| Leucemia Linfoblastica Acuta (LAL) |
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1. INFORMAZIONI GENERALI
2. PATOLOGIA E BIOLOGIA 3. DIAGNOSI 4. STADIAZIONE 5. PROGNOSI 6. TRATTAMENTO 7. SEQUELE TARDIVE 8. FOLLOW-UP Bibliografia Autori e Revisori Tradotto da
1. INFORMAZIONI GENERALI
1.1 Incidenza La Leucemia Linfoblastica Acuta (LAL) è rara negli adulti. Ogni anno, in Europa, vengono diagnosticati circa 10.000 nuovi casi. La LAL rappresenta circa il 15% delle leucemie nell'adulto: la forma cronica è cinque volte più frequente. La LAL è più comune negli uomini, con un rapporto maschio/femmina di 1.4. L'incidenza annua in Europa è di 1.3 casi ogni 100.000 per gli uomini e 0.9 per le donne. Negli adulti con più di 15 anni, la metà dei casi ha meno di 50 anni e sono rari quelli con più di 70 anni. La LAL è più comune nei bambini dove rappresenta il 30% di tutti i tumori e l'80% delle leucemie. In Europa l'incidenza annuale è 2-4 casi ogni 100.000 persone, molto simile a quella di altri paesi sviluppati. Il picco di incidenza si registra nei bambini di 4 anni e nelle bambine di 2 anni; quasi i due terzi dei casi riguardano bambini con età compresa tra i 2 e 6 anni. L'incidenza globale della LAL è stabile o in leggero aumento. Comunque, una sostanziale riduzione di mortalità, particolarmente in età pediatrica, con conseguente miglioramento della sopravvivenza, si è osservata a partire dagli anni settanta, grazie ai progressi fatti in campo terapeutico (Ferlay 1999; Ferlay 2001; Stewart 2003; Parkin 2002). 1.2 Sopravvivenza1.2.1 La prevalenza della LAL, cioè il numero di persone viventi con diagnosi di leucemia acuta linfoblastica, è di 38 su 100.000. 1.4 Fattori di rischioPer ciò che concerne i fattori di rischio legati alla LAL dell'infanzia si sa poco, eccezion fatta per l'esposizione prenatale ai raggi X ed alcune specifiche sindromi. Sesso, età, razza e condizione socioeconomica sono un gruppo di fattori di rischio noti. In generale, l'incidenza aumenta del 30% nei ragazzi rispetto alle ragazze, ed il rischio è circa 2 volte maggiore nei bambini bianchi rispetto ai neri. Uno stato socioeconomico (SES) elevato aumenta il rischio di diagnosi di LAL tra i 2-5 anni d'età, ma non si conosce quale aspetto particolare sia importante. L'esposizione a radiologia diagnostica in utero ha comportato in passato un aumento del rischio (1.5 volte), ma la giorno d'oggi le tecniche di "shielding" dovrebbero averlo ridotto. Il rischio di LAL da esposizione a radiazioni, come nell'incidente alla centrale nucleare di Chernobyl, era significativamente aumentato nei soggetti esposti a più di 10mSv. Condizioni genetiche come la sindrome di Down, la neurofibromatosi, la sindrome di Schwachman, la sindrome di Bloom, l'atassia telangiectasia, l'istiocitosi a cellule di Langherans e la sindrome di Klinefelter sono associate ad una maggiore frequenza di LAL. In particolare nella sindrome di Down è riportato un rischio 20 volte aumentato. Qualche studio ha riportato aumento del rischio in aree con campi elettromagnetici ad elevata intesità (Noshchenko 2002; Smith 1999; Little 1999). Molte professioni ed alcuni prodotti chimici utilizzati durante il lavoro sono associati con un aumentato rischio di LAL. Tra i 25 prodotti chimici considerati cancerogeni per l'uomo (IARC gruppo 1), il benzene e l'ossido di etilene sono associati alla leucemia. Nel gruppo di prodotti chimici considerati come probabili cancerogeni umani (IARC gruppo 2A) il 1,3 butadiene, il bifenile policlorinato sono correlati alla leucemia. Inoltre alcune industrie ed occupazioni sono classificate come cancerogene: calzaturifici, fabbriche di lavorazione della gomma (IARC gruppo 1) e raffinerie di petrolio (IARC Group 2A) (Stewart 2003). 