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Bettiol, Alessandra (2018) Valutazione del management del paziente affetto da leucemia mieloide cronica nella pratica clinica dell'Azienda ULSS 2 marca trevigiana, distretto di Treviso
Evaluation of the management of patients affected by chronic myeloid leukemia in the clinical practice of the Health Authority n.2 Marca Trevigiana, Distric of Treviso.
[Ph.D. thesis]

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Abstract (english)

Introduction
Chronic myeloid leukemia (CML) is a myelodysplastic neoplasia accounting for around 15% of all cases of leukemia in adults. CML treatment is mainly based on tyrosine kinase inhibitors (TKIs). Current TKIs approved as first line treatments are imatinib or second-generation TKIs such as dasatinib and nilotinib. Overall, TKIs have modified the natural progression of CML, prolonging survival. As CML has progressively switched from a fatal to a “chronic” pathology, time-limited clinical trials may not evaluate such long-term outcomes adequately. On the brink of the commercialization of generic imatinib, this thesis examines a decade of CML management in the real clinical practice, focusing on treatment effectiveness, therapeutic switches, and adverse effects (AEs).
Methods
A retrospective cohort study was performed on all CML patients followed up in the Local Health Authority of Treviso (Region of Veneto, Italy) between 2005 and 2015. Data were captured integrating both administrative databases and physicians' patient record. The therapeutic pattern was evaluated separately according to CML phase at diagnosis, considering frontline treatments, occurrence of treatment switches and their causes. For patients diagnosed in chronic phase (CP), the effectiveness of different frontline TKIs was assessed using an intention-to-treat approach, considering the achievement of complete hematologic, cytogenetic and molecular response. Occurrence of AEs among different frontline TKIs treatments was compared. All data and statistical analysis were performed using the software STATA version 14.
Results
A total cohort of 119 CML patients was examined; the majority of them were diagnosed in CP (n=97). 60% of subjects were asymptomatic at diagnosis; even when present, symptoms were mainly unspecific. Imatinib was the most common first line treatment for CP subjects (n=73); among second generation TKIs, only nilotinib was used as first line. Nilotinib proved more effective than imatinib, both considering achievement of responses and treatment switches; 28 CP-CML patients with frontline imatinib needed to switch, mainly due to intolerance but there were no therapeutic switches in patients with frontline nilotinib. AEs were common; in particular, osteoarticular pain was significantly more frequent for imatinib compared to nilotinib (50 out of 73 vs 2 out of 8, respectively; p=0.02).
Conclusion
Although based on a small population, this study shows the importance of choosing the most appropriate frontline treatment, in order to allow rapid disease control. Results indicate a superiority of nilotinib as first line therapy for CP-CML, both in terms of effectiveness and of treatment switches and AEs occurrence. While this might be seen as an argument to use nilotinib first line, it might also argue strongly for the continued use of imatinib first line, reserving nilotinib for imatinib intolerant or resistant patients. AEs remain a major concern, highlighting the importance of close monitoring of patients. A full health economic evaluation is required to determine the most cost effective care pathways using these expensive drugs.

Abstract (italian)

