Acute leukemia orientation tube.
\r\n\tThe applications are those related to intelligent monitoring activities such as the quality assessment of the environmental matrices through the use of innovative approaches, case studies, best practices with bottom-up approaches, machine learning techniques, systems development (for example algorithms, sensors, etc.) to predict alterations of environmental matrices. The goal is also to be able to protect natural resources by making their use increasingly sustainable.
\r\n\r\n\tContributions related to the development of prototypes and software with an open-source component are very welcome.
\r\n\r\n\tThis book is intended to provide the reader with a comprehensive overview of the current state of the art in the field of Ambient Intelligence. A format rich in figures, tables, diagrams, and graphical abstracts is strongly encouraged.
",isbn:"978-1-83969-069-3",printIsbn:"978-1-83969-068-6",pdfIsbn:"978-1-83969-070-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"3fbf8f0bcc5cdff72aaf0949d7cbc12e",bookSignature:"Dr. Carmine Massarelli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10391.jpg",keywords:"Embedded Systems, Technologies, Sensors, Remote Sensing, Smart Homes, Smart Cities, Integrated Monitoring Techniques, Agroecosystem, Smart Public Spaces, Computer Vision, Image Processing, Open-Source",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 12th 2020",dateEndSecondStepPublish:"November 9th 2020",dateEndThirdStepPublish:"January 8th 2021",dateEndFourthStepPublish:"March 29th 2021",dateEndFifthStepPublish:"May 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Environmental technologist expert in the development of Smart Technologies for water management and environmental monitoring, characterization, and monitoring of contaminated and degraded sites, integration of spatial data such as standard methodologies, interoperability, spectral data infrastructures.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"315689",title:"Dr.",name:"Carmine",middleName:null,surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli",profilePictureURL:"https://mts.intechopen.com/storage/users/315689/images/system/315689.jpg",biography:"Main activities:\n-development of Smart Technologies for water management and environmental monitoring;\n-characterization and monitoring of contaminated and degraded sites;\n-implementation of early warning systems and impact assessment systems also from multitemporal monitoring;\n-integration of spatial data: methodologies, standards, interoperability, spatial data infrastructures;\n-use of open source IT systems for the processing, analysis, and integration of remote sensing data with airborne and satellite sensors for thematic purposes such as characterization, control, and analysis of the territory in support of environmental policies relating to contaminated sites;\n-evaluation of the contamination of environmental matrices with specific tests and chemical analyses;\n-installation of airborne sensors and definition of flight parameters for Earth observation, CASI-1500 hyperspectral and TABI-320 thermal sensors;\n-acquisition of spectral signatures of objects through Fieldspec portable spectroradiometer and creation of databases in SQL language;\n-use of tools such as Ground Penetrating Radar for the advanced investigation of the subsoil with law enforcement agencies.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"45032",title:"Congenital Aortic Stenosis in Children",doi:"10.5772/54806",slug:"congenital-aortic-stenosis-in-children",body:'Congenital aortic stenosis (AS) is caused by abnormal morphological development of the aortic valve. [1, 2] Valvular abnormalities may be accompanied by supra- or sub-valvular stenosis. The embryogenic process that forms aortic valves begins approximately 31–32 days of gestation. Cavity formation in the basal portion of the truncus arteriosus is a key process in the development of the leaflet and sinus of Valsalva, which are important components of the aortic valve. Therefore, incomplete formation of the cavity causes various morphological abnormalities of the aortic valve, including bicuspid valve with or without commissural fusion, tricuspid valve with commissural fusion, monocuspid valve, and myxomatoid leaflet valve (dysplastic valve). The most frequent type of congenital AS is a bicuspid aortic valve, [3] accounting for approximately 90% of AS cases.
Although the morphological features of the aortic valve are closely associated with the AS severity, the pathophysiology and resultant clinical manifestation of AS are fundamentally determined by the severity of the stenosis (effective orifice area). In this sense, congenital AS in children is classified into 2 major types: severe AS that becomes symptomatic and necessitates interventions during the neonatal period or early infancy and a milder form of AS with signs and/or symptoms that develop later in childhood.
In this chapter, we will outline the pathophysiology, clinical characteristics, and management of congenital AS observed in children (from fetus to adolescence) for each type of AS mentioned above. We will also briefly discuss the differences in ventricular adaptation, which are strongly linked to the clinical manifestation of AS, to the increased afterload caused by AS between children and adults.
The mechanism underlying the increase in severity of AS in children is similar to that seen in adults. The orifice size can decrease because of increased thickness and rigidity of the valve leaflets, independent of the morphological anomalies of the aortic valve, although native abnormal morphological features have greater impact on the progression of stenosis in children than in adults. The mechanisms underlying the exacerbation of stenosis also need to be determined. Valvular fibrosis, lipid accumulation, [4,5] inflammatory changes, [6] and acquired fibrotic fusion of commissures, which increase cusp thickness/stiffness, [5,7] could also be associated with the development of valvular stenosis, even in childhood AS. Metabolic syndrome is an emerging issue even in children and may be associated with these exacerbating mechanisms, [8] resulting in calcification, which reduces the possibility of valvular plastic surgery. In addition, bicuspid aortic valves possibly develop aortic calcification earlier than tricuspid aortic valves. [9,10] In this section, we will discuss the hemodynamic aspects of aortic stenosis in fetuses, neonates, and children.
The fundamental underlying pathophysiology of AS involves an increase in afterload to the left ventricle (LV). The mechanism by which the LV copes with this increase in afterload is an increase of myocardial mass (hypertrophy) to generate a higher force to confront the increased afterload. If the aortic valve stenosis is too severe to allow the LV to become adaptive, LV contractility is depressed and the LV becomes markedly dilated. In this critical condition, the fetal circulation can maintain, to some extent, the systemic output using the right ventricle (RV), because there are interatrial communication (foramen ovale) and ductus arteriosus in the fetal ciculation. The ascending aortic flow and sometimes even the coronary arterial flow rely on retrograde blood flow from the ductus arteriosus. However, an LV exposed to massive afterload with relatively reduced coronary blood flow supply is at high risk of progressive ventricular failure, and is associated with an increased risk of sudden cardiac death. If the patient can survive this condition for a certain period, a marked increase in LV end-diastolic pressure (EDP) hinders the blood flow from the left atrium entering into the LV, leading to a gradual reduction of LV cavity volume. This process is postulated as one mechanism of evolving hypoplastic left heart syndrome (HLHS). Degeneration of the endocardium may accompany this process, representing a condition known as endocardial fibroelastosis. [11]
In other cases, an increase in LV afterload may allow the LV to exert its adaptive mechanism of hypertrophy, which also inhibits LV inflow due to increased LV stiffness and resultant EDP rise. [12] This is another form of evolving HLHS physiology (Figure 1A).
Of course, the above pathophysiological mechanisms should be understood as a continuum, [13, 14] and some patients may be born with a markedly dilated LV and depressed contractility, known as critical AS (Figure 1B). Such patients suffer from severe circulatory failure and pulmonary congestion, which is often life threatening and requires emergency intervention, either by catheters or surgery, as discussed below.
A schema of hypoplastic left heart syndrome (A) and that of critical aortic stenosis (B).
When the severity of AS is mild such that the LV can cope with the increased afterload, patients present with clinical symptoms during late infancy or school age. Although their LV exhibits hypertrophy, AS may be mild enough in patients such that they will be asymptomatic. There are also a group of patients who had no signs and symptoms other than heart murmur. In general, the aortic valves of this group of patients can supply the systemic blood flow during the neonatal period. This is verified by the fact that the ductus flow during the neonatal period shows left-to-right shunting. The timing of the onset of AS symptoms in this group is dependent on the severity of stenosis that is associated with the LV’s capability to exert its adaptive mechanism to increased afterload. Of note, unlike adult onset AS, the severity of AS in children is also influenced by somatic growth, which induces a relative increase in the blood flow through the aortic valve and thereby causes augmentation of LV afterload. In addition, it was reported that an increased pressure gradient across the aortic valve is related to earlier progression of stenosis and a higher frequency of complicating aortic regurgitation. [15, 16] Therefore, the pathophysiology of AS in this age group may be dependent on preload change due to aortic regurgitation as well as the increasing afterload. In the clinical setting, it is important to follow-up with these patients periodically to detect such changes and to determine the appropriate timing and method of treatment. Therefore, we will discuss methods for monitoring the dynamic changes in AS in this particular group of patients in the following section.
Clinical symptom evaluation, physical examination, electrocardiogram (ECG), and echocardiography are essential sources for obtaining comprehensive information for appropriate management of AS in this patient group. If fainting, convulsion, or resuscitated cardiac arrest are observed, relieving AS is indicated for preventing further adverse events. [17, 18] Although angina and syncope are reported to be observed only in <10% of patients whose peak-to-peak pressure gradient is greater than 80 mmHg, chest pain is an important clinical sign indicating the need for intervention, as adverse events are likely to occur within a few years after the complaint of initial chest pain.