1.5 RiferimentoPer la difficoltà e complessità della valutazione diagnostica e prognostica, la scelta di protocolli di trattamento adattati al rischio e all'età, la cura della malattia ed il trattamento delle complicanze ed il bisogno di un follow-up accurato e prolungato, è decisamente raccomandato con un livello di evidenza di tipo C, che i casi di LAL dell'adulto siano sempre inviati a centri Onco-Ematologici qualificati. 1.6 Revisionieziologia
2. PATOLOGIA E BIOLOGIA
2.1 Studio diagnostico 2.1.1 Classificazione morfologica
2.1.2 Immunofenotipo E' opinione generale considerare un livello del 20% come soglia minima per definire la positività dei blasti ad un anticorpo monoclonale. Circa il 75% delle LAL dell'adulto appartengono alla linea B. I marcatori B sono il CD19, CD20, CD22, CD24, e CD79a
(Hurwitz 1992, Huh 2000). I marcatori più precoci di linea B sono il CD19, CD22 (di membrana e citoplasmatico) e il CD79a (Campana 1988, Janossy 1989). Una reazione positiva isolata per almeno due di questi marcatori identifica la LAL pro-B. La presenza dell'antigene CD10 (CALLA) definisce il sottogruppo della LAL (comune). I casi positivi per IgM citoplasmatiche (solo catene pesanti di tipo mu), costituiscono il gruppo delle LAL pre-B, mentre la presenza di immunoglobuline di superficie con catene leggere monoclonali definisce la LAL B matura. Le LAL a cellule T costituiscono circa il 25% dei casi. I marcatori delle cellule T sono il CD1a, CD2, CD3 (di membrana e citoplasmatico), CD4, CD5, CD7 e CD8. Gli antigeni CD2, CD5 e CD7 sono i marcatori delle cellule T immature ma non sono assolutamente specifici, cosicchè la diagnosi inequivocabile di LAL-T si basa sulla dimostrazione del CD3 di superficie o intracitoplasmatico. Le LAL sia B che T possono esprimere antigeni mieloidi o l'antigene delle cellule staminali CD34. Quest'ultimo non ha rilevanza diagnostica ma può essere prognosticamente importante
(Czuczman 1999, Khalidi 1999, De Waele 2001). Il sistema di valutazione recentemente introdotto dal gruppo EGIL è rivolto alla caratterizzazione delle leucemie acute (LAL, di linea B o T, e mieloidi) attraverso l'utilizzo combinato di marcatori altamente linea specifici e altri di differenziazione cellulare, più alcuni marcatori delle cellule staminali. Il sistema ha introdotto una terminologia specifica per fase di maturazione nell'ambito delle LAL B e T (EGICL 1995) e si è dimostrato clinicamente adeguato (Thalhammer-Scherrer 2002). L'uso della classificazione EGIL viene raccomandato con un livello di evidenza di tipo R.
2.1.3 Citogenetica 2.1.4 Alterazioni genomiche 2.2.1
3. DIAGNOSI
3.1 Obiettività e diagnosi strumentale 3.1.1 Presentazione clinica 3.1.2 Esami di laboratorio 3.2.1 Campioni diagnostici appropriati 3.2.2 Adeguata manipolazione di campioni diagnostici
4. STADIAZIONE
4.1 Procedure di stadiazione Le procedure di stadiazione di routine nei casi di LAL dell'adulto includono
(Hoelzer 1991):
La LAL è una malattia disseminata sin dall'inizio. Così, sistemi di stadiazione come quelli utilizzati per altri tumori non risultano utili. Piuttosto, ogni quadro che rifletta una maggiore aggressività clinica dovrebbe essere considerato per una classificazione improntata al rischio .
