphomas with double- and triple-hit B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincris- translocations? The gray zone between Burkitt’s lymphoma and prognostic markers in diffuse large B-cell lymphoma: validation of diffuse large B-cell lymphoma from a genetics perspective. J Clin tissue microarray as a prerequisite for broad clinical applications–a Oncol. Landsburg DJ, Nasta SD, Svoboda J, Morrissette JJ, Schuster SJ. MYC and BCL2 clinicopathological characteristics and is highly associated with overall protein expression predicts survival in patients with diffuse large B-cell survival in B cell lymphoma patients. Gebauer N, Bernard V, Gebauer W, Thorns C, Feller AC, Merz H. The unique immunophe- mutations are frequent events in double-hit B-cell lymphomas with notype of double-hit lymphomas. Prognostic factors for diffuse large B-cell lymphomas show a common immunophenotype by flow cytometry that lymphoma in the R(X)CHOP era. Green TM, Nielsen O, de Stricker K, Xu-Monette ZY, Young KH, lymphoma - a single centre’s experience. High levels of nuclear MYC protein predict the presence of 63-71. Expression profile of MYC protein in quently extranodal lymphomas distinct from BCL2 double-hit B-cell lymphoma subtypes. Li S, Lin P, Young KH, Kanagal-Shamanna R, Yin CC, Medeiros LJ. Growing importance of MYC/BCL2 immunohisto- prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and chemistry in diffuse large B-cell lymphomas. R-CHOP with iodine-131 therapy in patients with Myc-positive and double-hit non-Hodgkin tositumomab consolidation for advanced stage diffuse large B-cell lymphoma is associated with prolonged progression-free survival. Concurrent expression of Anderson Cancer Center clinical experience. MYC/BCL2 protein in newly diagnosed DLBCL is not associated with 37. MYC translocation partner an inferior survival after EPOCH-R therapy [abstract]. Blood (ASH gene determines survival of patients with large B-cell lymphoma with Annual Meeting Abstracts). In LPL, mutations of the adaptor protein MYD88 (L265P) in the Toll-like receptor pathway have been recognized recently as being a hallmark of the disease and indicate a dependence of the tumor on this pathway. In CLL, functional studies have implicated BCR activation in the tissue microenvironment as a pivotal pathway in the pathogenesis. Bruton’s tyrosine kinase (BTK) and the PI3K isoform are essential for BCR signaling and also seem to be required for signal transduction in LPL cells, even if the role of BCR signaling in this disease remains less well defined. Ibrutinib, a covalent inhibitor of BTK approved by the Food and Drug Administration as a second-line treatment for CLL, and idelalisib, a selective inhibitor of PI3K , achieve excellent clinical responses in both diseases irrespective of classic markers indicating high-risk disease. Several additional inhibitors targeting BTK and PI3K , as well as the spleen tyrosine kinase, have entered clinical trials. This review discusses the biologic basis for kinase inhibitors as targeted therapy for CLL and LPL and summarizes the clinical experience with these agents. Median progression-free ● Gain an overview of the role of BCR signaling in the survival (PFS) after first-line chemoimmunotherapy can be 2 pathogenesis and treatment of CLL and LPL years in patients with adverse cytogenetic markers, in particular in ● Be able to identify kinases that can be targeted therapeutically those with deletion of chromosome 17p (del17p) or in those in CLL and LPL carrying somatic mutations in TP53, NOTCH1,orSF3B1. For example, del17p is present in ● Be able to discuss the pros and cons of targeted treatment with 10% of patients at the time of first-line therapy, but in up to 1/3 of kinase inhibitors patients with relapsed disease. Identifying treatment options for patients with relapsed/refractory disease and for those with del17p Introduction has been and remains a major need. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature monoclonal B cells in the blood, bone Lymphoplasmacytic lymphoma (LPL) is a malignancy of mature B marrow (BM), lymph nodes, and spleen. The diagnosis of CLL cells residing in BM and lymph nodes that secrete immunoglobulin, mostly of the IgM type. Other common disease biological characteristics of CLL, but is distinguished by having manifestations include cytopenias and constitutional symptoms. In 5000 tumor cells/ L of blood in the presence of pathologic many regards, LPL is an intermediary between CLL and multiple lymphadenopathy, splenomegaly, or BM disease. The standard of myeloma and treatment often consists of drugs used in either of the care for CLL is watchful waiting of asymptomatic patients; other diseases, including nucleoside analogs, anti-CD20 mAb, and proteasome inhibitors. Expression of a functional BCR is required for the neous natural history of the disease. Although the median survival survival of all B cells past the earliest development stages. PI3K , of all patients in a large referral center was 11 years,3 it can be much spleen tyrosine kinases (SYK), and Bruton’s tyrosine kinase (BTK) shorter for patients in high-risk disease groups; on the other hand, are essential for BCR signal transduction, and their knockout in patients with indolent CLL can have a life expectancy comparable mouse models leads to impaired antigen-driven maturation and to age-matched controls. Over the years, an increasing number of B-cell malignancies were recognized to depend on BCR signaling for The combination of chemotherapy with anti-CD20 monoclonal proliferation and/or survival. The BCR consists of a surface transmembrane Ig receptor associated with the Ig alpha (Ig , CD79A) and Ig beta (Ig , CD79B) chains. BCR signaling in response