ECG examinations are informative if ST-segment changes are observed. Usually, severe AS shows a 0–90°QRS-axis with high voltages in the left precordial leads. However, it is important to note that the above ECG findings of LV hypertrophy do not necessarily reflect the severity of the stenosis. Wagner et al. reported that one-third of AS patients with peak-to-peak pressure gradients greater than 80 mmHg do not exhibit the above LV hypertrophic findings on ECG. [17] In contrast, the ST strain pattern in the left precordial leads is thought to be more specific to LV hypertrophy and reflects the severity of AS (Figure 2).
Electrocardiogram of severe aortic stenosis. This is an electrocardiogram (ECG) of a patient with severe aortic stenosis with an estimated pressure gradient of 140mmHg. Surprisingly, ECG shows no prominent finding of left ventricular hypertrophy other than changes in ST-T segment.
Holter ECG is also useful for predicting sudden deaths, even in asymptomatic AS patients. Wolfe et al. reported that multiform ventricular premature contraction, couplet, and ventricular tachycardia are serious arrhythmias that are associated with sudden cardiac death. [19]
Exercise testing may provide more accurate information about the risk of cardiac events than other examinations. Lewis et al. demonstrated the usefulness of exercise testing to identify subclinical ischemia in patients with severe AS. [26] Thus, exercise testing and Holter ECG may play a key role in clinician decision making for the management of AS patients.
Echocardiography is a direct method for evaluating the anatomical features and severity of AS. Valvular anatomy can be assessed for leaflet number, balance, thickening, or doming. The annulus diameter is also important, particularly when intervention is indicated. M-mode study in short-axis view provides information regarding LV pressure calculated by Glanz’s equation: LV systolic pressure=225*LVPWs/LVIDs, where LVPWs and LVIDs represent LV systolic posterior wall thickness and LV systolic diameter, respectively. [20] This equation is clinically useful, because the peak-to-peak pressure gradient can be evaluated when coupled with the arterial pressure measurement. The LV dimension and wall thickness values provide information regarding the risk of cardiac events and ischemia. In addition, combining an echocardiography study with exercise testing may be useful for predicting a higher risk of cardiac events, even in asymptomatic patients. [21] Velocity measurement by spectral pulse wave and continuous wave Doppler reflects the severity of AS if cardiac function is not impaired. The pressure gradient calculated by applying the Bernoulli equation in the outflow tract is one of the guides for determining the need for intervention, although it has some limitations. [22, 23] Spectral pulse wave Doppler could also be a powerful tool for confirming the localization of obstruction and estimating the valvular area.
The indication for the catheter examination is limited, but this modality provides accurate information regarding coronary arteries and severity of AS. Because the LV outflow tract is truncated, the severity of AS tends to be over-estimated by velocity-derived pressure gradient. In contrast, a precise PIPG as well as a peak-to-peak gradient can be evaluated by the catheter examination (Figure 3). The aortic valve area is also calculated by Gorlin’s method. [24]
Simultaneous measurements of ascending aortic pressure and left ventricular pressure by the catheter examination. Both instantaneous and peak to peak pressure gradient can be clearly monitored. A; normal, B; aortic stenosis
If the patients have an established HLHS circulation with an underdeveloped LV, all the treatment options are directed to the future completion of the Fontan circulation, a final goal for patients with single ventricular circulation. However, if the LV size and components are to be sufficient to generate systemic output when the excessive afterload due to AS is relieved, interventions for the aortic valve per se are indicated, including either catheters or surgery. [25] The most attractive merit of catheter intervention (percutaneous transluminal aortic valvuloplasty [PTAV]) is that it is less invasive. In this procedure, cardiopulmonary bypass, which is a prerequisite for surgical procedures, can be avoided. PTAV is known to accelerate annular growth even in small sized aortic valve [26] if mitral valve stenosis is not complicated [27] .In performing PTAV, the carotid artery is generally used for blood access because lower body hypoperfusion makes it difficult to achieve access from the femoral artery and has a high risk of arterial obstruction with a prolonged sheath insertion, and because the curvature of aortic arch makes it difficult to manipulate the catheter and successfully pass it through the tiny aortic orifice (Figure 4). Therefore, central nervous system damage can be a potential adverse event associated with PTAV. More importantly, PTAV is a procedure used to enlarge the aortic orifice area by tearing the weak portions of the valve, not necessarily in the anatomically proper portion (commissures). Therefore, PTAV cannot be applied to valves with pre-existing aortic regurgitation because the procedure generally worsens this condition, which could be fatal. It was reported that 15% of 113 patients younger than 60 days old who had undergone PTAV developed significant aortic regurgitation. [26] Surgical interventions in this patient group include aortic valve plasty (AVP) and aortic valve replacement (AVR) with the autologous pulmonary artery valve (Ross procedure). The advantage of open AVP is that surgeons can perform the procedure on the basis of a detailed examination of the valve anatomy, which may reduce the risk of aortic regurgitation. Bhabra et al. [28] reported that if the aortic valve is tricuspid, the rate of freedom from reintervention after open AVP was 92% and that of AVR was 100% at a 10-year follow-up. These rates for bicuspid valves were only 33% and 57%, respectively. This report emphasizes the importance of valve morphology as a determinant of outcome following AVP. The other surgical option is the Ross procedure, which is particularly useful when sub/suprastenosis coexists with valvular stenosis (Ross-Konno procedure). The survival rate for the Ross procedure was 77% and rate of freedom from reintervention was 50%, comparable to the results of the Norwood procedure. [29-31] To apply the Ross procedure, autologous graft (pulmonary valve) function is important. Concha et al. reported that the rate of freedom from autograft failure at a 5-year follow-up was 95%, demonstrating a low incidence of autograft failure. [32] However, future pulmonary insufficiency remains as a matter of concern in long-term follow-ups.
Percutaneous transluminal aortic valvuloplasty performed for a patient with critical aortic stenosis
We often encounter intermediate cases between established HLHS with underdeveloped LV and potentially normal-sized LV under excessive afterload. In such situations, accurate diagnosis about whether the LV has the potential to generate systemic output after relieving afterload is of primary importance. If the LV is judged to be incapable of generating systemic output, then the systemic circulation should rely on the RV. In such a case, the Fontan procedure becomes a goal of treatment. Multicenter studies have elucidated that the outcome of biventricular repair with a small LV is much worse than that of the Fontan procedure [13, 14], although the survival rate of Fontan completion for patients with a small LV or severely reduced LV function is only approximately 50-70%, even in the recent reports. [33-35]
Based on the pathophysiology of evolving HLHS as previously discussed and the poor survival rate of HLHS patients, fetal intervention has been attempted, aimed at relieving AS at earlier stages before the LV cavity is reduced. For the first time, Maxwell et al. reported their experience of intrauterine balloon dilatation of the fetal aortic valve in 1991. [36] Thereafter, a case series of 12 fetuses that underwent balloon valvuloplasty in the third trimester were reported, with no improvement was observed in their LV growth. [37] Tworetzky et al. also reported the results of fetal intervention for 24 AS patients (ranging from 21 to 29 weeks of gestation) who were thought to have a high probability of developing HLHS. [38] Technical success was achieved in 14 patients, but only 3 patients were able to undergo two-ventricular repair. Therefore, fetal intervention should be regarded as experimental at present, as many issues remain to be solved.
The treatment strategy for AS in which signs and/or symptoms develop later in childhood is different from that for neonatal AS. The American College of Cardiology/American Heart Association Guidelines for the management of AS of this group [31] recommended that patients with a peak instantaneous pressure gradient (PIPG) measured by Doppler echocardiography ≥70 mmHg be considered for cardiac catheterization and treatment in asymptomatic children and young adults. If the patients desire to participate in competitive sports or become pregnant, a PIPG of 50–70 mmHg is an indication for further evaluation and interventions. If patients have symptoms (angina, syncope, or dyspnea on exertion), a PIPG ≥50 mmHg is the indication for treatment. If the PIPG is less than 50 mmHg and a symptom is present, another origin of the symptom should be investigated.
There are several treatment options for cases in which intervention is indicated, including PTAV, open AVP, the Ross procedure, and AVR. Procedure selection is primarily dependent upon whether the patient’s somatic size (aortic annular size) is large enough to use a prosthetic valve, because AVR is considered as the first-line procedure at present. If the prosthetic valve is not available, procedures other than AVR are selected so that patients can live with their own valve until they can use a prosthetic aortic valve. In such situations, the most important concept for treatment is that the procedure should be regarded as a bridge to AVR. Therefore, the aim of any intervention should be to reduce the afterload without any significant aortic regurgitation so that patients can grow uneventfully until AVR can be performed. In this sense, if these patients do not have heart failure but have exertion-induced ischemic signs, restriction of exercise without invasive intervention may be selected to achieve a better outcome. Application of PTAV in this age group is relatively limited because AVP is thought to be better than PTAV in terms of preserving aortic valve function, [39, 40] and because aortic insufficiency caused by valvuloplasty is known to be progressive in nature. [15, 16] However, some patients may still benefit from PTAV to achieve the therapeutic goal in this AS group. The Ross procedure is also not regarded as a definitive repair surgery, because neoaortic regurgitation and pulmonary insufficiency are frequently observed postoperative complications, which require further interventions in the future. [40, 41] Therefore, the Ross procedure indication is limited to patients who cannot grow due to severe aortic insufficiency.