5. PROGNOSI
5.1 Storia naturale La LAL non trattata è rapidamente fatale a seconda del grado di compromissione dell'emopoiesi, della citopenia relativa e degli effetti dei blasti circolanti e dei loro metaboliti sugli organi vitali. I casi non trattati muoiono rapidamente per infezione o emorragia. L'interessamento del SNC si verifica precocemente nei pazienti non trattati o trattati in modo inadeguato, specialmente quelli con LAL-B L3 e T (Fenaux 2001). La remissione completa (RC) viene raggiunta nel 70-85% dei pazienti. Il 10-20% dei pazienti decede durante la terapia di induzione, ed un altro 10% manifesta refrattarietà ai programmi di induzione. Oltre a ciò, più della metà dei pazienti che ottengono una remissione completa recidivano successivamente. Di questi, solo una minoranza può ottenere una seconda, duratura remissione con gli schemi di salvataggio attuali. In generale i moderni trattamenti consentono di curare il 20-40% circa dei pazienti con nuova diagnosi di LAL. 5.2 Fattori prognostici cliniciI più importanti fattori prognostici sono l'età del paziente ed il numero totale di leucociti o blasti circolanti; questi fattori esercitano un effetto prognostico cumulativo ed indipendente, sia sulla risposta al ciclo di induzione sia sulla successiva fase di consolidamento della remissione (Chessells 1995). 5.2.1 Età 5.2.2 Leucociti e blasti circolanti 5.2.3 Tempo alla remissione completa Si raccomanda con un livello di evidenza di tipo C di considerare immunofenotipo e citogenetica in modo congiunto, per identificare i diversi sottogruppi immuno-biologici di LAL. E' importante riconoscere le sindromi di LAL con prognosi infausta, che quindi richiedono approcci terapeutici non convenzionali. 5.3.1 Immunofenotipo 5.3.2 Citogenetica e biologia molecolare
5.4 Fattori predittivi 5.4.1 Meccanismi di farmacoresistenza 5.4.2 malattia minima residua I fenotipi anomali riflettono una contaminazione da LAL, in base base a combinazioni diverse e/o espressioni asincrone e/o intensità di espressione dei diversi antigeni (linea-B: CD19/CD34/TdT/CD10/CD22/CD45/CD38/CD45; linea-T: TdT, CD2/cyt CD3/CD5/CD7 etc.) (Coustan-Smith 1998, Ciudad 1998, Ciudad 1999, Griesinger 1999, Lucio-Parreira 1999, Van Wering 2000, Middleton 2000, Lucio- Parreira 2001, Coustan-Smith 2002 , Dworzak 2002, Sanchez 2002). In alternativa, la PCR (polymerase chain reaction) e la nuova RQ-PCR (real-time quantitative PCR) permettono di individuare sequenze specifiche di DNA riarrangiato, con un livello di sensibilità <10-5 (Kwan 2000). Possibili bersagli per PCR e RQ-PCR sono i riarrangiamenti associati con le più frequenti anomalie citogenetiche (linea-B: BCR-ABL per t(9;22), MLL-AF4 per t(4;11), TEL-AML1 per t(12;21), E2A-PBX1 per t(1;19), MYC-IgH per t(8;14); linea-T: RHOM2-TCRgamma per t(11;14), HOX11-TCRalpha per t(10;14), TAL1 deletion), oppure i riarrangiamenti delle immunoglobuline o di sequenze del recettore delle cellule T (TCRdelta e gamma, IgH, IgK-Kde), che sono unici per ciascun caso di LAL (Janssen 1994, Foroni 1997, Pongers-Willemse 1998, Szczepanski 1998, Foroni 1999, Neale 1999, Brumpt 2000 , Cimino 2000, Nakao 2000, de Haas 2000, Donovan 2000, Szcwepanski 2000, Nirmala 2002, van der Velden 2002a, van der Velden 2002b, Willemse 2002). In questi studi è obbligatorio ottenere due o più sonde per ogni caso, in previsione di una elevata percentuale di instabilità genomica che può comportare risultati falsamente negativi. Queste tecniche devono essere considerate criticamente nelle condizioni di altissimo rischio, come la LAL Ph+, dove l'ottenimento di uno stato di negatività MRD non è equivale alla cura, eccetto che dopo trapianto allogenico (van Rhee 1995, Radich 1997, Preud'homme 1997, Mitterbauer 1999, Dombret 2002, Yokota 2002). Inoltre, sia l' intervallo temporale che il numero dei test da eseguire probabilmente variano a seconda del sottotipo di LAL e del disegno dei protocolli di trattamento ( Biondi 2000). Lo studio della MRD potrebbe diventare il più sensibile ed accurato strumento per predire il rischio di recidiva dei pazienti in RC, e quindi per guidare la scelta della miglior terapia postremissionale. Pertanto la valutazione della MRD è raccomandata con un livello di evidenza 3 5.5 Gruppi di rischio5.5.1
Negli schemi prognostici recenti, l'immunofenotipo T non figura più come fattore sfavorevole. Tuttavia il nuovo sistema prognostico tedesco identifica casi LAL-T ad alto rischio. Si prevede, per il futuro, l'aggiunta delle infomazioni biologiche e emolecolari ai modelli di rischio clinico.
