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Varotto, Elena (2018) Transient Switch to myeloid lineage in Acute Lymphoblastic Leukemia in Induction: role of CD371 expression and implication for Minimal Residual Disease detection. [Ph.D. thesis]

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Abstract (italian or english)

Background: ImmunoPhenotyping (IP) by multi-colour flow cytometry (FCM) is a cornerstone of pediatric B-lineage acute lymphoblastic leukemia (BCP-ALL) diagnosis and is gaining ever greater prognostic role in minimal residual disease (MRD) monitoring. It allows also to detect lineage switch (SW), defined as any variation of blast IP during therapy. SWs to myeloid lineage were described in ALLs with KMT2A rearrangements and BCP-ALL expressing antigen CD2. We observed a transient SW to myelomocitic lineage during the first phase of AIEOP-BFM ALL 2009 protocol (Induction IA-steroid phase) in a subset of BCP-ALL. This behaviour was seen in association with the aberrant expression of myeloid antigen CD371 at diagnosis. We retrospectively compared CD371-positive (CD371+) to CD371-negative (CD371-) BCP-ALLs.
Aims of our study: to verify the association between CD371 expression at diagnosis and transient SW during Induction phase; to define SW blasts immunophenotypic changes and redefine a standardized approach to accurate FCM-MRD analysis on Day (D) 15.
Materials and Methods: Inclusion criteria: new diagnosis of BCP-ALL, except B-IV-ALL according to EGIL classification; treatment regimen: AIEOP BFM ALL 2009 protocol; enrolment period: 01/06/2014 – 31/01/2017. Eight-hundred-twenty-three paediatric patients (pts) were included in our study (age: 1-17 years; male/female 446/377 pts). Peripheral and bone marrow samples were centralized from all Italian AIEOP Centres to the Laboratory of Diagnosis and Research of Pediatric Hematology Oncology, University of Padua. Samples were processed and analysed according to standardized operating protocols designed by the AIEOP-BFM Flow Network. Nine combinations of 8 monoclonal antibodies were used for IP at diagnosis, 2 for FCM-MRD from June 2014 to May 2016; subsequently dry 10 colours pre-formulated DuraClone 10 Conj Custom Mix, Per Test, 2500 Test per Yr (Beckman Coulter) was adopted. BD FACS Canto II (Becton Dickinson) and Navios (Beckman Coulter) cytometers were used for samples acquisition and analysis.
Results: CD371+ was detected in 75/823 pts (9.1%) at diagnosis. CD371+ was associated with older age (>9 years: 34/75 vs 130/748 pts, p<.001); DNA index=1.0 (65/75 vs 437/748 pts, p<.001); immature immunophenotype according to EGIL classification (BI-ALL 10/75 vs 12/748 pts; BII-ALL 65/75 vs 555/748 pts, BIII-ALL 0/75 vs 181/478 pts, p<.001); CD2 positivity (38/75 vs 3/748 pts, p<.001); other 3 myeloid antigen positivity (42/75 vs 240/748 pts, p<.001); worse response to Induction therapy (high risk group: 27/75 vs 147/748 pts, p<.001). Samples of 72/75 pts (96%) were available for FCM-MRD analysis. SW was defined as the appearance of a «monocytoid» population characterized by the following immunophenotype: CD34 strong; CD58 strong; CD19 dim positive/negative; increased CD45 expression and Side Scatter characteristic. SW was observed in 50/72 CD371+ pts vs 4/748 CD371- pts (sensitivity 0.93, 95%IC ±0.06; specificity 0.98, 95%IC ±0.005; PPV 0.82; NPV 0.99; accuracy 0.98). CD371+ pts: SW was detected in 26/42 evaluated pts (61.9%) on D8 and 50/72 pts (69.4%) on D15. No more SW was detectable on D33 and D78, despite chemotherapy regimen according to AIEOP-BFM ALL 2009 protocol had been carried on.
Conclusions: CD371 is an accurate marker for the detection of transient SW in BCP-ALL. CD371+ is associated with worse response to Induction therapy. It should suggest peculiar attention in FCM-MRD analysis on Day 15 in these pts.

Abstract (a different language)