In this last section, we briefly comment on the differences in LV geometric and functional changes between adult- and child-onset of AS. The natural history of LV geometric and functional changes in adult-onset AS is characterized by LV concentric hypertrophy in the early stage, followed by diastolic dysfunction, systolic dysfunction with eccentric hypertrophy, and heart failure at the end-stage. [42] Most of the patients who are candidates for surgical intervention are ranked in the state between diastolic and systolic ventricular dysfunction. Delayed relaxation characterizes early-stage ventricular diastolic dysfunction, and thus is observed in almost all AS patients, [43] while increased diastolic stiffness is observed in more advanced stages in which LV hypertrophy and fibrosis may coexist. The degree of diastolic dysfunction is important for predicting prognosis because it takes years to achieve reverse remodeling of diastolic function after normalization of afterload. [44]
In contrast to the relatively uniform geometric and functional LV changes observed in adult-onset AS, such changes in children’s AS are diverse and somewhat different from those of adults. The difference primarily stems from the diversity of the initial impact of afterload on the LV. Because adult onset of AS is largely due to a bicuspid valve or atherosclerotic change with aging, AS gradually increases LV afterload. This allows the LV to confront the increased afterload by inducing hypertrophic changes. However, the severity of AS that initially imposes afterload on the LV is diverse in children, as previously discussed, thus excessive afterload may not allow the LV to become hypertrophic, resulting in LV dilation and systolic dysfunction as observed in critical AS. With increasing age, the LV geometry and function gradually resembles those of adult AS: a hypertrophic LV with diastolic dysfunction. However, it is rare in children to observe a marked increase in LV diastolic stiffness, even in cases of hypertrophic LV (Figure 5). In addition, it is interesting that LV relaxation appears to be relatively preserved in children with AS and hypertrophic LV. These differences in LV functional responses between children and adults may have a clue to a better management of patients with AS.
Examples of left ventricular pressure-volume relationships in a control patient (A) and a patient with aortic stenosis (B). The steep slope of the end-systolic pressure-volume relationship (solid line) and arterial elastance (dashed line) indicate increased ventricular contractility and afterload. Note that the slope of the end-diastolic pressure-volume relationship in aortic stenosis is comparable to that of control.
In adults, AS generally develops slowly, with the progression of valve calcification or leaflet degeneration being independent of the existence of substrates for congenital abnormalities. This allows the LV to adapt to the increased afterload by becoming concentrically hypertrophied. Therefore, it takes a long time before LV systolic function is severely impaired and critical events occur.45 Because valvular calcification is a commonly observed morphological change and because a prosthetic valve is generally available for adults, aortic valve replacement is selected as a first-line treatment and plastic surgery is seldom chosen for this population. Thus, the treatment strategy is rather straightforward.
In contrast, as discussed in this chapter, a wide range of clinical phenotypes is seen in pediatric AS. Depending on the severity of the native aortic valve abnormality and associated hemodynamic features, AS could be one of the most severe forms of congenital heart defects in children, leading to a critical condition in neonates or even during fetal life. In the milder form of pediatric AS, no clinical symptoms are seen throughout the patient’s life. Therefore, the complexity of the treatment approach depends upon the patient’s age, body size, and associated cardiac anomalies. In particular, because of the limited availability of prosthetic aortic valves for small children, the native valve morphological features constitute an extremely important determinant of treatment strategy. A detailed assessment of LV function as well as accurate anatomical diagnosis, including analysis of the potential utility of the native aortic valve, is essential for achieving a better outcome for patients. The use of specific medications [46] and prevention of metabolic syndrome from childhood may help improve outcomes.
Accumulation of information regarding the outcomes of underdeveloped valves, detailed mechanisms underlying disease progression, surgical outcomes, and improvements in surgical techniques should lead to considerably improved outcomes in the pediatric population.
Control of response to chemotherapy is an intrinsic part of current treatment protocols [1, 2, 3, 4, 5]. Assessment of response in key points of chemotherapy programs helps both to stratify patients by risk groups more accurately and to avoid serious chronic side effects and patient overtreatment [6, 7, 8, 9, 10, 11, 12]. In case of acute leukemia, the number of tumor blasts undetectable in bone marrow (BM) morphologically at different therapy stages or minimal residual disease (MRD) is a criterion for such assessment.
\nIn adult patients, problems of most significant points of immunological detection and the role of MRD levels are a matter of discussion [2]. The MRD significance is demonstrated in full in pediatric oncology. The MRD is of importance both in prognosis of acute lymphoblastic leukemia (ALL) and in prediction of recurrence [13]. Key points for MRD assessment are determined as well as their clinical significance and MRD levels that help in detailed risk stratification of patients [1].
\nImmunological quantification of MRD cells solves different problems depending on chemotherapy stages. In the middle of induction therapy (day 15), it evaluates primary response [14]. While at the end of induction therapy (day 33), the purpose is final risk stratification of patients with respect to clinical and immunological prognostic factors [1, 14, 15]. MRD assessment at the end of induction consolidation (day 78) identifies a patient group with so called slow response. These patients remain MRD-positive by days 15 and 33 and reach MRD-negativity by day 78 only. This group is characterized by good prognosis [3].
\nMany international research groups have developed flow cytometry (FC) protocols for MRD diagnosis; however, there is not a common approach yet. The St Jude Children’s Research Hospital (Memphis, USA) has proposed a simplified 3-color FC assay to detect MRD cells on day 15 of induction therapy [16] that is based on elimination of normal B-cell precursors (BCP) under the effect of corticosteroids [17] that are a basis for therapy at the given stage. The BFM international study group has developed an MRD monitoring protocol basing on the detection of B-LP with aberrant (leukemia-associated) immunophenotype (LAIP). Antigens CD58 and CD38 are most common markers to characterize the aberrant immunophenotype [18, 19]. However, tumor lymphoblasts show no aberrance by these antigens [20]. There are no clearly identified alternative combinations of aberrant markers.
\nIn ALL from T-cell precursors (T-ALL), there are no clearly cut criteria for MRD assessment [21] and research in this field is ongoing.
\nThe aim of this chapter is to compare immunophenotyping features of normal B-cell precursors and B-lymphoblasts in acute leukemia and to show possibilities of use of a leukemia-associated immunophenotype in monitoring of the MRD.
\nThe study involved 191 ALL cases (160 B-ALL [142—primary diagnosis, 18—diagnosis in relapse] and 31 T-ALL). The diagnosis was made basing on a combination of morphocytochemical and immunophenotyping assays of BM puncture biopsies.
\nIn most cases (88.8% of B-ALL and 87.1% of T-ALL), the immunophenotyping at diagnosis was performed by 3-color FC (at least 20 markers was analyzed). The immunophenotyping using EuroFlow 8-color standardized panels was made in 11.2% of B-ALL and 12.9% of T-ALL cases. Lineage of blasts was determined using ALOT (acute leukemia orientation tube) (Table 1).
\nNo./fluorochrome | \nMarkers | \n|||||||
---|---|---|---|---|---|---|---|---|
FITC | \nPE | \nPerCP-cy5.5 | \nPE-cy7 | \nAPC | \nAPC-117 | \nV450 | \nV500 | \n|
1 | \ncy MPO | \ncy CD79a | \nCD34 | \nCD19 | \nCD7 | \nsm CD3 | \ncy CD3 | \nCD45 | \n
Acute leukemia orientation tube.
A more accurate B-ALL (Table 2) or T-ALL (Table 3) 8-color standardized panel was used depending upon the identified blast lineage. The BCP aberrance was assessed basing on expression of the following antigens: CD58, CD38, CD81, CD9, CD123, CD66c, CD13, CD33, CD20, CD21, and CD24; T-cell precursors (TCP) were characterized with respect to CD99, CD56 expression.
\nNo./fluorochrome | \nMarkers | \n|||||||
---|---|---|---|---|---|---|---|---|
FITC | \nPE | \nPerCP-cy5.5 | \nPE-cy7 | \nAPC | \nAPC-117 | \nV450 | \nV500 | \n|
1 | \nCD58 | \nCD66c | \nCD34 | \nCD19 | \nCD10 | \nCD38 | \nCD20 | \nCD45 | \n
2 | \ncyIgM | \nCD33 | \nCD34 | \nCD19 | \nCD117 + sIgM | \nsIg-λ | \nsIg-κ | \nCD45 | \n
3 | \nnuTdT | \nCD13 | \nCD34 | \nCD19 | \nCD22 | \nCD24 | \nCD9 | \nCD45 | \n
4 | \nCD15 + CD65 | \nNG2 | \nCD34 | \nCD19 | \nCD123 | \nCD81 | \nCD21 | \nCD45 | \n
EuroFlow consortium 8-color standardized panel for B-ALL diagnosis.