6.1 Principi della fase di induzione della remissione 6.1.1 Idratazione pre-trattamento 6.1.2 Chemioterapia d'induzione della remissione Comunque una sospensione precoce dio Lç-asparaginasi per reazioni avverse non ha impatto significativo su RC o DFS (Larson 1998b). L'asparaginasi peghilata, con una attività superiore nella LAL refrattaria pediatrica e dell'adulto (Abshire 2000, Aguayo 1999), dovuta a metabolismo più lungo, è in valutazione in diversi trials clinici (Gokbuget 2000, Larson 2000). Gli schemi a quattro/cinque farmaci si associano ad una percentuale di RC > 80% in diversi studi non controllati (Kantarjian 1993a, Larson 1995, Kantarjian 2000). I programmi di induzione di questo tipo (German multicentre ALL/GMALL phase 1, CALGB, MDACC) (Larson 1995, Hoelzer 1993a, Kantarjian 2000) possono attualmente essere considerati appropriati per l'utilizzo clinico con un livello di evidenza 3 per i
pazienti a basso rischio, e trattamento standard con un livello di evidenza di tipo R per pazienti a rischio intermedio-alto (Linker 1991, Nagura 1994, Kantarjian 1993a, Larson 1995, Hoelzer 1993a, Rohatiner 1990, Todeschini 1998, Bassan 2000, Kantarjian 2000, Halbook 2002). Con questi schemi, la RC dovrebbe ottenersi nel 75% o più dei pazienti a rischio intermedio e nel 90% dei pazienti a rischio standard
. Non c'è finora alcuna dimostrazione che regimi ad alte dosi diversi da V+P + antraciclina +/- ciclofosfamide e/o L-asparaginasi siano da considerare superiori. Trattamenti intensivi (es. introducendo alte dosi di citarabina, alte dosi di mitoxantrone o metotrexate) possono risultare dannosi per l'aumento di tossicità da farmaci (Weiss 1996, Wernli 1994, Weiss 2001). Quindi, regimi d'induzione più aggressivi restano materia sperimentale. I pazienti con LAL tipo Burkitt (morfologia L3 con fenotipo B-maturo/EGIL B-IV) dovrebbero ricevere trattamenti con programmi specifici che comprendono alte dosi frazionate di ciclofosfamide, citarabina, methotrexate, epipodofilotossine (Magrath 1996, Hoelzer 1996, Fenaux 2001, Lee 2001), con un livello di evidenza 3. Lo schema Iper-CVAD associato a terapia antivirale può essere usato nei pazienti HIV+ che sviluppano una LAL-B L3
(Cortes 2002).
**che corrisponde all'intisificazione precoce nei pazienti che raggiungono la risposta entro 4 settimane. Farmaci: V, vincristina; P, prednisolone; mP, metilprednisolone; Dex, desametasone DNR, daunorubicina; ADR, adriamicina; ASP, L-asparaginasi; CY, ciclofosfamide; Ara-C, citosina arabinoside; MP, mercaptopurina; MTX, methotrexate. SNC sistema nervoso centrale 6.1.3 Effetti collaterali e complicanze dei regimi d'induzione della remissione 6.1.4 Fattori di crescita mieloide durante l'induzione della remissione 6.2.1 Terapia di consolidamento
*ara-C, citosina arabinoside; VM-26, teniposide; DXM, desametasone; VCR, vincristina; ADR, adriamicina; TG, 6-tioguanina; MP, mercaptopurina; MTX, methotrexate. Tipo di somministrazione: i.v., endovena; p.o., orale.
*MTX, methotrexate; CY, ciclofosfamide; MP, mercaptopurina; ara-C, citosina arabinoside; VCR, vincristina; ASP, L-asparaginasi; ADR, adriamicina; DXM, desametasone; TG, 6-tioguanina. Tipo di somministazione: i.t., intratecale; i.v., endovena; p.o., orale; s.c., sottocutanea.
*MTX, methotrexate; MP, mercaptopurina; ara-C, citosina arabinoside; VCR, vincristina; P, prednisone; mP, metilprednisolone; IFN, alpha-interferone **Ciclo 1 come ciclo di induzione, cicli 2-8 come cicli di consolidamento Tipo di somministrazione: i.t., intratecale; i.v., endovena; p.o., orale; s.c., sottocutanea.
