BA no BE no BE sì Klebsiella CA no DI sì Klebsiella DI no FA no MA sì Klebsiella MA no MI sì Aspergillus PE sì Klebsiella SA no
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4. CONCLUSIONI
Sulla base dei dati appena mostrati sembra evidente come la Decitabina, nel nostro caso specifico, ma più in generale gli agenti ipometilanti, abbiano un ruolo cruciale nel
trattamento dei pazienti affetti da Leucemia Mieloide Acuta sopra i 65 anni di età: si rendono responsabili infatti di una risposta positiva non solo nel migliorare
quantitativamente la vita dei pazienti, ma anche e soprattutto qualitativamente.
Nonostante i 4 decessi e soprattutto, nonostante un unico caso in cui la valutazione midollare abbia certificato una remissione completa, dobbiamo focalizzare la nostra attenzione sugli altri pazienti che non hanno avuto progressione di malattia, che sono rimasti esattamente allo stesso stadio in cui erano prima di iniziare la terapia e che per raggiungere questo obbiettivo non sono stati sottoposti a particolari tossicità.
È sicuramente un dato incontrovertibile come la chemioterapia standard dia dei risultati migliori in termini di remissione e sopravvivenza, ma questo a prezzo di tossicità e mortalità elevate che in pazienti anziani e soprattutto "unfit” non sono tollerabili; infatti prima dell’avvento dei farmaci ipometilanti, per la preoccupazione da un lato per la resistenza terapeutica, dall’altro della tossicità eccessiva o addirittura della mortalità correlata al trattamento, molti pazienti anziani considerati non idonei da un punto di vista medico (“unfit” appunto) a sopportare trattamenti intensivi, non venivano sottoposti a chemioterapia standard. Ed è proprio in questi pazienti che la Decitabina rappresenta ad oggi un’alternativa terapeutica efficace e ben tollerata con effetti collaterali accettabili.
Il punto focale da tenere sempre a mente è infatti che stiamo parlando di pazienti over 65, con altre comorbidità e per questo con un performance status di partenza non certo ottimale, che però, nonostante il trattamento chemioterapico cui sono sottoposti e che sta dando dei buoni risultati, non vedono modificare in maniera importante il loro stato di salute.
In questo sicuramente aiuta il fatto che la Decitabina mostri effetti terapeutici a bassi dosaggi, nonché il suo scarso metabolismo epatico e la minima quota di farmaco immodificata escreta con le urine, tutte condizioni che fanno sì che il composto
64
interagisca poco con la normale popolazione cellulare. Altro punto cruciale è che il farmaco, per essere attivato, deve subire delle fosforilazioni sequenziali, reazioni
enzimatiche che avvengono soprattutto all’interno delle cellule leucemiche: ecco perché si assiste a una bassissima tossicità (3 pazienti su 12 nel nostro caso). Infine, ma non per questo meno importante, il trattamento con Decitabina si rende sì responsabile di eventi avversi tra cui quelli infettivi, conseguenti alla lisi leucemica, ma meno gravi rispetto a quelli indotti da chemioterapia standard in cui spesso le infezioni trattamento-correlate sono causa di morte.
In conclusione quindi il trattamento meno aggressivo della Leucemia Mieloide Acuta in pazienti over 65 anni con agenti ipometilanti quali la stessa Decitabina, ci permette di ottenere dei buoni risultati in termini di sopravvivenza accompagnati da una buona tolleranza degli eventi avversi, soprattutto considerando che spesso abbiamo a che fare con pazienti “unfit” dal punto di vista medico. In questo senso dovrebbero essere quindi incentivati gli studi che portino ad una miglior definizione dei criteri di ineleggibilità alla chemioterapia standard, considerando anche che l’incidenza della malattia sta
aumentando proprio nei pazienti anziani, in modo da avere una migliore stratificazione, e, con l’obbiettivo di migliorare la risposta alla terapia e mantenerla nel tempo, dovrebbe essere perseguita la ricerca di nuove combinazioni di farmaci includenti la stessa
Decitabina, con una maggiore specificità d’azione e una conseguente minor tossicità, da indirizzare soprattutto nel trattamento dei pazienti anziani.
Ad esempio, presso l’U.O. Ematologia di Pisa si stanno utilizzando due protocolli che prevedono l’uso di nuovi farmaci in fase di sviluppo, ovvero il protocollo MIRROS basato sulla somministrazione nei pazienti con forme di Leucemia refrattarie al trattamento, di Idasanutlin, un inibitore di MDM2, il gene trascrivente per l’omonima proteina che ha la funzione di inibire p53, fondamentale oncosoppressore tumorale, associato ad alte dosi di Citarabina, oppure il protocollo QUANTUM FIRST che prevede l’uso di Quizartinib, un inibitore di FLT3-IDT, recettore fondamentale per la sopravvivenza e differenziazione delle cellule ematopoietiche, nei soggetti alla diagnosi di Leucemia Mielodie Acuta con tale mutazione, con l’intento di avere migliori risposte terapeutiche e una maggior
sopravvivenza, agendo su bersagli farmacologici sempre più specifici, associati a una buona tollerabilità da parte di tutti i pazienti.
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Da queste basi è auspicabile una possibile applicazione futura di questi farmaci (magari in associazione proprio con la Decitabina) anche nei pazienti “unfit”, che potranno
66
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