No./fluorochrome | \nMarkers | \n|||||||
---|---|---|---|---|---|---|---|---|
FITC | \nPE | \nPerCP-cy5.5 | \nPE-cy7 | \nAPC | \nAPC-117 | \nV450 | \nV500 | \n|
1 | \nnuTdT | \nCD99 | \nCD5 | \nCD10 | \nCD1a | \nsmCD3 | \ncyCD3 | \nCD45 | \n
2 | \nCD2 | \nCD117 | \nCD4 | \nCD8 | \nCD7 | \nsmCD3 | \ncyCD3 | \nCD45 | \n
3 | \nTCRγδ | \nTCRαβ | \nCD33 | \nCD56 | \ncyTCRαβ | \nsmCD3 | \ncyCD3 | \nCD45 | \n
4 | \nCD44 | \nCD13 | \nHLA-DR | \nCD45RA | \nCD123 | \nsmCD3 | \ncyCD3 | \nCD45 | \n
EuroFlow consortium 8-color standardized panel for T-ALL diagnosis.
MRD quantification was made in 397 BM specimens from ALL patients at different therapy stages (days 15, 33, and 78, Table 4).
\nALL immuno-subtype FC color number | \nMRD monitoring points | \n|||||||||
---|---|---|---|---|---|---|---|---|---|---|
Day 15 | \nDay 33 | \nDay 78 | \n||||||||
3 col. | \n4–6 col. | \n8 col. | \n3 col. | \n4–6 col. | \n8 col. | \n3 col. | \n4–6 col. | \n8 col. | \n||
В-ALL | \nTotal | \n139 | \n148 | \n54 | \n||||||
No. | \n59 | \n68 | \n12 | \n51 | \n79 | \n18 | \n3 | \n38 | \n13 | \n|
Percentage | \n42.4 | \n49.0 | \n8.6 | \n34.4 | \n53.4 | \n12.2 | \n5.6 | \n70.4 | \n24.0 | \n|
Т-ALL | \nTotal | \n30 | \n26 | \n— | \n||||||
No. | \n9 | \n19 | \n2 | \n6 | \n18 | \n2 | \n— | \n— | \n— | \n|
Percentage | \n30.0 | \n63.3 | \n6.7 | \n23.1 | \n69.2 | \n7.7 | \n— | \n— | \n— | \n
The number of analyses at each MRD monitoring point.
At diagnosis, every BM specimen was characterized both morphologically and immunologically. Myelogram count was made by two morphologists (250 cells each) on Giemsa stained BM smears. The following M-types were identified basing on standard morphological criteria for the number of blasts: M1—specimens with ≤5% of blasts, M2—specimens with 5.0–25.0% of blasts, and M3—specimens with ≥25% of blasts. After that, a more detailed analysis was made, and the morphological criteria were compared with immunological findings. Detailed analysis of MRD levels was made in M1, M2, and M3 specimens. Subgroups of specimens within each group were identified with respect to the number of MRD cells. The subgroups were identified according to the BFM protocol for MRD assessment on induction chemotherapy as follows: standard risk <0.1% (including negative cases), medium risk 0.1–10.0%, and high risk ≥10%/the level of 0.01% of tumor cells in a specimen was taken as a standard threshold for MRD negativity.
\nStatistical analysis was made using IBM-SPSS Statistics v.17 software. Parametric data were analyzed by comparison of means using Student’s t-test. Comparison of nonparametric data was made by Pearson’s χ2-test.
\nA total of 186 patients with ALL (five patients were treated in debut and in relapse of the disease) managed at the N.N. Blokhin Cancer Research Center during 2006 through 2017 were entered in the study.
\nThe B-ALL group included 155 patients 1–18 years of age: 78 boys (48.7%) and 82 girls (51.3%) (Table 5). In 142 cases (88.8%), the diagnosis was made at the disease onset. In 18 cases (11.2%), the diagnosis was made in recurrence stage. Five patients were followed up both in the debut and recurrences stages.
\nCharacteristic | \nNumber | \nPercentage | \n|
---|---|---|---|
Gender | \nM | \n78 | \n48.4 | \n
F | \n83 | \n51.6 | \n|
Age | \n1–18 years (mean 5.9 ± 0.3 years) | \n||
Time of diagnosis | \nDebut | \n142 | \n88.8 | \n
Recurrence | \n18 | \n11.2 | \n|
Immunosubtype | \nPre-pre-В | \n150 | \n93.8 | \n
Pro-В | \n10 | \n6.2 | \n
Patient characteristics in the B-ALL group.
The T-ALL group consisted of 31 patients aged 2–17 years including 26 boys (83.9%) and 5 girls (16.1%) (Table 6).
\nCharacteristic | \nNumber | \nPercentage | \n|
---|---|---|---|
Gender | \nМ | \n29 | \n83.9 | \n
F | \n7 | \n16.1 | \n|
Age | \n1–17 years (mean 7.3 ± 4.7 years) | \n||
Time of diagnosis | \nDebut | \n31 | \n100 | \n
Pre-T-cell | \n12 | \n38.7 | \n|
Cortico-thymocytic | \n19 | \n61.3 | \n
Patient characteristics in the T-ALL group.
Treatment was given according to the ALL IC BFM 2002 and 2009 protocols. Data on risk stratification are shown for 79 patients with B-ALL receiving treatment by the ALL IC BFM 2009 protocol (data for 63 patients with B-ALL onset are not available). The majority of patients (67.1%) were classified into an intermediate risk group. Only 5.1% of patients were a high risk group. And 27.8% of patients were assigned to a standard risk group.
\n71.0% of T-ALL patients received treatment by ALL IC BFM 2009 protocol. The majority of patients (72.7%) were classified into an intermediate risk group. Other patients (27.3%) were assigned to a high risk group.
\nMRD monitoring was made on days 15, 33, and 78 of chemotherapy according to the treatment protocols used at the Research Institute of Pediatric Oncology and Hematology of the FBI N.N. Blokhin NMRCO and international recommendations.
\nTable 7 shows B-lymphoblast immunophenotype characteristics at primary diagnosis. These immunological characteristics were used further in MRD monitoring.
\nAntigen | \nNo. of cases analyzed | \nFrequency of Ag-positive cases (%) | \n
---|---|---|
CD10 | \n142 | \n93.0 | \n
CD34 | \n139 | \n74.1 | \n
nuTdT | \n24 | \n100.0 | \n
smCD22 | \n137 | \n50.3 | \n
CD20 | \n129 | \n14.7 | \n
Pan-myeloid (CD13, CD33) | \n137 | \n46.0 | \n
CD58++CD38low/− | \n50 | \n54.0 | \n
CD38+/++ | \n93 | \n54.8 | \n
Additional criteria of aberrance | \n||
CD123 | \n8 | \n100.0 | \n
CD66c | \n8 | \n75.0 | \n
CD81 | \n7 | \n14.3 | \n
CD9 | \n8 | \n87.5 | \n
CD21 | \n7 | \n0.0 | \n
CD24 | \n7 | \n100.0 | \n
Tumor blast immunophenotype characteristics at primary diagnosis at disease onset.
CD58 and CD38 are currently most commonly used antigens as main criteria of tumor B-lymphoblast aberrance. Blasts are considered aberrant if they are characterized by overexpression of CD58 in combination with low or no expression of CD38 (immunophenotype CD58++CD38low/−, Figure 1).
\nBlasts with aberrant immunophenotype CD58++/CD38low. Cytogram A: blasts (gate 2, green) demonstrate bright CD19 expression (X-axis) against side scattering parameters (SSC, Y-axis). Cytogram B: B-lymphoblasts demonstrate bright CD58 expression (Y-axis) in combination with low CD38 expression (X-axis) as compared to normal BCP (CD58+CD38+, gate 4).
Analysis for this antigen combination demonstrated that blasts do not always have the CD58++CD38low/− immunophenotype, that is, aberrance by both antigens is found in 54.3% of cases only (Table 8). Figure 2 shows an example of no aberrance by CD58 and CD38 antigens.
\nCD58/CD38 expression | \nNumber | \nPercentage | \n
---|---|---|
CD58++/CD38low/− | \n25 | \n54.3 | \n
CD58+/CD38low/− | \n2 | \n4.3 | \n
CD58++/CD38+ | \n8 | \n17.4 | \n
CD58+/CD38+ | \n11 | \n24.0 | \n
Total | \n46 | \n100.0 | \n
Blast immunophenotypes with respect to CD58 and CD38 expression at primary diagnosis.