*simile al protocollo base GMALL più assegnazione random a: braccio A: Ara-C ad alte dosi+ mitoxantrone o braccio B: methotrexate ad alte dosi + L-asparaginasi **la seguente sequenza viene ripetuta una volta: 1.daunorubicina/vincristina/prednisone/L-asparaginasi; 2. alte dosi di Ara-C/VP-16; 3. alte dosi di metotrexate/mercaptopurina. Mantenimento standard con mercaptopurina/metotrexate. 6.2.2 Profilassi del sistema nervoso centrale (SNC) 6.2.3 Terapia di mantenimento 6.3.1 Reinfusione di cellule staminali emopoietiche autologhe ed allogeniche 6.3.2 Purificazione di cellule staminali autologhe
6.3.3 Ruolo del regime di condizionamento 6.4.1 Prevenzione e trattamento delle complicanze metaboliche 6.4.2 Trattamento delle infezioni Il trattamento empirico standard, con un livello di evidenza di tipo C, nei pazienti febbrili, è la monoterapia con una cefalosporina di terza generazione o con un carbapenemico (Freifeld 1995, Sanders 1991) o, meglio ancora, una terapia combinata. In questo caso, si raccomanda l'uso di un antibiotico anti Pseudomonas (penicillina ad ampio spettro o cefalosporina di nuova generazione) più un aminoglicoside. L'aggiunta di un terzo antibiotico per batteri Gram positivi (vancomicina o teicoplanina) o di un antifungino (anfotericina B, anfotericina B liposomiale), o ulteriori modifiche della terapia iniziale (imipenem, aztreonam, metronidazolo, clindamicina, cotrimosazolo), è appropriato per uso clinico individualizzato sulla base di indagini microbiologiche e dell'andamento clinico. L'uso routinario della vancomicina, senza infezione del catetere, non è raccomandato con un livello di evidenza 1 (Ramphal 1992, EORTC 1991). La persistenza di febbre in assenza di isolamenti microbiologici richiede la ricerca di infezioni fungine profonde, di eventuali infezioni virali e di cause non infettive come le reazione a farmaci o la sindrome da recupero ematologico. L'uso profilattico dei nuovi azolici (fluconazolo ed itraconazolo) non è stato ancora associato ad una chiara riduzione dell'infeziosità e dell'uso terapeutico di anfotericina B (Winston 1993). L'utilizzo profilattico di questi farmaci dovrebbe essere considerato appropriato per uso clinico individualizzato con un livello di evidenza di tipo R. La terapia antimicotica empirica va iniziata in caso di febbre per oltre 3-5 giorni dopo l'avvio della terapia antibiotica ad ampio spettro. Le infezioni da virus herpetici si trattano con acyclovir. La profilassi con acyclovir orale, nei pazienti con sierologia positiva per HSV, è raccomandata con un livello di evidenza 2 (Saral 1983). L'infezione da citomegalovirus si tratta con immunoglobuline, ganciclovir o foscarnet, e, nei pazienti CMV negativi, con la trasfusione di emoderivati da donatori CMV negativi. L'infezione da VZV si tratta con acyclovir per via endovenosa. La somministrazione precoce di immunoglobuline anti VZV (entro 96 ore) è raccomandata per ridurre il rischio di infezione dopo esposizione. 6.4.3 Trattamento delle alterazioni della coagulazione
Una terapia di supporto ottimale è il primo intervento richiesto per tutti i pazienti. I programmi d'induzione convenzionali basati sulla combinazione di vincristina e prednisone più un'antraciclina sono il trattamento standard con un livello di evidenza 2 (Gottlieb 1984, Stryckmans 1992). L'aggiunta di un quarto o quinto farmaco, come la L-asparaginasi e la ciclofosfamide, nel programma di induzione può essere considerato appropriato per uso clinico individualizzato, con un livello di evidenza 3, per i pazienti a basso rischio e raccomandato come trattamento standard, con un livello di evidenza di tipo R, nei pazienti a rischio intermedio ed alto (Kantarjian 1993a, Larson 1995, Hoelzer 1993a, Rohatiner 1990, Kantarjian 2000). L'aumento dell' intensità del trattamento oltre questo limite (per esempio con citarabina ad alte dosi, methotrexate) può essere controindicato per l'aumento della tossicità (Weiss 1996, Wernli 1994, Bassan 1993). Non c'è finora alcuna dimostrazione che regimi ad alte dosi diversi da V+P + antraciclina +/- ciclofosfamide e/o L-asparaginasi siano superiori. Questi regimi restano materia di studio. L' utilizzo del G-CSF alle dosi di 5 mg/Kg/die in aggiunta alla terapia di induzione è raccomandato con un livello di evidenza 1 (Ottmann 1995, Ottmann 1996, Larson 1998a, Geissler 1997, Ottmann 1998), in particolar modo negli schemi più mielotossici che utilizzano antracicline in tre giorni consecutivi e negli anziani. La profilassi precoce del SNC durante il ciclo di induzione è il trattamento standard con un livello di evidenza