Role of early anthracycline dose-intensity according to expression of Philadelphia chromosome/BCR-ABL rearrangements in B-precursor adult acute lymphoblastic leukemia.
BACKGROUND
The use of anthracycline antibiotics in adult acute lymphoblastic leukemia (ALL) has resulted in an improved outcome to remission induction therapy. However,the exact role of these drugs in consolidation therapy is less clear, especially in specific ALL subsets.


METHODS
A retrospective analysis was conducted on the outcome of 308 patients (median age 35 years, range 13-75) with the most frequent subtype, early-B ALL, treated between 1974 and 1998 on eight consecutive protocols. Anthracycline-related effects were assessed by evaluating the impact of planned anthracycline dose-intensity (A-DI) on long-term outcome. A-DI (in mg/m(2)/week) during the first twelve weeks of consolidation therapy was classified as either "high" (doxorubicin>20, idarubicin>7) or "low".


RESULTS
Complete remission was achieved in 78% of cases. With a median follow-up of 6.5 years, on multivariate analysis, disease-free survival (DFS) correlated only with expression of the Philadelphia (Ph) chromosome and/or associated BCR-ABL rearrangements (Ph/BCR(+)) (P=0.0001) and planned A-DI (P<0.0001). On this basis, four major prognostic groups with significantly different DFS could be identified: (1) Ph/BCR(-), "high" A-DI (n=102), median 3.5 years and 41% at five years, respectively; (2) Ph/BCR(-), "low" A-DI (n=64), 1.3 years and 16%; (3) Ph/BCR(+), "high" A-DI (n=35), 1.7 years and 20%; (4) Ph/BCR(+), "low" A-DI (n=39), 0.75 years and 0%. When analyzed separately for Ph/BCR(-) (n=166) and Ph/BCR(+) (n=74) patients, the A-DI effect on DFS was preserved in the former (P=0.018) whereas, in Ph/BCR(+) patients, only age <50 years (P=0.004) and blast count <25 x 10(9)/l (P=0.02) correlated with better DFS. However, Ph/BCR(+) patients with the best prognostic profile (age <50 years and blast count <25 x 10(9)/l; n=21) who were treated on "high" A-DI regimens experienced a median DFS of 2.2 years with DFS 21% at five years, compared to 0.67-1 years and 0-10% in other cases (n=53, P<0.01).


CONCLUSIONS
A "high" A-DI may act as a positive treatment-related prognostic factor in early B-lineage ALL. Although mainly restricted to patients with Ph/BCR(-) ALL, A-DI could also influence the outcome in Ph/BCR(+) patients with other favorable prognostic factors.
Bassan
R
R
Divisione di Ematologia, Ospedali Riuniti, Largo Barozzi 1, 24100 Bergamo, Italy.
Rohatiner
A Z
AZ
Lerede
T
T
Di Bona
E
E
Rambaldi
A
A
Pogliani
E
E
Rossi
G
G
Fabris
P
P
Morandi
S
S
Casula
P
P
Carter
M
M
Lambertenghi-Deliliers
G
G
Lister
T A
TA
Barbui
T
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D002330:Carmustine / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage*; D015993:Life Tables; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D015122:Mercaptopurine / Q000008:administration & dosage; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000628:therapy; D011241:Prednisone / Q000008:administration & dosage; D012074:Remission Induction; D012189:Retrospective Studies; D013713:Teniposide / Q000008:administration & dosage; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D003561:Cytarabine; D014750:Vincristine; D005047:Etoposide; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D013713:Teniposide; D015122:Mercaptopurine; D016044:Fusion Proteins, bcr-abl; D001215:Asparaginase; D008558:Melphalan; D002330:Carmustine; D011241:Prednisone; D015255:Idarubicin