Tumor B-lymphoblasts with immunophenotype CD58+/CD38+. Cytogram A: tumor B-lymphoblasts are identified basing on CD19 expression (X-axis) and low SSC characteristics (Y-axis). Blasts (CD45lowCD19+) are characterized by bright CD38 expression (X-axis) in combination with normal CD58 expression (Y-axis) (cytogram B).
The following markers were studied as additional criteria of aberrance: CD123 (Figure 3), CD66c, CD81 (Figure 4), CD9, CD21, CD24 with their expression presented in Table 9. Figures 3 and 4 show an example of aberrant expression of CD123 and CD81 in B-lymphoblasts at primary diagnosis.
\nTumor B-lymphoblast aberrance by CD123 at primary diagnosis. Cytogram A: blasts (gate 1, red) are detected by low CD45 expression (X-axis) and low SSC characteristics (Y-axis). Cytogram B: tumor lymphoblasts demonstrate bright expression of pan-B-cell antigen CD19 (Y-axis) in combination with bright (aberrant) CD123 expression (X-axis).
Normal (A) and aberrant (B) expression of CD81 on B-LP. Cytogram A: normal bright CD81 expression on tumor B-lymphoblasts (green) in X-axis (CD81) against Y-axis (CD45) coordinates. Cytogram B: tumor B-lymphoblasts (green) with aberrant (weak) CD81 expression in X-axis (CD81) against Y-axis (CD45).
Antigen | \nNo. of cases studied | \nFrequency of Ag-positive cases (%) | \n
---|---|---|
nuTdT | \n31 | \n80.6 | \n
CD34 | \n31 | \n19.4 | \n
CD10 | \n31 | \n38.7 | \n
CD4+CD8+ | \n31 | \n35.5 | \n
CD1a | \n31 | \n54.8 | \n
CD5 | \n31 | \n90.3 | \n
CD7 | \n31 | \n96.8 | \n
Detection frequency of antigens associated with various TCP differentiation stages in T-ALL.
A total of 18 patients were examined at relapse of the disease. Five patients were examined at both disease onset and relapse. Blast characterization was made using a 3-color FC protocol in 66.7% (12/18) patients. In six patients (33.3%), immunophenotyping used the EuroFlow consortium 8-color protocol.
\nExpression of main CD58/CD38 aberrance markers at disease recurrence was assessed in 13 patients.
\nBlast immunophenotype with respect to CD58 and CD38 expression intensity as compared with the primary diagnosis changed in 2 of 5 cases. In the first case, blasts at primary diagnosis were immunophenotypically close to normal BCP as concerns CD58 and CD38 expression (CD58+CD38++), while acquiring aberrant CD58 and CD38 expression (CD58++CD38+) at relapse. In the second case, on the opposite, blasts lost aberrant CD38 sign and became close to normal non-tumor B-lymphoblasts by this antigen expression.
\nWe compared morphological and immunological findings from BM analysis on day 15 of therapy. In group M1, morphological and FC data were fully similar (no blasts by morphology and complete MRD negativity [MRD cells < 0.01%] by FC) in 11.5% of cases.
\nSpecimens from the M1 group were characterized by a marked percentage of lymphocytes (mean > 60.0%). The presence of MRD-positive specimens (FC) in the M1 group (good morphological response) may be explained by blast mimicry, that is, similarity with lymphocytes. This makes difficult accurate morphological verification of residual leukemic blasts.
\nIn group M1, there was no contradiction between morphological and FC data. Most M3 specimens (85.7%) contained ≥10.0% of MRD-positive cells by FC. The fraction of MRD-positive cells was 5.5% in one case only; that is, in terms of FC, this patient might be referred to the intermediate risk group and did not require therapy intensification.
\nComparison of two FC protocols for MRD monitoring on day 15 (3-color St. Jude [28] based on identification of CD10+/CD34+ BCP among BM mononuclear fraction, and BFM protocol based on identification of BCP with aberrant immunophenotype among nucleated cells [NC]) demonstrated that the mononuclear approach was a more strict criterion for risk stratification of patients.
\nMRD on day 15 of induction therapy in B-ALL is always represented by BCP. Their identification is based on detection of CD10 and CD34 expression or no expression of pan-leukocyte antigen CD45 and combination of the above mentioned markers in B-cells. Quantification of MRD cells on the basis of each of the progenitor markers demonstrated that CD10 was the most reliable criterion for evaluation of BCP cells on day 15 of chemotherapy in children with pre-pre-B ALL. While in pro-B B-ALL, the count of BCLP should be made basing on nuTdT-positive cyCD22-expressing B-cells.
\nCD58/CD38 expression was assessed on day 15 of induction chemotherapy in 28 patients. All BCP, that is, MRD cells demonstrated aberrant immunophenotype CD58++/CD38low only in 15 of 28 patients (54%) (Figure 5).
\nBCP immunophenotype features on day 15 of induction therapy. Cytogram A: 16.6% CD19+CD45low BCP (gate 3, green) in CD19 (X-axis) against CD45 (Y-axis) coordinates. The cells demonstrate bright CD10 (cytogram B), CD19 (X-axis) expression against CD10 (Y-axis) and marked CD34 expression (cytogram C), CD19 (X-axis) against CD34 (Y-axis). MRD cells show aberrant immunophenotype CD58++CD38low (cytogram D, CD38 [X-axis] against CD58 [Y-axis]).
CD58++/CD38low/− BCP content was analyzed in patients with no aberrance by this antigen combination at primary diagnosis (n = 11). The proportion of CD10+ B-cells was similar to that of CD58++/CD38low/− BCP in four specimens only. This example is illustrated in Figure 5. In the remaining cases, the number of CD58++/CD38low BCP was less than the number of CD10+ B-cells.
\nThe analysis demonstrated a significant predominance of MRD on day 15 of therapy in pro-B ALL as compared to pre-B (p = 0.016).
\nDay 15 of induction chemotherapy is characterized by BM hypocellularity and a marked fraction of debris that can interfere with results (Figure 6). To avoid this, a nucleotropic Syto die (Sito16 and Sito16 in our study) was included in the MRD detection panel.
\nDay 15 of induction therapy. The specimen has much debris. Cytogram A: NC detection basing on expression of nucleotropic die Syto16 against SSC. The specimen has 3.65% of NC (gate 1, red). Cytogram B: evaluation of B-cell fraction (gate 2, blue): CD19 (X-axis) against SSC. The B-cell fraction without NC is 0.57%, with recount for NC CD19+ cells are 15.6% in this specimen. CD34+ BCP are 0.0021% without NC, that is, MRD-negativity. Recount with respect to Syto16 results in CD34+ BCP being 0.06%, that is, MRD-positivity.
In the group, as a whole MRD-negative status was found on day 15 of induction chemotherapy in 11.5% of patients, which allowed reduction in anthracycline dose to be considered with respect to clinical prognostic factors without the risk of recurrence in this subgroup.
\nMRD quantification was based on count of CD58++CD38low/− BCP. If specimens demonstrated no aberrance by this antigen combination at primary diagnosis, MRD was assessed by CD58++CD10++ or CD38lowCD10++ combinations.
\nAccording to the morphological risk stratification criteria, all specimens contained less than 5.0% of blasts (1.2% ± 0.1, n = 80) and were included in the M1 group. There were no blasts in 6.25% of specimens (5/80). MRD-positivity by immunology was identified in 40.0% of cases (32/80). In two patients (2.5%), MRD cells were >1.0%. There were no high risk specimens (MRD ≥ 10.0%) in our study.
\nCD58 and CD38 primary tumor aberrance on day 33 of induction chemotherapy was assessed in 50.0% of patients. CD58 aberrance was found in 28 of 40 cases (70%), and CD38 aberrance was detected in 60.0% of cases (24/40). 55.0% of cases (22/40) were CD58/CD38 aberrant and 45.0% (18/40) demonstrated no aberrance.
\nCases without CD58/CD38 aberrance at the primary diagnosis were examined for markers identifying cells of residual tumor by the literature.
\nWe analyzed CD81, CD123, CD9, CD21, CD24 expression in 21 BM specimens. As a result, most informative marker combinations for detection of aberrant B-lymphoblasts were identified: combinations of CD58 or CD38 with CD10 (aberrant immunophenotypes CD58++CD10+ or CD38+CD10++) were the most informative in terms of FC. In case of CD20-positive ALL MRD could be detected by asynchronous CD20 and CD34 expression (aberrance characterized by CD34+CD20+ phenotype, Figure 7). In most cases, residual tumor may be detected by marked expression of CD123 in combination with weak or no expression of CD81 (aberrant immunophenotype CD123++CD81low, Figure 8). In some cases, CD9 monomorphic tumor expression especially in combination with one of clear-cut aberrance criteria (CD58++, CD123++, CD38low, CD81low, Figure 9) are a sign of tumor aberrance and criterion for MRD assessment.