di tipo C. 6.6 Strategia postremissione: approcci differenti per classi di rischio o trattameno uniforme?Sono possibili tre diversi approcci post-remissionali, nessuno dei quali si è finora dimostrato superiore. La prima opzione è incentrata sulla classe di rischio clinico, e comporta la variazione del tipo e della intensità del trattamento in funzione della classe di rischio. I pazienti a rischio basso-intermedio e/o con caratteristiche diagnostiche particolari (es. LAL-T, LAL-B) sono trattati con programmi chemioterapici che incorporano elementi specifici, mentre le terapie ad alte dosi con trapianto sono riservati ai sottogruppi ad alto rischio. Questa strategia sviluppata nell'ultimo decennio dal gruppo GMALL ed altri ( Gokbuget 2000, Goekbuget 2001, Bassan 2001, Hunault 2001, Linker 2001), è soggetta a modifiche considerando il ruolo predittivo per la ricaduta della malattia minima residua. La seconda opzione comporta una comparazione diretta (randomizzazione) tra i vari trattamenti, cercando in primo luogo di definire quale sia il migliore. Alcuni studi sono stati pubblicati e aggiornati (Horowitz 1991, Fière 1993, Sebban 1994, Attal 1995, Ueda 1998, Oh 1998, Thiebaut 2000, Thomas 2001b) and some are ongoing (Ribera 2000, Durrant 2000, Rowe 2001). Questa seconda opzione comporta un rischio di sovratrattamento per molti pazienti a basso rischio (Gale 1998, Finiewicz 1999), considerando una mortalità da trapianto che può arrivare al 21% (Rowe 2001). La terza possibilità consiste nell'applicazione di una chemioterapia o di un regime basato sull'autotrapianto, ricorrendo al trapianto allogenico solo nei casi ad altissimo rischio come quelli con LAL Ph+ e LAL t(4;11) (Larson 1995, Todeschini 1998, Daenen 1998, Bassan 1999a, Kantarjian 2000, Martin 2001a, Powles 1995, Forman 1997, Powles 2002). In questi studi, il ruolo esatto del trapianto autologo e del mantenimento post-trapianto non è definito. 6.7 Strategia postremissionale per pazienti a basso rischioUn programma di chemioterapia standard viene considerato adeguato per i pazienti con LAL a basso rischio con un livello di evidenza di tipo C (Hoelzer 1994, Stryckmans 1992, Ellison 1991, Marcus 1986, Larson 1995, Hoelzer 1993a, Hoelzer 1993b, Lluesma-Gonalons 1991, Todeschini 1998, Kantarjian 2000, Bassan 2001). Una terapia di mantenimento prolungata, dopo consolidamento, è considerata terapia standard con un livello di evidenza di tipo C, eccetto che per la LAL-B matura. Il trapianto di midollo allogenico non è considerato necessario, non essendovi esperienze che ne dimostrino la chiara superiorità (Gale 1998 , Finiewicz 1999, Thiebaut 2000). Per questi pazienti, il ruolo di un trattamento ad alte dosi in prima remissione è in fase sperimentale (Durrant 2000). 6.8 Strategia postremissionale per pazienti a rischio intermedio6.8.1 6.9.1 Quando possibile, il trapianto allogenico piuttosto dell' autologo è appropriato per uso clinico individualizzato con un livello di evidenza 2 (Fière 1993, Vernant 1988, Attal 1995, Dombret 2002). Nei pazienti ad alto rischio senza donatori compatibili (Horowitz 1991, Zhang 1995, Sierra 1993, Doney 1993, Tiley 1993, Carella 1994, Powles 1995, Martin 2001a, Hunault 2001), il supporto di cellule staminali autologhe può essere considerato appropriato per uso clinico individualizzato, nonostante nessun trial clinico abbia dimostrato una sucura efficacia di questo approccio in questa classe di rischio (Thiebaut 2000, Bassan 2001, Ribeira 2000, Durrant 2000, Linker 2001, Sotomayor 2002). Un prolungamento della sopravvivenza, in un piccolo gruppo di pazienti con LAL Ph+, potrebbe essere ottenuto con doppio trapianto autologo di cellule staminali purificate (Martin 1999, Atta 2000). Il trapianto allogenico da donatore familiare parzialmente compatibile o da donatore compatibile non familiare potrebbe essere considerato sperimentale in pazienti ad alto rischio senza donatore compatibile, ed è specialmente indicato nei casi Ph+ (Szydlo 1997, Marks 1998, Arnold 2002). Non si conosce ancora iI ruolo del trapianto aploidentico nella LAL (Aversa 1996). 