Efficacy of liposomal daunorubicin and cytarabine as reinduction chemotherapy in relapsed acute lymphoblastic leukaemia despite expression of multidrug resistance-related proteins.
The treatment of relapsed adult acute lymphoblastic leukaemia (ALL) is frequently unsuccessful with current chemotherapy regimens, and often there is an overexpression of multidrug resistance (MDR)-related proteins. Liposomal encapsulation makes daunorubicin (DNR) less sensitive to the efflux effect of P-glycoprotein (PGP), and in vitro data indicate that liposomal-encapsulated DNR (Daunoxome-DNX) is more toxic than DNR against ALL cell lines. In this study, we assessed the in vivo and in vitro efficacy and toxicity of DNX plus cytarabine (Ara-C) as reinduction chemotherapy in 25 relapsed ALL patients (pts). The expression of MDR-related proteins (PGP, MRP1 and LRP) was also analysed. Of the 25 pts, 12 were males and 13 females; median age was 32 yr (range 18-58). Six cases were ALL T and 19 ALL B; eight pts were Ph+ (32%), and nine Bcr-Abl+ (36%). The expression of MDR-related proteins, and DNR and DNX retention and induction of apoptosis in leukaemic cells were evaluated in all cases. Seventeen of 25 (68%) pts were at first relapse and eight (32%) at second or subsequent relapse. The DNX was given in a dose of 80 mg/m(2)/d (days 1-3) in 11/25 pts (44%) and in a dose of 100 mg/m(2)/d (days 1-3) in 14/25 pts (66%). In all pts, Ara-C was administered in a dose of 2 g/m(2) (days 1-5). Twenty pts (80%) achieved a complete remission (CR) and two (8%) entered a partial remission (PR) for an overall response (OR) rate of 88% (22/25), with a tolerable toxicity and without significant cardiotoxicity. Before the start of DNX therapy, 18/25 (72%) cases overexpressed at least one MDR-related protein compared with 9/25 (36%) cases with MDR overexpression at diagnosis (P = 0.01). Taking into account the small number of cases, the response rate was not affected by MDR expression and the in vitro results also showed a higher uptake and apoptotic cell death by DNX compared with DNR. Twelve pts subsequently underwent allogeneic bone marrow transplantation (11 unrelated donor BMT, and one sibling BMT). The overall survival was 39% after 12 months. These data show the efficacy (OR rate 88% and CR rate 80%) of DNX plus Ara-C as reinduction therapy in very poor-risk ALL pts and the response rate seems not to be affected by MDR overexpression. Moreover, the high rate of remissions and the good clinical tolerance in heavily pretreated pts suggest a promising role of DNX in ALL chemotherapy regimens.
Candoni
Anna
A
Division of Haematology and Bone Marrow Transplantation, Department of Medical and Morphological Researches (DMMR), University of Udine, Udine, Italy. candoni.a@tiscali.it
Michelutti
Angela
A
Simeone
Erica
E
Damiani
Daniela
D
Baccarani
Michele
M
Fanin
Renato
R
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012008:Recurrence
D003561:Cytarabine; D003630:Daunorubicin; D008081:Liposomes; D027425:ATP-Binding Cassette, Sub-Family C Proteins