\nMRD quantification basing on asynchronous expression of stage-specific Ag CD34/CD20 in a patient with CD20+ pre-pre-B B-ALL immunosubtype. Cytogram A: tumor B-lymphoblasts (CD45lowCD19+) at primary diagnosis (X-axis CD20 against Y-axis CD10), of which 60.0% express CD20. Cytogram B: MRD detection basing on simultaneous CD20 (X-axis) and CD34 (Y-axis) expression. MRD cells are 0.027% of NC specimen, that is, MRD-positivity.
MRD quantification basing on aberrance by CD58/CD38 and CD123/CD81. Cytogram A: BCP detection basing on bright CD10 (Y-axis) expression in combination with low CD45 expression (X-axis), gate 4 (0.03% of NC) within CD19+ B-cells. Cytogram B: BCP are characterized CD58 overexpression (Y-axis) in combination with no CD38 expression (X-axis) and demonstrate CD123++CD81low immunophenotype (cytogram C: CD123 [Y-axis] against CD81 [X-axis]). Therefore, B-lymphoblasts are aberrant by all four Ag analyzed, and there are no normal BCP in this specimen. Aberrant BCP are 0.027% of NC specimen, that is, MRD-positivity.
MRD quantification basing on aberrance by CD9 and CD81. Cytogram A: tumor B-lymphoblasts (CD45lowCD19+) at primary diagnosis with bright nuTdT expression (Y-axis) in combination with monomorphous CD9 overexpression (X-axis). Cytogram B: tumor cells are aberrant by CD81 (X-axis CD81 against Y-axis CD45). As compared to residual normal BCP (gate 4, pink) with bright CD81 expression, tumor B-lymphoblasts demonstrate low (aberrant) Ag expression. Cytogram C: MRD detection basing on bright monomorphous CD9 overexpression (Y-axis) in combination with low CD81 expression (X-axis) (gate 4, dark blue). They are 0.015% of NC specimen: MRD-positivity.
In cases with monomorphic co-expression of myeloid antigens (CD66c, CD13 or CD33), MRD assessment may be based on these markers.
\nOf the whole patients, cohort (80 patients) MRD-negative status was determined by FC in 60.0% (48 patients), and 40.0% (32 patients) were found MRD-positive. Comparison of basic morphological and immunological characteristics in these groups identified significant differences in the number of blasts (p = 0.012) and CD19+ B-cells (p = 0.044).
\nBasing on FC quantification of MRD, most patients (65.0%) receiving treatment by ALL IC BFM 2009 protocol were included in the intermediate risk group.
\nMRD assessment on day 78 of therapy was made in 42 patients and was based on detection of BCP with aberrant immunophenotype (CD58++CD38low/−).
\nAs recommended by BFM protocols, BM specimens were divided into MRD-positive and MRD-negative subgroups. Most BM specimens were MRD-negative (n = 27), and 15 of 42 specimens (35.7%) were MRD-positive.
\nIn 14 patients, MRD status was assessed at three points of treatment protocol (days 15, 33 and 78). Seven of them achieved MRD-negativity by day 78 and met the criterion of slow response to therapy.
\nAfter 1 block of anti-recurrence therapy, MRD was detectable in 15 BM specimens. By FC, 40.0% of patients (0.004 ± 0.0008%, n = 6) were MRD-negative and 60.0% of patients (7.3 ± 4.8%, n = 9) were MRD-positive with 77.0% of the MRD-positive specimens (0.9 ± 0.6%, n = 7) containing <5.0% of blasts by morphological study.
\nIn our study, one patient with early recurrence of ALL (pre-pre-B immunosubtype) received anti-recurrence targeted agent blinatumomab (biospecific anti-CD19 monoclonal antibody). Blinatumomab mechanism of action involves specific binding with CD19+ cells and recruitment of effector T-cells to enhance response. According to the literature data, CD19 is not expressed on cells during blinatumomab therapy which makes difficult BCP identification. We chose an alternative BCP identification procedure to monitor MRD in this patient category: BCP identification and characterization on blinatumomab (anti-CD19) therapy should be based on expression of cyCD22 and nuTdT due to lost of CD19 expression.
\nA total of 31 patients with T-ALL were included in our study. About 61.3% of patients (n = 19) presented with cortico-thymocytic immunosubtype (CD1a expression and/or the presence of CD4+CD8+ population) as determined by primary immunophenotyping. Table 9 shows characteristics of blast immunophenotype at the stage of primary diagnosis.
\nSince T-cell ontogenesis is characterized by the absence of T-cell progenitors in normal BM, MRD monitoring by FC at all therapy stages involves detection and count of TCP.
\nAccording to BFM protocol, MRD detection in T-ALL is based on identification of T-cells with aberrant immunophenotype within CD7-positive fraction. However, CD7 demonstrates a broad range of expression and is present not only on TCP (NK-cells and myeloid progenitor cells); therefore, a cytometric protocol for TCP detection in BM (MRD cells) was developed that was based on expression of pan-T-cell antigen CD3 in cytoplasm (cyCD3) as the most stable lineage-specific pan-T-cell antigen. Choice of appropriate antigen clone is an important requirement for detection of cytoplasmic CD3 expression. For instance, SK7 clone is used to detect membrane determinant, while UCHT-1 binds to cytoplasmatic determinant. So, only UCHT-1 monoclonal antibody should be used in analysis of cyCD3.
\nIn our study, quantification of TCP in BM was based on detection of subpopulations smCD3−CD7+, smCD3−TdT+, smCD3−CD1a+, and CD4+CD8+ within cyCD3-positive BM T-cells at all time points of MRD monitoring.
\nTo simplify recount and exclusion of debris, the quantification was made within NC of specimens as identified by Syto dies. The highest values were used as recommended by MRD detection protocols.
\nQuantification of residual blasts on day 15 of induction chemotherapy was made in 30 BM specimens.
\nThe morphological and immunological findings were as a whole similar. The group M2 was heterogeneous demonstrating variability in blast numbers and MRD levels; however, these specimens belonged to intermediate risk group both by M-subtypes and MRD levels and therefore did not interfere in patient stratification.
\nBM characteristics on day 15 of treatment were analyzed with respect to T-ALL immunosubtype. The pre-T immunosubtype was characterized by significantly higher MRD level on day 15 as compared to cortico-thymocytic one (p = 0.044).
\nAbout 76.2% of patients composed the intermediate risk group (according to ALL-IC-BFM 2009 protocol), and 23.8% were stratified into the high risk group. There were no patients meeting criteria for standard risk in our study
\nBasing on MRD level on day 15 of induction chemotherapy, 25.0% were transferred from the intermediate to the high risk group.
\nIt is important to note that MRD negativity was not reported on day 15 of induction chemotherapy in any of the patients, that is, none of the patients achieved complete leukemic cytoreduction in the middle of remission induction therapy.
\nQuantification of residual blasts on day 33 of induction chemotherapy was made in 26 patients.
\nMost BM specimens (25/26) were included into group M1, while there was only one specimen meeting the M2 criteria. None of the specimens was included in group M3 basing on morphological characteristics.
\nWe compared morphological and immunological findings. Specimens from the standard and intermediate risk groups were analyzed in detail with respect to MRD content.
\nAll BM specimens from group M1 were MRD-positive. Basing on the immunological criteria, 16.0% of BM specimens (n = 4) were included in the standard risk group (MRD < 0.1%). The intermediate risk group consisted of 20 of 25 BM specimens (80.0%). One BM specimen from this group contained no blast cells by morphology, though FC discovered 2.69% of MRD cells (Figure 10).
\nAn example of MRD-positivity with no blasts in the BM specimen by morphology on day 33 of therapy. Cytogram A: shows NC of the specimen (gate 1, red) basing on reactivity with Syto16 (X-axis) against SSC. Cytogram B: cyCD3+ T-cells within NC (gate 2, blue) with low SSC parameters (cyCD3, X-axis against SSC Y-axis). Cytogram C: CD7, X-axis against smCD3, Y-axis (gate 2) shows TCP (MRD cells) with CD3+CD7+ smCD3− immunophenotype that are 2.69% of myelokaryocytes: MRD-positivity.
One specimen was included in the high risk group by MRD assessment (MRD ≥ 10.0%).
\nNote that specimens from this sample demonstrated rather high lymphocytosis (more than 28.0%).
\nBy morphological criteria, only one BM specimen was included in the M2 group (blasts 10.8%), while by immunological characteristics, this specimen might be referred to the standard risk group (MRD cells 0.04%).
\nCD7 in combination with CD3 are used to assess MRD in T-ALL in the BFM protocol. However, CD7 is commonly found on myelokaryocytes including both lymphoid and myeloid progenitors. Basing on ontogenetic characteristics of expression of T-lineage antigens, we propose to detect TCP (that is MRD cells) by expression of cytoplasmatic CD3 as the earliest lineage-specific T-cell marker.
\nComparison of these two approaches to MRD monitoring (the standard BFM protocol basing on MRD cell count within CD7-positive cells and MRD count within cyCD3+ cells), both on days 15 and 33 of induction chemotherapy allowed us to make the conclusion that MRD quantification in T-ALL by detection of cyCD3+ smCD3− populations is more accurate.