6.10 LAL nell'anzianoI pazienti con età >60 anni costituiscono un gruppo prognostico particolare con percentuali di remissione e sopravvivenza inferiori. L'incidenza della LAL dell'anziano varia dal 15 al 31% nell'ambito degli studi clinici sulla LAL dell'adulto; il valore più alto riguarda uno studio di popolazione (Annino 2002a, Taylor 1992). La percentuale di remissione in questo gruppo, utilizzando protocolli con quattro o cinque farmaci, varia dal 39% al 77% ( Ferrari 1995, Bassan 1996c). Tuttavia, la durata della remissione e della sopravvivenza, nonostante la somministrazione di più farmaci e di un consolidamento relativamente intensivo, risulta essere <10% a 3 anni in tre studi e solo 5% a 5 anni in uno studio più recente (Thomas 2001b). In un sottogruppo di pazienti relativamente più giovani (50-65 anni), il gruppo GMALL, con il protocollo 04/89, ha riportato un miglioramento di DFS: 31% a 3 anni. In conclusione, il trattamento standard nei pazienti anziani, con un livello dievidenza di tipo R, dovrebbe includere un ciclo d'induzione a dosi convenzionali, mantenimento e maintenance come nei pazienti più giovani. Tuttavia, le riduzioni delle dosi sono frequenti poiché difficilmente i pazienti più anziani tollerano dosaggi pieni (Ferrari 1995, Kantarjian 1994, Legrand 1997, Thomas 2001a). La somministrazione del fattore di crescita granulocitario nei pazienti anziani è raccomandato con un livello di evidenza 2 (Larson 1994). 6.11 LAL in gravidanzaPoiché i chemioterapici utilizzati nella LAL sono teratogeni, soprattutto gli antifolici e gli alchilanti, la gravidanza non é raccomandato durante il trattamento, in particolare nel primo trimestre, con un livello di evidenza di tipo C (Zuazu 1991). Se, tuttavia, la gravidanza è assolutamente desiderata, il successivo trattamento non dovrebbe essere rimandato poichè ciò riduce significativamente le possibilità di cura della madre. Il trattamento standard di questi casi, considerando la classe di rischio del paziente, dovrebbe cercare di evitare i farmaci più tossici come antifolati, alchilanti e la radioterapia. Durante ogni ciclo di chemioterapia è stato osservato un transitorio oligoidramnios del feto. Non appena il feto raggiunge il limite della vitalità, è consigliato indurre il parto od il parto cesareo (Zuazu 1991, Durie 1977, Fassas 1984, Hansen 2001). 6.12 Criteri di risposta e ristadiazione6.12.1 Definizione di risposta 6.12.2 Strategia di ristadiazione e problemi di valutazione della risposta 6.13.1 Chemioterapia della recidiva 6.13.2 Trapianto di cellule staminali come terapia di salvataggio
6.13.3 Salvataggio della malattia refrattaria 6.14.1 Terapia biologica 6.14.2 Indicazioni per la terapia biologica
Nuove possibilità terapeutiche stanno forse emergendo dai campi di ricerca nell'apoptosi e nella farmacoresistenza. Sono in fase di studio sistemi per contrastare la MDR e gli altri meccanismi di farmacoresistenza. E' stata dimostrata in vitro la possibilità di inibire il fenomeno della MDR con l'uso della ciclosporina o del PSC 833 (Slater 1986, Gonzalez 1995, Jiang 1995). La riduzione della captazione cellulare del metotrexate è molto più comune nella LAL dell'adulto rispetto a quella del bambino. Recenti studi su topi SCID che ospitano la linea T-linfoblastica CCRF-CEM metotrexate-resistente hanno mostrato che la combinazione di trimetrexate con rescue di acido folico seguita ancora da methotrexate senza acido folico può ridurre la resistenza al primo farmaco (Lacerda 1995). I meccanismi di resistenza alla citarabina sono poco conosciuti nella LAL dell'adulto, probabilmente per l'uso limitato di questo farmaco. Le alte dosi di Ara-C sono una componente dei nuovi regimi; si rende quindi necessaria una adeguata valutazione di questo problema. L'esperienza recente nella LAM a basso rischio indica una modulazione della resistenza all'Ara-C da parte dell'analoga purina fludarabina, attraverso l'inibizione della kinasi deossicitidina e l'aumento intracellulare dell'Ara-CTP (Gandhi 1995). Non ci sono ancora metodi noti per superare la farmacoresistenza alle tiopurine o quella dovuta alla glutatione-s-transferasi. Sia il topotecan, un nuovo inibitore della topoisomerasi I, sia l'IL-4 sono risultati efficaci nel provocare la morte cellulare per apoptosi nelle cellule LAL-B radioresistenti, incluse le cellule t(4;11)+, t(8;14)+ e t(9;22)+ (Kantaraijan 1993b, Manabe 1994, Uckun 1995). Altri nuovi farmaci sono la troxacitabina, un inibitore farnesiltransferasi, il composto GW 506 per la LAL-T, e gli agenti antiangiogenesi (Giles 2001, Karp 2001). Tutte queste forme di trattamento devono essere considerate sperimentali. I risultati riguardanti l'ingegneria molecolare, dagli oligonucleotidi antisenso alla terapia genica, sono teoricamente interessanti ma non ancora sufficientemente sviluppati per essere impiegati in campo clinico. 6.15.1 Ultimi sviluppi
7. SEQUELE TARDIVE