Background: L’analisi immunofenotipica mediante citometria a flusso multiparametrica è una metodica fondamentale per la diagnosi delle leucemie linfoblastiche acute a precursori B (BCP-ALL) in età pediatrica. Essa sta acquisendo sempre maggiore rilevanza nel monitoraggio della malattia residua minima. Permette inoltre di identificare eventuali variazioni nell’immunofenotipo delle cellule blastiche in corso di chemioterapia, fenomeno definito come “switch” immunofenotipico. In passato è stato descritto uno SW a leucemia mieloide acuta in BCP-ALL associate a riarrangiamenti del gene KMT2A; più recentemente è stato descritto uno switch mieloide transitorio in un subset di BCP-ALL caratterizzate dall’espressione dell’antigene di superficie CD2, in assenza di riarrangiamenti del gene KMT2A. Il Laboratorio di Diagnositica e di Ricerca di Padova è il centro di riferimento nazionale a cui vengono centralizzati i campioni per la diagnosi morfologica e la CMF dei pazienti con ALL provenienti da tutti i centri AIEOP. Qui e’ stata osservata la possibile comparsa di blasti di linea mielo-moniciticitica in un subset di BCP-ALL apparentemente caratterizzato, alla diagnosi, dall’espressione dell’antigene mieloide CD371. Tale fenomeno è stato individuato solo nelle prime fasi della chemioterapia (terapia steroidea della fase di Induzione IA secondo protocollo internazionale AIEOP-BFM ALL 2009), per poi scomparire con la prosecuzione della terapia stessa. E’ stato pertanto deciso di condurre un’analisi retrospettiva per confrontare le BCP-ALL con espressione, alla diagnosi, dell’antigene CD371(CD371+) con quelle negative per tale antigene (CD371-).
Gli obiettivi del nostro studio sono i seguenti: verificare l’associazione tra espressione di CD371 alla diagnosi e lo SW mielomonicitico transitorio durante la terapia di Induzione; definire l’immunofenotipo delle cellule che presentano lo SW; ridefinire un approccio standardizzato per un’accurata analisi della CFM-MRM al giorno 15.
Materiali e metodi: Criteri di inclusione: nuova diagnosi di BCP-ALL, escluso il sottotipo B-IV secondo la classificazione EGIL; trattamento secondo protocollo internazionale AIEOP-BFM ALL 2009; periodo di arruolamento: dall’ 01/06/2014 al 31/01/2017. 823 pz pediatrici sono stati inclusi nel nostro studio (età 1-17 anni, maschi/femmine 446/377 pz). I campioni di sangue periferico e midollare sono stati centralizzati al Laboratorio di Diagnostica e Ricerca di Padova per l’analisi dell’immunofenotipo alla diagnosi ed il monitoraggio della malattia residua minima 5 molecolare ai giorni 8, 15, 33 e 78, come previsto dal protocollo di cura. I campioni sono stati processati ed analizzati secondo protocolli operativi standardizzati, definiti dal gruppo di lavoro internazionale AIEOP-BFM Flow Network. Pannelli di 8 anticorpi monoclonali sono stati allestiti presso il nostro Laboratorio (di cui 9 sono stati utilizzati per l’IF alla diagnosi e 2 per lo studio della malattia residua minima molecolare); a partire dal mese di maggio 2016, lo studio della malattia residua minima molecolare è stato effettuato con l’utilizzo di un pannello di 10 anticorpi monoclonali cristallizzati (DuraClone 10 Conj Custom Mix, Per Test, 2500 Test per Yr, Beckman Coulter). I campioni sono stati acquisiti e analizzati con i citofluorimetri a flusso multiparametrici BD FACS Canto II (Becton Dickinson) e Navios (Beckam Coulter).
Risultati: 75/823 pz (9.1%) sono risultati caratterizzati dall’espressione di CD371+ alla diagnosi. CD371+ è risultato associato a: età maggiore alla diagnosi (> 9 anni: 34/75 vs 130/748 pz, p<.001); DNA index=1.0 (65/75 vs 437/748 pz, p<.001); immufenotipo più immaturo secondo la classificazione EGIL (B-I 10/75 vs 12/748 pz; B-II 65/75 vs 555/748 pz, B-III 0/75 vs 181/478 pz, p<.001); positività per CD2 (38/75 vs 3/748 pz, p<.001); positività per altri antigeni mieloidi (42/75 vs 240/748 pz, p<.001); peggiore risposta alla terapia di Induzione (gruppo terapeutico di rischio alto: 27/75 vs 147/748 pz, p<.001). 72/75 pz (96.0%) sono risultati valutabili per la malattia residua minima in citofluorimetria al giorno 15. Lo switch è stato definito come la comparsa di una popolazione “monocitoide” caratterizzata dal seguente immunofenotipo: CD34 positivo forte; CD58 positivo forte; riduzione dell’intensità di CD19 fino a completa negativizzazione; aumento dell’intensità di CD45; aumento del Side Scatter, parametro fisico che identifica la granulosità cellulare. Lo switch è stato osservato in 50/72 pz CD371+ vs 4/748 pz CD371- (sensibilità 0.93, 95%IC ±0.06; specificità 0.98, 95%IC ±0.005; VPP 0.82; VPN 0.99; accuratezza 0.98). Nei pz CD371+ lo SW è stato individuato in 26/42 pz valutati (61.9%) al giorno 8 e in 50/72 pz (69.4%) al giorno 15. Lo switch si è completamente negativizzato a partire dal giorno 33, proseguendo la terapia in atto come da protocollo per pB-LLA (AIEOP BFM ALL 2009).
Conclusioni: il nostro studio ha permesso di identificare un nuovo sottotipo di BCPALL, caratterizzato dall’espressione aberrante di CD371 e potenziale switch mielomonocitario durante la fase terapeutica di Induzione.

EPrint type:Ph.D. thesis
Tutor:Buldini, Barbara
Ph.D. course:Ciclo 31 > Corsi 31 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE SANITARIA
Data di deposito della tesi:30 November 2018
Anno di Pubblicazione:01 October 2018
Key Words:acute lymphoblastic leukemia, CD371, minimal residual disease, flow cytometry
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:11383
Depositato il:05 Nov 2019 17:39
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