Introduzione
La leucemia mieloide cronica (LMC) è una neoplasia mielodisplastica che rappresenta circa il 15% di tutti i casi di leucemia negli adulti. Il trattamento della LMC è principalmente basato sui farmaci inibitori della tirosin chinasi (TKI); in particolare, i TKI attualmente approvati per il trattamento dei pazienti di nuova diagnosi sono l'imatinib e i TKI di seconda generazione quali dasatinib e nilotinib. Complessivamente, questi farmaci hanno radicalmente modificato la naturale progressione della patologia, prolungando significativamente la sopravvivenza di questi pazienti. Alla luce della progressiva cronicizzazione della LMC, i dati provenienti da trials clinici condotti su brevi periodi di studio risultano inadeguati nella valutazione di outcome a lungo termine. All'alba della commercializzazione dell'imatinib generico, questa tesi si propone di esaminare il management della LMC nella reale pratica clinica, focalizzando l'attenzione sull'effectiveness dei trattamenti, sull'occorrenza di switch terapeutici e sugli effetti avversi (EA).
Metodi
E'stato condotto uno studio di coorte retrospettivo sui pazienti affetti da LMC e seguiti presso l'Azienda ULSS 2 Marca Trevigiana, distretto di Treviso (Regione del Veneto, Italia), nel periodo compreso tra il 2005 e il 2015. I dati sono stati ottenuti integrando i flussi amministrativi e le informazioni contenute nei diari clinici di reparto. Il pattern terapeutico è stato valutato separatamente a seconda della fase di esordio della LMC, considerando il trattamento di prima linea, l'eventuale occorrenza di switch terapeutici e la relativa motivazione. Per i pazienti esorditi in fase cronica (FC), è stata inoltre valutata l'effectiveness dei diversi TKI prescritti in prima linea, impiegando un approccio intention-to-treat, e considerando il raggiungimento della risposta ematologica completa, citogenetica completa, e molecolare maggiore e completa. Il verificarsi di EAs è stato comparato tra i diversi TKI prescritti in prima linea. Tutte le analisi statistiche sono state condotte impiegando il software STATA versione 14.
Risultati
La coorte in esame comprendeva 119 soggetti affetti da LMC. La maggior parte era esordita in FC (n=97). Il 60% dei soggetti risultava asintomatico al momento della diagnosi; anche quando presenti, i sintomi erano principalmente aspecifici. L'imatimib era il farmaco di prima linea maggiormente usato nei soggetti in CP (n=73), mentre tra i TKI di seconda generazione solamente il nilotinib era impiegato in prima linea. Il nilotinib risultava più efficace dell'imatinib sia nell'indurre il raggiungimento di risposte profonde sia in termini di switch. Infatti, 28 pazienti esorditi in FC e trattati con imatinib erano andati incontro ad uno switch terapeutico, principalmente a causa di intolleranza al trattamento. Al contrario, non si riscontravano casi di switch tra i pazienti in FC trattati con nilotinib in prima linea. Gli EAs erano comuni; in particolare, il dolore osteoarticolare risultava significativamente più frequente nei soggetti in FC trattati con imatinib rispetto a nilotinib (50 su 73 soggetti in imatinib vs 2 su 8 soggetti in nilotinib, rispettivamente; p=0.02).
Conclusioni
Nonostante l'esigua coorte di soggetti in esame, questo studio ha messo in luce l'importanza di un'accurata scelta del trattamento farmacologico nei soggetti con nuova diagnosi di LMC, al fine di garantire un rapido controllo della patologia. I risultati di questo studio indicano una superiorità del nilotinib come terapia di prima linea nei soggetti con LMC in FC, in termini di effectiveness, di switch terapeutici, e di occorrenza di EAs. Nonostante questi dati siano a favore di un maggior uso di nilotinib in prima linea, i risultati di questo studio mostrano un ruolo ancora centrale dell'imatinib come trattamento di prima scelta nei soggetti in FC, riservando la terapia con nilotinib ai casi di intolleranza o resistenza all'imatinib. Inoltre, questo studio evidenzia come gli EAs rimangono un problema centrale nella gestione dei soggetti con LMC, sottolineando l'importanza di un attento monitoraggio di questi pazienti. Un'accurata valutazione economica risulta di cruciale importanza al fine di determinare il pattern di trattamento più costo-efficace, alla luce dell'alto costo di questi farmaci.

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EPrint type:Ph.D. thesis
Tutor:Giusti, Pietro
Ph.D. course:Ciclo 30 > Corsi 30 > SCIENZE FARMACOLOGICHE
Data di deposito della tesi:12 January 2018
Anno di Pubblicazione:12 January 2018
Key Words:leucemia mieloide cronica; reale pratica clinica; imatinib; nilotinib chronic myeloid leukemia; real clinical practice; imatinib; nilotinib
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:10701
Depositato il:09 Nov 2018 09:38
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