7.1 Effetti tardivi del trattamento 7.1.1 I tumori secondari possono insorgere successivamente a pregressi regimi chemio-radioterapici. I farmaci anti LAL inclusi gli alchilanti, etoposide e la radioterapia aumentano il rischio di seconda neoplasia (Pederson-Bjergaard 1991). L'incidenza stimata di seconda neoplasia sembra in aumento nel tempo, da 0.59% a 3.63% (solo i tumori ematologici secondari, 942/1170 in pazienti in remissione) rispettivamente, a 5 e 10 anni, come documentato da una grande analisi retrospettiva del gruppo GIMEMA (Pagano 1998), al 8% e 27% (tutti gli altri tumori) rispettivamente, a 10 e 20 anni, in una piccola popolazione (34 pazienti) nel Bart's Hospital (Micallef 2001). I pazienti survivors al trapianto hanno una incidenza globale di neoplasie secondarie di 0.6/100 persone anno, che corrisponde al 6% (no TBI) e 10 % (TBI) a 10 anni. I tumori posttrapianto in ordine di prevalenza sono le malattie linfoproliferative (che possono essere o no associate all'infezione da EBV), carcinoma, glioblastoma, leucemia acuta (ALL>AML), sindrome mielodisplastica, e melanoma. Molti di questi tumori sono mortali. L'etoposide, il cui utilizzo nella LAL è aumentato, induce alterazioni cromosomiche nella regione del 11q, portando rapidamente (in 2 anni) ad una leucemia acuta mielomonocitica/monoblastica con riarrangiamenti del 11q23. Il rischio di questa complicanza può aumentare con l'uso contemporaneo degli inibitori della topoisomerasi II e della L-asparaginasi (Pui 1995), ed era superiore al 6% in un recente studio pediatrico (Winick 1993). In qualunque modo, non si cononosce ne l'incidenza della LAL 11q23 ne i fattori di rischio nei pazienti con LAL survivors. The recently described occurrence of secondary ALL with chromosomal rearrangements at 11q23 raises the challenging question of therapy-related ALL (link 1.2) in patients previously cured of ALL.
8. FOLLOW-UP
8.1 Principi generali ed obiettivi La scoperta della recidiva ed il trattamento delle complicanze sono i due obiettivi di un regolare follow-up. I pazienti in remissione senza complicanze che hanno un buon performance status vanno incoraggiati a riprendere gradualmente a lavorare ed ad condurre una vita normale. Al termine del trattamento, è possibile dire al paziente o ai parenti quali sono le possibilità di cura in quel caso specifico. Dovrebbe essere anche sottolineato il fatto che anche alla recidiva è possibile una terapia con intento curativo. Because of this possibility, patient's notes must include retreatment plans and family HLA and DR typing. 8.2 Protocolli suggeritiDurante la fase di mantenimento è raccomandato, con un livello di evidenza di tipo C, di monitorare accuratamente i pazienti ogni 2-3 settimane, per migliorare l'aderenza al protocollo e l'appropriata assunzione dei farmaci. Il dosaggio dei farmaci va modificato in modo da ottenere una conta di leucociti tra 2.5-3 x109/l. Poiché non vi è dimostrazione che la scoperta precoce di una recidiva subclinica alteri il successivo trattamento e la prognosi, non è raccomandato eseguire periodici aspirati midollari. Allo stesso modo, in pazienti in remissione asintomatici non è raccomandato eseguire rachicentesi esplorative. La scoperta di una precoce recidiva molecolare durante il periodo di monitoraggio della MRD può aumentare il problema di trattare pazienti asintomatici. Questo problema dovrebbe essere affrontato in studi clinici ben disegnati. I casi che sviluppano una inspiegata citopenia devono innanzitutto sospendere la terapia e poi essere rivalutati ad intervalli settimanali. L'aspirato midollare viene eseguito se c'è una progressione della citopenia o compaiono blasti nello striscio di sangue periferico. Esami ematochimici di routine devono essere eseguiti periodicamente, poiché i farmaci di mantenimento possono alterare la funzionalità epatica. Una modesta alterazione delle transaminasi non richiede una riduzione della terapia, ma essendo pazienti politrasfusi, è raccomandato eseguire la sierologia per le epatiti B e C. Al termine di tutta la chemioterapia, i pazienti potranno essere seguiti ad intervalli di 2-3 mesi per il primo anno ed ad intervalli maggiori nel periodo successivo fino ad una volta all'anno dal quinto anno in poi. Gli esami a cui vengono sottoposti questi pazienti sono rivolti ad individuare, eventualmente, la malattia (linfonodi, fegato, milza, fundus oculi) ed emocromo completo con formula. Altri esami e l'aspirato midollare dipenderanno dai sintomi attuali ed eventuali problemi.
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Dr. Renato Bassan (Associate Editor) Dr. Gemma Gatta (Consultant) Dr. Carlo Tondini (Editor)
Dr. Roel Willemze (Reviewer)
Dr.ssa Tamara Intermesoli
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