\nSuccessful treatment of patients with acute leukemia is associated with escalation of chemotherapy doses which requires effective monitoring of response. Assessment of response in key points of chemotherapy protocols helps both to stratify patients by risk groups more accurately and to avoid serious long-term side effects or patient overtreatment.
\nSearch for adequate approaches to assessment of response was started since the 1970s. For a long time, response to therapy was assessed basing on the number of blasts in BM specimens as determined by morphological study, and as a result so called M-types were defined as follows: M1: <5.0% of blasts, M2: 5–25% of blasts, and M3: ≥25% of blasts [22].
\nHowever, the progress in molecular methods such as polymerase chain reaction (PCR) and flow cytometry (FC) allowed quantification of minimal number of residual blasts at submicroscopic level (<0.01%).
\nIn recent years, quantification of residual tumor cells in BM, that is, minimal residual disease (MRD) was a main criterion of response to chemotherapy. Opposite to myeloid leukemias when molecular genetic methods play the leading role in MRD detection, it is immunological approaches involving FC alone that can detect MRD cells in more than 95.0% of cases [23].
\nBoth PCR and FC have their advantages and disadvantages. Implementation of multiparameter FC able to assess up to 12 parameters of a single cell and development of computer software that allows tens of millions of cells to be examined makes FC close to PCR by sensitivity [24]. FC is currently the most rapid and less costly approach to MRD monitoring.
\nIn adults, problems of the most important detection points are a matter of discussion [2]. The MRD significance is most vivid in pediatrics. MRD is found to play a role both in ALL prognosis and recurrence prediction [1]. Key points of MRD monitoring and their clinical significance have been determined as well as MRD levels that allow detailed risk stratification of patients.
\nIt is in childhood oncology that the MRD effects of the patient faith have been studied [1, 25]. The current protocols defined three mandatory time points such as the middle and end of remission induction chemotherapy (days 15 and 33) and the end of consolidation induction (day 78).
\nMRD monitoring plays different roles at different chemotherapy stages. The most important point in terms of the patient faith is the middle of induction chemotherapy when primary tumor response and prognosis are determined.
\nFor a long time, there were multiple attempts to make the earliest possible assessment of response. One of the approaches is count of blasts in peripheral blood on day 8 of treatment. Patients with blast reduction below 1000 cells/mcl are a group of good response and good prognosis. However, the blast clearance on day 8 is found to reflect response to steroids only [5], while MRD level on day 15 of induction chemotherapy is the most accurate reflection of leukemic cytoreduction, that is, primary response to treatment [5, 14].
\nThe key moment is the selection of good response patients (MRD < 0.01%) in whom reduction of anthracycline dose may be considered [11, 26]. In our study, FC discovered MRD-negativity in 11.5% of patients in whom reduction of anthracycline dose could be considered. These patients did not develop recurrence.
\nThe situation in BM by day 15 of therapy is unique in terms of immunology. Since BCP are highly sensitive to glucocorticoids [17] that are the basis for treatment at the given stage, these cells are fully eliminated from BM [16]. This observation was a basis for a FC protocol developed by the St Jude Children’s Research Hospital (Memphis, USA) study group for detection of MRD cells on day 15. This protocol involves MRD monitoring within BM mononuclear fraction, while the BFM protocol uses recount for NC in the specimen.
\nWe compared the two approaches to conclude that recount for NC (the St. Jude Hospital protocol) is the most robust criterion for risk stratification of patients. Moreover, analysis of MRD cell immunophenotype with respect to CD58 and CD38 expression demonstrated that the number of CD10+ B-cells was similar to that of CD58++/CD38low/− BCP in 36.4% of cases only. While the number of CD58++CD38low BCP was less as compared to CD10+ B-cells in the remaining specimens of aberrant BCP. We conclude therefore that quantification of MRD should be based on detection of BCP rather than of aberrant blasts.
\nMRD cells on day 15 are BCP. We used a variety of monoclonal antibodies for their monitoring. In pre-pre-B and pre-B ALL immunosubtypes, it is just enough to count CD34+ and/or CD10+ BCP. In case of pro-B immunosubtype (CD10− and/or CD34−), MRD detection should involve a combination of nuclear TdT with cytoplasmatic CD22 or CD79α that show stable expression as demonstrated already in early studies of B-cell ontogenesis [27, 28].
\nImportant properties of BM on day 15 are hypocellularity and a marked proportion of debris, that is, destroyed cells under the effect of systemic chemotherapy [29, 30]. This requires modification of FC protocols for MRD monitoring, namely use of special dies able to identify viable, not destroyed cells in specimens. Our study showed reasonable to use Syto nucleotropic dies that can clearly select NC and as a consequence help to avoid debris dilution that may result in a considerable underestimation of MRD count and interfere with risk stratification.
\nBy the end of induction chemotherapy, appearance (regeneration) of normal B-lineage progenitors in BM makes MRD detection more difficult. Clear-cut distinguishing between MRD cells and regenerating BCP is possible basing on LAIP or aberrant immunophenotype.
\nAberrance is currently defined as follows:
Different levels of Ag expressions (overexpression of some molecules [CD58, CD10, CD9], low or no expression of Ag such as CD38, CD81)
Expression of Ag of uncommon differentiation lineages (e.g., co-expression of myeloid Ag such as CD13, CD33, CD66c, CD123 on tumor blasts)
Asynchronous expression of lineage-specific Ag (expression of Ag of mature B-cells, e.g., CD20 on CD34+ BCP)
A combination of CD58 and CD38 is the most frequently used Ag combination for assessment of B-lymphoblast immunophenotype aberrance in the AIEOP-BFM and COG FC protocols.
\nNormal BCP are characterized by CD58+/low/CD38+/++ immunophenotype, while aberrant immunophenotypes demonstrate CD58 overexpression and no or low CD38 expression.
\nAs shown by the I-BFM-ALL-MRD Study group, CD58 overexpression is present on overwhelming majority of tumor B-lymphoblasts and is found in 93.5% of cases [31, 32, 19].
\nCD38 molecule with receptor and enzymatic activities that is involved in B- and T-cell ontogenesis is brightly expressed on normal BM progenitor cells. Low CD38 expression in BCP is considered aberrant [19, 41] and is found in 61.2% of B-ALL according to Min Xia et al.
\nIn our study, CD58 was overexpressed in 71.7% of B-ALL cases, that is, less frequently that by literature data. An explanation may be that the boundary between Ag normal and overexpression may be unclear. To make a more accurate evaluation of aberrant immunophenotype in primary diagnosis, Ag tumor expression should be compared with the number of residual normal BCP that is not always large. To make visualization more determinant, one has to select a considerable amount of cells (≥1 million), which was not possible in early studies.
\nThere were only 58.6% of ALL with aberrant (low) CD38 expression which was in accord with foreign data.
\nIf one of two Ag is not aberrant, MRD may be assessed basing on alternative combinations such as CD58/CD10, CD58/CD34, CD38/CD10, and CD38/CD34.
\nOf note, in our study, about one fourth of all cases (24.0%) had tumor B-lymphoblasts with no aberrance by this Ag combination. Therefore, additional criteria to identify aberrant immunophenotype are needed.
\nThis requires MRD criteria to be used at time of diagnosis and most informative MRD markers to be selected in every specific case at the stage of ALL primary diagnosis.
\nMulticolor FC that simultaneously evaluates up to 12 various cell characteristics makes the most complete characterization of LAIP. This approach may be implemented by use of the EuroFlow consortium 8-color panels with optimal combination of stable markers and fluorochromes [33, 34, 35].
\nThe panel for more accurate B-ALL diagnosis includes 3 basic (repeated in all specimens) Ag and 20 specific Ag. This helps to make multiple aberrance evaluation by expression of nonlineage-specific CD45, CD58, CD38, CD9, CD123, and CD81; by expression of noncommon differentiation lineages such as pan-myeloid CD13, CD33, CD66c, CD15, CD65; and by asynchronous expression of Ag of different stages of B-cell differentiation CD10, CD34, CD, CD22, CD20, CD21, CD24. It is of much importance that expression of all above-mentioned markers may be assessed within a single cell population, that is, CD19+CD34+CD45low BCP.
\nThe protocol makes possible indirect prediction of clinically significant abnormalities basing on a proper immunophenotype [36]. For instance, immunophenotypes of cells with mutations BCR-ABL, MLL, Tel-AML-1, and E2APBX1 are described.
\nWhen analyzing capacities of EuroFlow 8-color protocols with respect to MRD monitoring, we paid attention to CD81 [35]. The CD81 molecule belongs to the tetraspanin family and is directly associated with CD19, thus forming a signal complex CD19-CD21-CD81 that realizes its functional activity in normal B-cell ontogenesis. By the literature [37], aberrant (weak) CD81 expression is found in 82% of B-ALL cases. Our evaluation of CD81 expression in primary diagnosis coincided with international study data. For instance, aberrant expression was found in 85.7% of primarily diagnosed ALL.