to antigen binding induces LYN- and SYK-dependent phosphorylation of tyrosine motifs (phosphorylation denoted by “P” in yellow circle) on CD79A and CD79B. Several protein tyrosine kinases (red symbols) and the lipid kinase PI3K (green symbol) transmit survival and proliferation signals and regulate cell maturation and migration. Small-molecule inhibitors of select kinases in the BCR pathway that have demonstrated significant clinical activitgips2 indAR ed. Here, I briefly BCR signaling in CLL review the BCR signaling pathway and its role in CLL, summarize Comparative analysis of CLL cells isolated from the blood and the clinical experience with these targeted agents, and provide an lymph nodes provided direct evidence for ongoing antigen- outlook on their possible future role in the therapeutic approach to dependent signaling through the BCR in vivo and suggested that CLL and LPL. This conclusion is also supported by the BCR and Toll-like receptor (TLR) signaling in CLL observations of a reversible down-modulation of surface IgM and LPL expression on CLL cells and the anergic state of some CLL cells. Consis- immunoglobulin heavy chain variable (IGHV) region genes, which 13,14 tent with these in vitro data, the degree of BCR activation in CLL encode the antigen-binding domains of the BCR. Naive B cells cells in vivo correlates with increased tumor proliferation and acquire these IGHV mutations after antigen biding as part of a 20 shorter time to progression. The presence or absence of somatic mutations in the clonal The transduction of signals from the BCR involves a network of IGHV gene distinguishes 2 major CLL subtypes; IGHV mutated kinases and adaptor molecules that connect antigen stimulation to (M-CLL) and IGHV unmutated (U-CLL, which has 98% se- 29 1 intracellular responses (Figure 1). In vivo, additional elements quence homology to the germline IGHV). M-CLL cells appear to present in the tissue microenvironment cooperate with the BCR and be “anergic,” that is, in a state of hyporesponsiveness to BCR may influence the cellular response. The term “microenvironment” activation that can result from frequent BCR stimulation. Extensive in vitro studies identified many pathways and is a more rapidly progressive disease with inferior survival com- factors that enhance CLL cell survival and promote limited prolifera- pared with M-CLL indicates that the degree of BCR activation tion, including TLRs, cytokines, chemokines, CD40, B-cell- and/or the type of antigen may be important. LPL cells derive from a activating factor of tumor necrosis factor family (BAFF), integrins, postgerminal center B cell and typically express mutated IGHV and components of the extracellular matrix. Select inhibitors of kinases in the BCR pathway in clinical trials Target Drug, company Notes SYK Fostamatinib (R788),83 Rigel Oral prodrug of R406, an inhibitor of SYK and several other kinases. Common adverse effects: fatigue, diarrhea, hypertension, cytopenias. CLL: ORR 55% GS-9973,90,91 Gilead Highly selective for SYK; common AEs in phase 2: fatigue, diarrhea, transaminase elevations. BTK Ibrutinib (PCI-32765),53,64 Pharmacyclics First FDA-approved BTK inhibitor for second-line treatment of CLL and MCL. Covalent binding to Cys481 leads to irreversible inhibition. ORR 71% in relapsed/refractory CLL patients, additional 18% with PRL. CC-292 (AVL-292),103 Celgene Covalent binding to Cys481 leads to irreversible inhibition. ONO-4059,104 Ono Pharma Covalent binding to Cys481 leads to irreversible inhibition. Orally once a day, preliminary ORR in relapsed/refractory CLL comparable to ibrutinib. ACP-196, Acerta Pharma Covalent binding to Cys481 leads to irreversible inhibition. PI3K Idelalisib (GS-1101, CAL-101),52,63 Gilead Selective inhibitor of PI3K. Single-agent ORR in relapsed/refractory CLL patients, 39% plus 33% PRL; in SLL, 61%; in LPL, 80%. In combination with rituximab, ORR 81% and PFS at 6 months 93%. IPI-145,105 Infinity Selective inhibitor of PI3K and PI3K. To what degree such tumor-extrinsic effects contrib- to estimate to what degree any single factor or pathway may be ute to efficacy or to adverse events are becoming an important area necessary or sufficient for CLL pathogenesis. Davide 2 months before gradually resolving, but there is considerable Rossi in this publication. A subset of patients may show persistent lymphocytosis for many months to years on monotherapy and this does not appear to be a harbinger of treatment failure. Most advanced in their clinical development are inhibi- increase in ALC was also recorded in patients with indolent tors of BTK, PI3K, and SYK (Table 1). Many of these inhibitors non-Hodgkin’s lymphoma (NHL) treated with idelalisib, mostly in were initially developed for use in inflammatory diseases. Preclini- SLL (64% of patients), and less commonly in follicular lymphoma cal in vitro and in vivo studies identified these kinases as promising (18%). Treatment-induced lymphocytosis was not seen in patients with LPL. Characteristic clinical observations in CLL patients treated Ibrutinib with kinase inhibitors Ibrutinib (formerly PCI-32765) is an orally bioavailable BTK Treatment-induced lymphocytosis inhibitor that irreversibly inactivates the kinase by covalently binding to a cysteine residue (Cys481) near the active site. Loss-of-function mutations in BTK block B-cell maturation at the Due to redistribution of cells out of the lymph node (tissues) into the pre-B-cell stage and cause X-linked agammaglobulinemia (also blood. Although BTK is Mostly well tolerated oral agents and limited myelosuppression. Rate of infection higher in relapsed/refractory patients, appears to be due to underlying disease.

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