\nAnother molecule from the tetraspanin family is of interest as a criterion for MRD detection, that is, CD9 [38, 39, 40]. Its expression is evaluated both in 4- and 6-color FC protocols of the COG study group (M. Borowitz). CD9 is brightly expressed on early BCP, disappears at the pre-B stage, and appears again on mature B-cells. Its monomorphic overexpression on BCP is considered aberrant. In our study, 87.5% of B-ALL cases demonstrated CD9 aberrant expression on tumor B-lymphoblasts.
\nIn case of monomorphous co-expression of myeloid Ag such as CD13, CD33 and CD66c [31, 41] and also CD123 [42], they may be used as LAIP of tumor B-lymphoblasts. Prognostic significance of myeloid Ag co-expression on tumor cells is disputable, though CD66c (KORSA) is shown to be associated with BCR/ABL1 reconstructions [43, 44]. N. Guillaume et al. analyzed immunophenotype of ALL from BCP to discover CD66c co-expression to be the most frequent (40.0%), while pan-myeloid Ag CD13 and CD33 were detected in 15.0% of cases only.
\nIn our evaluation of primary immunophenotype of tumor B-lymphoblasts, CD66c co-expression was found in 75.0% of cases, while CD13 and CD33 were present in 46.0%, which is similar to international study data.
\nAs concerns interleukin-3 receptor α-chain (CD123), all B-ALL were aberrant (i.e., the Ag was expressed on tumor cells), which is in accord with L. Munoz et al. [45].
\nAsynchronous expression of Ag of noncharacteristic differentiation lineages is an additional criterion for tumor B-lymphocyte LAIP. CD20 is such a marker in CD20-positive B-ALL whose expression is characteristic of mature B-cells only. However, CD20 co-expression on tumor B-lymphoblasts is found in 6.4–15.3% of B-ALL [29, 30]. CD20 is included in most FC panels for MRD diagnosis though it is appropriate rather for more clear-cut identification of CD20− BCP than for evaluation of its aberrant expression. This finding may be explained by a small cohort of B-ALL patients (up to 16.0% of all B-ALL patients) in whom residual blasts may be identified on the basis of CD34+CD20− immunophenotype. In our study, only 14.7% of ALL patients demonstrated CD20 co-expression on tumor B-lymphoblasts.
\nSo in terms of FC approaches to evaluation of small populations which may also include MRD determination of LAIP is most effective using a combination of two Ag with aberrance manifesting itself as overexpression or a combination of molecules with over- and low/no expression. We propose the following Ag combinations: CD123+CD81low, and CD9++CD81low.
\nRemission completeness is clinically assessed on day 33 of treatment. In our study, MRD-negative status was detected in 600% of patients.
\nMost patients (65.0%) receiving treatment by ALL IC BFM 2009 schedule were stratified into the intermediate risk group by MRD content.
\nDay 78 of treatment (end of consolidation induction) is the third time point with undoubted prognostic value for MRD detection. Basing on this evaluation, a group of so called slow response may be identified basing on MRD status. These patients are MRD-positive on days 15 and 33 and reach MRD negativity by day 78 only. This cohort is characterized by good prognosis.
\nIn our study, 64.3% of patients were MRD negative, with 7 of 14 patients followed-up in all the three points belonging to the slow response group.
\nTumor immunophenotyping in disease recurrence is of special interest. Changes in Ag expression during treatment are studied and described rather well. According to international study data, changes as compared to disease onset may occur also in tumor cell immunophenotype in disease recurrence.
\nWe assessed blast immunophenotype both in disease onset and relapse in five patients. Tumor blast immunophenotype was the same by the main diagnostic Ag in disease onset and recurrence in four of the five patients. Of interest is that change in blast phenotype as concerns intensity of CD58/CD38 expression versus the primary diagnosis was found in two of the five patients.
\nClinical value of immunophenotype change as concern aberrance markers needs further clarification and may become an additional criterion in the protocol.
\nNovel targeted therapies that influence disease at molecular level are implemented in clinical practice every year and many are at various stages of clinical trial.
\nA new stage of progress in targeted therapy is associated with development of biospecific antibodies that are a new class of monoclonal antibodies (MAb) binding with a surface antigen target, on the one hand, and with T-cell receptor, on the other hand, thus recruiting effector T-cells and enhancing tumor response. Blinatumomab (Blinzito) is the first therapy in this class that is approved by FDA for the treatment of Ph-negative refractory/relapse ALL from B-LP [38]. This approval was based on results of phase II clinical trials with 43% of 189 adults achieving complete response and 82% achieving MRD-negativity [46].
\nNotwithstanding initial treatment results, some patients fail to respond to blinatumomab or develop progressive disease after initial response. Recurrence rate is 30%.
\nCharacterization of blast immunophenotype in recurrence on blinatumomab therapy discovered no CD19 expression on tumor cells. This interferes with BCP identification and requires new methodological approaches to MRD assessment.
\nInclusion of blinatumomab into B-ALL therapy requires an alternative MRD evaluation strategy.
\nThere was one patient receiving blinatumomab in our study [47]. The MRD monitoring and immunophenotyping at second recurrence was difficult due to the absence of CD19+ B-cells. An algorithm for BCP detection was proposed and tested that was based on alternative B-lineage differentiation markers. Nuclear nuTdT in combination with cytoplasmatic CD22 as most stably expressed Ag were chosen.
\nSo, given the appearance of new targeted therapies, FC algorithms for both MRD diagnosis and monitoring require certain flexibility and timely rational changes.
\nThere is an equivocal situation with T-ALL. On the one hand, search for aberrant immunophenotype for TCP ended in failure. Expression of main Ag studied with respect to LAIP, that is, CD99 and nuTdT is variable [21]. On the other hand, taking into account normal T-cell ontogenesis, MRD assessment may be based on the absence of TCP of the cyCD3++smCD3−nuTdT+CD7+ level in BM. One has therefore just to assess TCP number in order to quantify MRD at any therapy stage.
\nCorrect choice of antibody CD3 clone is of much importance for TCP identification. For instance, clone UCHT1 should be used to detect CD3 cytoplasmatic expression, while CD7 is needed to detect the membrane determinant.
\nThe AIEOP-BFM protocol suggests that MRD detection in T-ALL should be based on CD7.
\nWe compared the two approaches to TCP identification to find optimal TCP detection with CD7+/++smCD3+ immunophenotype within cyCD3+ population basing on T-cell ontogenesis.
\nAll T-ALL patients in our study were stratified into the intermediate and high risk groups. According to MRD levels on day 15, most patients remained in the initial stratification group though 25.0% were transferred from the intermediate into the high risk group.
\nOf note that all patients demonstrated MRD-positivity on day 15, that is, none of the T-ALL patients achieved complete leukemic cytoreduction on ALL-IC-BFM 2009 therapy.
\nSo, clinical significance of MRD in ALL arises no doubt. It is reasonable to make MRD quantification immunologically using FC assay.
\nSince there are no normal BCP on day 15 of induction chemotherapy, MRD quantification in case of pre-pre-B and pre-B ALL immunosubtypes should be based on detection of CD10+/CD34+ population within CD19+ B-cells. In case of pro-B (CD10− and/or CD34−), ALL immunosubtype MRD detection should be based on expression of nuclear nuTdT in combination with cyCD22.
\nDuring BM regeneration (end of remission induction therapy and long-term treatment stages), MRD quantification is based on identification of BCP with aberrant immunosubtype. Alongside with the most common CD58/CD38, the following Ag should be used in LAIP assessment: CD81, CD9, CD13, CD33, CD66c, CD123, and CD20. At the stage of diagnosis, the most informative personalized Ag combinations should be selected for further MRD monitoring to make a more accurate risk stratification of patients at different therapy stages and are an effective tool for its modification.
\nTumor immunophenotype in disease recurrence should be compared with that in disease onset taking into account its possible changes.
\nIn case of targeted therapy, for example, anti-recurrence treatment, FC protocol should be changed with respect to treatment features. For instance, BCP evaluation on blinatumomab therapy should be based on expression of nuTdt in combination with cyCD22.
\nIn T-ALL, MRD assessment at any therapy stage may be limited to quantification of CD7+/++smCD3− cells within cyCD3+ population.
\nThe authors declare no conflict of interests.
\n antibody antigene acute leukemia orientation tube acute lymphoblastic leukemia intercontinental acute lymphoblastic leukemia protocol of Berlin-Frankfurt-Munster study group ALL from B-cell precursors B-cell precursors Berlin-Frankfurt-Munster study group bone marrow cluster of differentiation cytoplasmic cluster of differentiation children oncology group flow cytometry leukemia-associated immunophenotype monoclonal antibodies minimal residual disease mononuclear cells nucleated cells membrane cluster of differentiation ALL from T-cell precursors T-cell precursors
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